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Sample records for hiv trans activator

  1. APOBEC3G inhibits HIV-1 RNA elongation by inactivating the viral trans-activation response element.

    Science.gov (United States)

    Nowarski, Roni; Prabhu, Ponnandy; Kenig, Edan; Smith, Yoav; Britan-Rosich, Elena; Kotler, Moshe

    2014-07-29

    Deamination of cytidine residues in viral DNA is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient human immunodeficiency virus type 1 (HIV-1) replication. dC-to-dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. Here, we demonstrate that A3G provides an additional layer of defense against HIV-1 infection dependent on inhibition of proviral transcription. HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription. We further show that free single-stranded DNA (ssDNA) termini are not essential for A3G activity and a gap of CCC motif blocked with juxtaposed DNA or RNA on either or 3'+5' ends is sufficient for A3G deamination. These results identify A3G as an efficient mutator and that deamination of (-)SSDNA results in an early block of HIV-1 transcription. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Trans-dissemination of exosomes from HIV-1-infected cells fosters both HIV-1 trans-infection in resting CD4+ T lymphocytes and reactivation of the HIV-1 reservoir.

    Science.gov (United States)

    Chiozzini, Chiara; Arenaccio, Claudia; Olivetta, Eleonora; Anticoli, Simona; Manfredi, Francesco; Ferrantelli, Flavia; d'Ettorre, Gabriella; Schietroma, Ivan; Andreotti, Mauro; Federico, Maurizio

    2017-09-01

    Intact HIV-1 and exosomes can be internalized by dendritic cells (DCs) through a common pathway leading to their transmission to CD4 + T lymphocytes by means of mechanisms defined as trans-infection and trans-dissemination, respectively. We previously reported that exosomes from HIV-1-infected cells activate both uninfected quiescent CD4 + T lymphocytes, which become permissive to HIV-1, and latently infected cells, with release of HIV-1 particles. However, nothing is known about the effects of trans-dissemination of exosomes produced by HIV-1-infected cells on uninfected or latently HIV-1-infected CD4 + T lymphocytes. Here, we report that trans-dissemination of exosomes from HIV-1-infected cells induces cell activation in resting CD4 + T lymphocytes, which appears stronger with mature than immature DCs. Using purified preparations of both HIV-1 and exosomes, we observed that mDC-mediated trans-dissemination of exosomes from HIV-1-infected cells to resting CD4 + T lymphocytes induces efficient trans-infection and HIV-1 expression in target cells. Most relevant, when both mDCs and CD4 + T lymphocytes were isolated from combination anti-retroviral therapy (ART)-treated HIV-1-infected patients, trans-dissemination of exosomes from HIV-1-infected cells led to HIV-1 reactivation from the viral reservoir. In sum, our data suggest a role of exosome trans-dissemination in both HIV-1 spread in the infected host and reactivation of the HIV-1 reservoir.

  3. Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4+ T cell proliferation

    International Nuclear Information System (INIS)

    Liu, Wan; Qin, Yan; Bai, Lei; Lan, Ke; Wang, Jian-Hua

    2013-01-01

    Infection of Kaposi's sarcoma-associated herpesvirus (KSHV) is commonly occurred in AIDS patients. KSHV and HIV-1 act cooperatively in regulating infection with each other and in human carcinogenesis. Dendritic cells (DCs), as the pivotal cells in host immunity, may be modulated by both viruses, for immunoevasion and dissemination, therefore, the interaction between DCs and each virus has been a prior focus for pathogenesis elucidation. Here, we assessed the potential effect of KSHV on DC–HIV-1 interaction. We found that KSHV stimulation could promote maturation of monocyte-derived DCs (MDDCs) and impaired the ability of MDDCs to drive proliferation of resting CD4 + T cells, demonstrating the immunosuppression induced by KSHV. More importantly, KSHV-stimulated MDDCs could capture more HIV-1 and efficiently transferred these infectious viruses to Hut/CCR5 T cell line. Our results reveal the novel modulation of DC-mediated HIV-1 dissemination by KSHV, and highlight the importance of studying DC–HIV-1 interaction to elucidate HIV/AIDS pathogenesis. - Highlights: ► KSHV impaired the ability of MDDCs to drive proliferation of resting CD4 + T cells. ► KSHV stimulation matured MDDCs and enhanced HIV-1 endocytosis. ► KSHV stimulated MDDCs increased ICAM-1 expression and tighten contact with T cells. ► KSHV-stimulated MDDCs promoted HIV-1 trans-infection of CD4 + T cells

  4. Kaposi's-sarcoma-associated-herpesvirus-activated dendritic cells promote HIV-1 trans-infection and suppress CD4{sup +} T cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Wan; Qin, Yan; Bai, Lei [Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, the Chinese Academy of Sciences, Shanghai (China); Graduate School of the Chinese Academy of Sciences, Beijing (China); Lan, Ke [Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, the Chinese Academy of Sciences, Shanghai (China); Wang, Jian-Hua, E-mail: Jh_wang@sibs.ac.cn [Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, the Chinese Academy of Sciences, Shanghai (China)

    2013-06-05

    Infection of Kaposi's sarcoma-associated herpesvirus (KSHV) is commonly occurred in AIDS patients. KSHV and HIV-1 act cooperatively in regulating infection with each other and in human carcinogenesis. Dendritic cells (DCs), as the pivotal cells in host immunity, may be modulated by both viruses, for immunoevasion and dissemination, therefore, the interaction between DCs and each virus has been a prior focus for pathogenesis elucidation. Here, we assessed the potential effect of KSHV on DC–HIV-1 interaction. We found that KSHV stimulation could promote maturation of monocyte-derived DCs (MDDCs) and impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells, demonstrating the immunosuppression induced by KSHV. More importantly, KSHV-stimulated MDDCs could capture more HIV-1 and efficiently transferred these infectious viruses to Hut/CCR5 T cell line. Our results reveal the novel modulation of DC-mediated HIV-1 dissemination by KSHV, and highlight the importance of studying DC–HIV-1 interaction to elucidate HIV/AIDS pathogenesis. - Highlights: ► KSHV impaired the ability of MDDCs to drive proliferation of resting CD4{sup +} T cells. ► KSHV stimulation matured MDDCs and enhanced HIV-1 endocytosis. ► KSHV stimulated MDDCs increased ICAM-1 expression and tighten contact with T cells. ► KSHV-stimulated MDDCs promoted HIV-1 trans-infection of CD4{sup +} T cells.

  5. HIV Prevalence, Sexual Partners, Sexual Behavior and HIV Acquisition Risk Among Trans Men, San Francisco, 2014.

    Science.gov (United States)

    McFarland, Willi; Wilson, Erin C; Raymond, Henry F

    2017-12-01

    We surveyed 122 trans men using a hybrid sampling method that included randomly selected physical and online venues and peer referral to measure HIV prevalence and risk behaviors. HIV prevalence was 0% (one-sided 97.5% confidence interval 0-3.3%). Of 366 partnerships described, 44.8% were with cisgender women, 23.8% with cisgender men, 20.8% with trans men, and 10.7% with trans women. Condomless receptive anal and front hole/vaginal sex averaged one to three episodes per six months. HIV prevalence in trans men is likely closer to heterosexual cisgender men and women in San Francisco than trans women or MSM. Prevention prioritizing trans women and MSM, coupled with individualized and relevant sexual health education for trans men with partners from these populations, may best address the HIV prevention needs of trans men. Systematic collection of transgender status in Census and health data is needed to understand other health disparities among trans men.

  6. Trans-activation of the 5' to 3' viral DNA strand transfer by nucleocapsid protein during reverse transcription of HIV1 RNA.

    Science.gov (United States)

    Darlix, J L; Vincent, A; Gabus, C; de Rocquigny, H; Roques, B

    1993-08-01

    Two DNA strand transfer reactions take place during reverse transcription of the retroviral genome. The first transfer, that of the minus-strand strong stop DNA from the 5' end of the viral RNA to the 3' end, has been studied in vitro with two RNAs mimicking the 5' and 3' regions of the HIV1 genome and with nucleocapsid protein, NCp7, and reverse transcriptase. The results show that NCp7 strongly activates the 5' to 3' DNA strand transfer during reverse transcription while a basic peptide resembling NCp7 is inactive. Activation of the first transfer by several NCp7 derived peptides and the influence of the terminal redundancies (R) present at the 5' and 3' ends of HIV1 RNA were also examined. The first transfer is optimal in the presence of intact NCp7 and necessitates R on both the 5' and 3' RNAs. Sequencing of full length viral DNA products reveals approximately 40% misincorporations at the first nucleotide beyond the transfer point. If such base misincorporations occur during proviral DNA synthesis with possible homologous recombinations it may well contribute to the high level of genetic variability of HIV.

  7. Fusion of Epstein-Barr virus nuclear antigen-1-derived glycine-alanine repeat to trans-dominant HIV-1 Gag increases inhibitory activities and survival of transduced cells in vivo.

    Science.gov (United States)

    Hammer, Diana; Wild, Jens; Ludwig, Christine; Asbach, Benedikt; Notka, Frank; Wagner, Ralf

    2008-06-01

    Trans-dominant human immunodeficiency virus type 1 (HIV-1) Gag derivatives have been shown to efficiently inhibit late steps of HIV-1 replication in vitro by interfering with Gag precursor assembly, thus ranking among the interesting candidates for gene therapy approaches. However, efficient antiviral activities of corresponding transgenes are likely to be counteracted in particular by cell-mediated host immune responses toward the transgene-expressing cells. To decrease this potential immunogenicity, a 24-amino acid Gly-Ala (GA) stretch derived from Epstein-Barr virus nuclear antigen-1 (EBNA1) and known to overcome proteasomal degradation was fused to a trans-dominant Gag variant (sgD1). To determine the capacity of this fusion polypeptide to repress viral replication, PM-1 cells were transduced with sgD1 and GAsgD1 transgenes, using retroviral gene transfer. Challenge of stably transfected permissive cell lines with various viral strains indicated that N-terminal GA fusion even enhanced the inhibitory properties of sgD1. Further studies revealed that the GA stretch increased protein stability by blocking proteasomal degradation of Gag proteins. Immunization of BALB/c mice with a DNA vaccine vector expressing sgD1 induced substantial Gag-specific immune responses that were, however, clearly diminished in the presence of GA. Furthermore, recognition of cells expressing the GA-fused transgene by CD8(+) T cells was drastically reduced, both in vitro and in vivo, resulting in prolonged survival of the transduced cells in recipient mice.

  8. Alterations in cholesterol metabolism restrict HIV-1 trans infection in nonprogressors.

    Science.gov (United States)

    Rappocciolo, Giovanna; Jais, Mariel; Piazza, Paolo; Reinhart, Todd A; Berendam, Stella J; Garcia-Exposito, Laura; Gupta, Phalguni; Rinaldo, Charles R

    2014-04-29

    ABSTRACT HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of professional antigen-presenting cells (APC), i.e., dendritic cells (DC) and B lymphocytes, from NP lacked the ability to mediate HIV-1 trans infection of CD4(+) T cells. In contrast, APC from HIV-1-infected progressors (PR) and HIV-1-seronegative donors (SN) were highly effective in mediating HIV-1 trans infection. Direct cis infection of T cells with HIV-1 was comparably efficient among NP, PR, and SN. Lack of HIV-1 trans infection in NP was linked to lower cholesterol levels and an increase in the levels of the reverse cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in APC but not in T cells. Moreover, trans infection mediated by APC from NP could be restored by reconstitution of cholesterol and by inhibiting ABCA1 by mRNA interference. Importantly, this appears to be an inherited trait, as it was evident in APC obtained from NP prior to their primary HIV-1 infection. The present study demonstrates a new mechanism wherein enhanced lipid metabolism in APC results in remarkable control of HIV-1 trans infection that directly relates to lack of HIV-1 disease progression. IMPORTANCE HIV-1 can be captured by antigen-presenting cells (APC) such as dendritic cells and transferred to CD4 helper T cells, which results in greatly enhanced viral replication by a mechanism termed trans infection. A small percentage of HIV-1-infected persons are able to control disease progression for many years without antiretroviral therapy. In our study, we linked this lack of disease progression to a profound inability of APC from these individuals to trans infect T cells. This effect was due to altered lipid metabolism in their APC, which appears to be an inherited trait. These

  9. Immediate-early gene region of human cytomegalovirus trans-activates the promoter of human immunodeficiency virus

    International Nuclear Information System (INIS)

    Davis, M.G.; Kenney, S.C.; Kamine, J.; Pagano, J.S.; Huang, E.S.

    1987-01-01

    Almost all homosexual patients with acquired immunodeficiency syndrome are also actively infected with human cytomegalovirus (HCMV). The authors have hypothesized that an interaction between HCMV and human immunodeficiency virus (HIV), the agent that causes acquired immunodeficiency syndrome, may exist at a molecular level and contribute to the manifestations of HIV infection. In this report, they demonstrate that the immediate-early gene region of HCMV, in particular immediate-early region 2, trans-activates the expression of the bacterial gene chloramphenicol acetyltransferase that is fused to the HIV long terminal repeat and carried by plasmid pHIV-CAT. The HCMV immediate-early trans-activator increases the level of mRNA from the plamid pHIV-CAT. The sequences of HIV that are responsive to trans-activation by the HDMV immediate-early region are distinct from HIV sequences that are required for response to the HIV tat. The stimulation of HIV gene expression by HDMV gene functions could enhance the consequences of HIV infection in persons with previous or concurrent HCMV infection

  10. HIV, HBV, and HCV molecular epidemiology among trans (transvestites, transsexuals, and transgender) sex workers in Argentina.

    Science.gov (United States)

    Carobene, Mauricio; Bolcic, Federico; Farías, María Sol Dos Ramos; Quarleri, Jorge; Avila, María Mercedes

    2014-01-01

    Commercial sex work is frequent among male-to-female transvestites, transsexuals and transgenders in Argentina, leading to high susceptibility to HIV, HBV, and HCV among other sexually transmitted infections. In a global context of scarce data on the trans sex workers population, this study was aimed to study the genomic characterization of these viruses. Plasma presence of HIV, HBV, and HCV genomic material was evaluated in samples from 273 trans sex workers. Genomic sequences of HIV-gag, pol, and vif-vpu genes, HBV-S gene, and HCV-5'UT and NS5B genes were obtained. Molecular characterization involved phylogenetic analysis and several in silico tools. Resistance-associated mutations in HIV and HBV pol genes were also analyzed. The HIV genomic characterization in 62 trans sex workers samples showed that 54.8% of the isolates corresponded to BF intersubtype recombinants, and 38.7% to subtype B. The remaining were classified as subtypes C (4.8%) and A (1.6%). HBV and HCV co-infection prevalence among HIV positive trans sex workers yielded rates of 3.2% and 6.5% respectively. Drug resistance-associated mutations were found in 12/62 (19%) HIV pol sequences, but none among HBV. Based on phylogenetic relationships, HIV isolates characterized as subtypes BF and B appeared intermingled with those from other high-risk groups. Despite trans sex workers declared not to have received antiviral treatment, complex drug resistance-associated mutation patterns were found in several HIV isolates. Planned prevention, screening, and treatment are needed to reduce further transmission and morbidity. © 2013 Wiley Periodicals, Inc.

  11. Inefficient HIV-1 trans infection of CD4+ T cells by macrophages from HIV-1 nonprogressors is associated with altered membrane cholesterol and DC-SIGN.

    Science.gov (United States)

    DeLucia, Diana C; Rinaldo, Charles R; Rappocciolo, Giovanna

    2018-04-11

    Professional antigen presenting cells (APC: myeloid dendritic cells (DC) and macrophages (MΦ); B lymphocytes) mediate highly efficient HIV-1 infection of CD4 + T cells, termed trans infection, that could contribute to HIV-1 pathogenesis. We have previously shown that lower cholesterol content in DC and B lymphocytes is associated with a lack of HIV-1 trans infection in HIV-1 infected nonprogressors (NP). Here we assessed whether HIV-1 trans infection mediated by another major APC, MΦ, is deficient in NP due to altered cholesterol metabolism. When comparing healthy HIV-1 seronegatives (SN), rapid progressors (PR), and NP, we found that monocyte-derived MΦ from NP did not mediate HIV-1 trans infection of autologous CD4 + T cells, in contrast to efficient trans infection mediated by SN and PR MΦ. MΦ trans infection efficiency was directly associated with the number of DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)-expressing MΦ. Significantly fewer NP MΦ expressed DC-SIGN. Unesterified (free) cholesterol in MΦ cell membranes and lipid rafting was significantly lower in NP than PR, as well as virus internalization in early endosomes. Furthermore, simvastatin (SIMV), decreased the subpopulation of DC-SIGN + MΦ, as well as MΦ cis and trans infection. Notably, SIMV decreased cell membrane cholesterol and led to lipid raft dissociation, effectively mimicking the incompetent APC trans infection environment characteristic of NP. Our data support that DC-SIGN and membrane cholesterol are central to MΦ trans infection, and a lack of these limits HIV-1 disease progression. Targeting the ability of MΦ to drive HIV-1 dissemination in trans could enhance HIV-1 therapeutic strategies. IMPORTANCE Despite the success of combination anti-retroviral therapy, neither a vaccine nor a cure for HIV infection has been developed, demonstrating a need for novel prophylactic and therapeutic strategies. Here we show that efficiency of macrophage (M

  12. Repair Activity of trans-Resveratrol toward 2'-Deoxyguanosine Radicals.

    Science.gov (United States)

    Cheng, Xing; An, Ping; Li, Shujin; Zhou, Liping

    2018-04-26

    In the present study, the repair activity of trans-resveratrol toward 2'-deoxyguanosine (dGuo) radicals in polar and nonpolar solvents was studied using density functional theory. The hydrogen transfer/proton coupled electron transfer and single electron transfer (SET) mechanisms between trans-resveratrol and dGuo-radicals were considered. Taking into consideration the molar fraction of neutral trans-resveratrol (ROH) and anionic trans-resveratrol (RO - ), the overall rate constants for repairing dGuo-radicals by trans-resveratrol are 9.94 × 10 8 and 2.01 × 10 9 dm 3 mol -1 s -1 in polar and nonpolar solvents, respectively, and the overall rate constant of repairing cation radical (dGuo •+ ) by trans-resveratrol via an SET mechanism is 7.17 × 10 9 dm 3 mol -1 s -1 . The repair activity of RO - toward dGuo-radicals is better than that of ROH, but the repair activity of ROH toward dGuo •+ is better than that of RO - . Unfortunately, neither ROH nor RO - can repair the 2'-deoxyribose radicals of dGuo. It can therefore be concluded that trans-resveratrol is an effective antioxidant for repairing base radicals of dGuo and dGuo •+ . The study can help us understand the repair activity of trans-resveratrol toward dGuo radicals.

  13. HIV prevalence and demographic determinants of condomless receptive anal intercourse among trans feminine individuals in Beirut, Lebanon

    OpenAIRE

    Rachel L Kaplan; Justine McGowan; Glenn J Wagner

    2016-01-01

    Introduction: Growing evidence suggests increased HIV incidence in the Middle East and North Africa among “key populations.” To date, epidemiological data have not accurately included and measured HIV prevalence and risk among trans feminine individuals in the region. Through the lens of the Gender Affirmation Framework, we assessed demographic correlates of risk behaviour and the prevalence of HIV among trans feminine individuals in Lebanon. Methods: Long-chain referral sampling was used to ...

  14. Cis elements and trans-acting factors involved in the RNA dimerization of the human immunodeficiency virus HIV-1.

    Science.gov (United States)

    Darlix, J L; Gabus, C; Nugeyre, M T; Clavel, F; Barré-Sinoussi, F

    1990-12-05

    The retroviral genome consists of two identical RNA molecules joined at their 5' ends by the Dimer Linkage Structure (DLS). To study the mechanism of dimerization and the DLS of HIV-1 RNA, large amounts of bona fide HIV-1 RNA and of mutants have been synthesized in vitro. We report that HIV-1 RNA forms dimeric molecules and that viral nucleocapsid (NC) protein NCp15 greatly activates dimerization. Deletion mutagenesis in the RNA 5' 1333 nucleotides indicated that a small domain of 100 nucleotides, located between positions 311 to 415 from the 5' end, is necessary and sufficient to promote HIV-1 RNA dimerization. This dimerization domain encompasses an encapsidation element located between the 5' splice donor site and initiator AUG of gag and shows little sequence variations in different strains of HIV-1. Furthermore, cross-linking analysis of the interactions between NC and HIV-1 RNA (311 to 415) locates a major contact site in the encapsidation element of HIV-1 RNA. The genomic RNA dimer is tightly associated with nucleocapsid protein molecules in avian and murine retroviruses, and this ribonucleoprotein structure is believed to be the template for reverse transcription. Genomic RNA-protein interactions have been analyzed in human immunodeficiency virus (HIV) virions and results showed that NC protein molecules are tightly bound to the genomic RNA dimer. Since retroviral RNA dimerization and packaging appear to be under the control of the same cis element, the encapsidation sequences, and trans-acting factor, the NC protein, they are probably related events in the course of virion assembly.

  15. Experiences of stigma and discrimination in social and healthcare settings among trans people living with HIV in the UK.

    Science.gov (United States)

    Hibbert, M; Wolton, A; Crenna-Jennings, W; Benton, L; Kirwan, P; Lut, I; Okala, S; Ross, M; Furegato, M; Nambiar, K; Douglas, N; Roche, J; Jeffries, J; Reeves, I; Nelson, M; Weerawardhana, C; Jamal, Z; Hudson, A; Delpech, V

    2018-07-01

    The People Living with HIV StigmaSurvey UK 2015 was a community led national survey investigating experiences of people living with HIV in the UK in the past 12 months. Participants aged 18 and over were recruited through over 120 cross-sector community organisations and 46 HIV clinics to complete an anonymous online survey. Trans is an umbrella term which refers to individuals whose current gender identity is different to the gender they were assigned at birth. Trans participants self-identified via gender identity and gender at birth questions. Descriptive analyses of reported experiences in social and health care settings were conducted and multivariate logistic regression analyses were used to identify sociodemographic predictors of reporting being treated differently to non-HIV patients, and being delayed or refused healthcare treatment in the past 12 months. 31 out of 1576 participants (2%) identified as trans (19 trans women, 5 trans men, 2 gender queer/non-binary, 5 other). High levels of social stigma were reported for all participants, with trans participants significantly more likely to report worrying about verbal harassment (39% vs. 23%), and exclusion from family gatherings (23% vs. 9%) in the last 12 months, compared to cisgender participants. Furthermore, 10% of trans participants reported physical assault in the last 12 months, compared to 4% of cisgender participants. Identifying as trans was a predictor of reporting being treated differently to non-HIV patients (48% vs. 30%; aOR 2.61, CI 1.06, 6.42) and being delayed or refused healthcare (41% vs. 16%; aOR 4.58, CI 1.83, 11.44). Trans people living with HIV in the UK experience high levels of stigma and discrimination, including within healthcare settings, which is likely to impact upon health outcomes. Trans-specific education and awareness within healthcare settings could help to improve service provision for this demographic.

  16. Powdered activated carbon adsorption of two fishy odorants in water: Trans,trans-2,4-heptadienal and trans,trans-2,4-decadienal.

    Science.gov (United States)

    Li, Xin; Wang, Jun; Zhang, Xiaojian; Chen, Chao

    2015-06-01

    Powdered activated carbon (PAC) adsorption of two fishy odorants, trans,trans-2,4-heptadienal (HDE) and trans,trans-2,4-decadienal (DDE), was investigated. Both the pseudo first-order and the pseudo second-order kinetic models well described the kinetics curves, and DDE was more readily removed by PAC. In isotherm tests, both Freundlich and Modified Freundlich isotherms fitted the experimental data well. PAC exhibited a higher adsorption capacity for DDE than for HDE, which could be ascribed to the difference in their hydrophobicity. The calculated thermodynamic parameters (ΔG0, ΔH0, and ΔS0) indicated an exothermic and spontaneous adsorption process. PAC dosage, pH, and natural organic matter (NOM) presence were found to influence the adsorption process. With increasing PAC dosage, the pseudo first-order and pseudo second-order rate constants both increased. The value of pH had little influence on HDE or DDE molecules but altered the surface charge of PAC, and the maximum adsorption capacity occurred at pH9. The presence of NOM, especially the fraction with molecular weight less than 1k Dalton, hindered the adsorption. The study showed that preloaded NOM impaired the adsorption capacity of HDE or DDE more severely than simultaneously fed NOM did. Copyright © 2015. Published by Elsevier B.V.

  17. Acetylcholinesterase Inhibition and Antioxidant Activity of N-trans-Caffeoyldopamine and N-trans-Feruloyldopamine

    Directory of Open Access Journals (Sweden)

    Muamer Dizdar

    2018-04-01

    Full Text Available Phenolic acids and their derivatives found in nature are well-known for their potential biological activity. In this study, two amides derived from trans-caffeic/ferulic acid and dopamine were synthesized and characterized by Fourier-transform infrared spectroscopy (FTIR, mass spectrometry, proton and carbon-13 nuclear magnetic resonance spectroscopy. The compounds were tested for the inhibition of acetylcholinesterase (AChE from Electrophorus electricus and for antioxidant activity by scavenging 2,2-diphenyl-1-pycrylhydrazyl free radical (DPPH• and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid radical cation (ABTS•+, reducing ferric ions, and ferrous ions chelation. N-trans-Feruloyldopamine displayed the highest inhibitory effect on AChE with half-maximal inhibitory concentration (IC50 values of 8.52 μM. In addition, an in silico study was done to determine the most favorable AChE cluster with the synthesized compounds. Further, these clusters were investigated for binding positions at the lowest free binding energy. Both synthesized hydroxycinnamates were found to be better antioxidants than the parent acids in in vitro tests applied. N-trans-Caffeoyldopamine showed the best antioxidant activity in the three tested methods—against non-biological stable free radicals IC50 5.95 μM for DPPH•, 0.24 μM for the ABTS•+ method, and for reducing power (ascorbic acid equivalent (AAE 822.45 μmol/mmol—while for chelation activity against Fe2+ ions N-trans-feruloyldopamine had slightly better antioxidant activity (IC50 3.17 mM.

  18. The Trans Pacific Partnership Agreement and access to HIV treatment in Vietnam.

    Science.gov (United States)

    Moir, Hazel V J; Tenni, Brigitte; Gleeson, Deborah; Lopert, Ruth

    2018-04-01

    In the Trans Pacific Partnership (TPP) Agreement negotiations, the USA successfully pursued intellectual property (IP) provisions that will affect the affordability of medicines, including anti-retrovirals (ARV) for HIV. Vietnam has the lowest GDP per capita of the 12 TPP countries and in 2013 provided ARVs for only 68% of eligible people living with HIV. Using the current Vietnamese IP regime as our base case, we analysed the potential impact of a regime making full use of legal IP flexibilities, and one based on the IP provisions of the final, agreed TPP text. Results indicate that at current funding levels 82% of Vietnam's eligible people living with HIV would receive ARVs if legal flexibilities were fully utilised, while as few as 30% may have access to ARVs under the TPP Agreement - more than halving the proportion currently treated.

  19. Epstein-Barr virus immediate-early gene product trans-activates gene expression from the human immunodeficiency virus long terminal repeat

    International Nuclear Information System (INIS)

    Kenney, S.; Kamine, J.; Markovitz, D.; Fenrick, R.; Pagano, J.

    1988-01-01

    Acquired immunodeficiency syndrome patients are frequently coinfected with Epstein-Barr virus (EBV). In this report, the authors demonstrate that an EBV immediate-early gene product, BamHI MLF1, stimulates expression of the bacterial chloramphenicol acetyltransferase (CAT) gene linked to the human immunodeficiency virus (HIV) promoter. The HIV promoter sequences necessary for trans-activation by EBV do not include the tat-responsive sequences. In addition, in contrast to the other herpesvirus trans-activators previously studied, the EBV BamHI MLF1 gene product appears to function in part by a posttranscriptional mechanism, since it increases pHIV-CAT protein activity more than it increases HIV-CAT mRNA. This ability of an EBV gene product to activate HIV gene expression may have biologic consequences in persons coinfected with both viruses

  20. HIV prevalence and demographic determinants of condomless receptive anal intercourse among trans feminine individuals in Beirut, Lebanon.

    Science.gov (United States)

    Kaplan, Rachel L; McGowan, Justine; Wagner, Glenn J

    2016-01-01

    Growing evidence suggests increased HIV incidence in the Middle East and North Africa among "key populations." To date, epidemiological data have not accurately included and measured HIV prevalence and risk among trans feminine individuals in the region. Through the lens of the Gender Affirmation Framework, we assessed demographic correlates of risk behaviour and the prevalence of HIV among trans feminine individuals in Lebanon. Long-chain referral sampling was used to recruit 53 participants for completion of a behavioural survey and optional free rapid HIV tests. Data were collected using interviewer-administered questionnaires. A multivariable logistic regression model was used to identify demographic determinants of HIV risk behaviour. Fifty-seven percent of participants reported condomless receptive anal intercourse (CRAI) with male partner(s) in the last three months, 40% of whom reported not knowing the HIV status of the partner(s). Of the participants tested for HIV as part of the study or via self-report, four (10%) were HIV positive; 13 declined HIV testing. Forty percent of the sample had no prior history of HIV testing. A history of trauma such as sexual abuse/assault was reported by almost half of the participants (49%). Sixty-eight percent reported experiencing physical violence and 32% police arrest, because of gender identity or presentation. A staggering 98% reported having experienced gender identity or gender presentation-related discrimination. Sixty-six percent of the sample reported current sex work; sex work was correlated with CRAI but was not significant in multivariate analysis. In regression analysis, "openness"/"outness" about transgender identity at work or school was significantly associated with CRAI. Surprisingly, a history of sexual abuse/assault was negatively correlated with CRAI, suggesting the need for further inquiry. The results of this study provide implications for how to address sexual health among trans feminine

  1. Colorectal mucus binds DC-SIGN and inhibits HIV-1 trans-infection of CD4+ T-lymphocytes.

    Directory of Open Access Journals (Sweden)

    Martijn J Stax

    Full Text Available Bodily secretions, including breast milk and semen, contain factors that modulate HIV-1 infection. Since anal intercourse caries one of the highest risks for HIV-1 transmission, our aim was to determine whether colorectal mucus (CM also contains factors interfering with HIV-1 infection and replication. CM from a number of individuals was collected and tested for the capacity to bind DC-SIGN and inhibit HIV-1 cis- or trans-infection of CD4+ T-lymphocytes. To this end, a DC-SIGN binding ELISA, a gp140 trimer competition ELISA and HIV-1 capture/ transfer assays were utilized. Subsequently we aimed to identify the DC-SIGN binding component through biochemical characterization and mass spectrometry analysis. CM was shown to bind DC-SIGN and competes with HIV-1 gp140 trimer for binding. Pre-incubation of Raji-DC-SIGN cells or immature dendritic cells (iDCs with CM potently inhibits DC-SIGN mediated trans-infection of CD4+ T-lymphocytes with CCR5 and CXCR4 using HIV-1 strains, while no effect on direct infection is observed. Preliminary biochemical characterization demonstrates that the component seems to be large (>100kDa, heat and proteinase K resistant, binds in a α1-3 mannose independent manner and is highly variant between individuals. Immunoprecipitation using DC-SIGN-Fc coated agarose beads followed by mass spectrometry indicated lactoferrin (fragments and its receptor (intelectin-1 as candidates. Using ELISA we showed that lactoferrin levels within CM correlate with DC-SIGN binding capacity. In conclusion, CM can bind the C-type lectin DC-SIGN and block HIV-1 trans-infection of both CCR5 and CXCR4 using HIV-1 strains. Furthermore, our data indicate that lactoferrin is a DC-SIGN binding component of CM. These results indicate that CM has the potential to interfere with pathogen transmission and modulate immune responses at the colorectal mucosa.

  2. Colorectal mucus binds DC-SIGN and inhibits HIV-1 trans-infection of CD4+ T-lymphocytes.

    Science.gov (United States)

    Stax, Martijn J; Mouser, Emily E I M; van Montfort, Thijs; Sanders, Rogier W; de Vries, Henry J C; Dekker, Henk L; Herrera, Carolina; Speijer, Dave; Pollakis, Georgios; Paxton, William A

    2015-01-01

    Bodily secretions, including breast milk and semen, contain factors that modulate HIV-1 infection. Since anal intercourse caries one of the highest risks for HIV-1 transmission, our aim was to determine whether colorectal mucus (CM) also contains factors interfering with HIV-1 infection and replication. CM from a number of individuals was collected and tested for the capacity to bind DC-SIGN and inhibit HIV-1 cis- or trans-infection of CD4+ T-lymphocytes. To this end, a DC-SIGN binding ELISA, a gp140 trimer competition ELISA and HIV-1 capture/ transfer assays were utilized. Subsequently we aimed to identify the DC-SIGN binding component through biochemical characterization and mass spectrometry analysis. CM was shown to bind DC-SIGN and competes with HIV-1 gp140 trimer for binding. Pre-incubation of Raji-DC-SIGN cells or immature dendritic cells (iDCs) with CM potently inhibits DC-SIGN mediated trans-infection of CD4+ T-lymphocytes with CCR5 and CXCR4 using HIV-1 strains, while no effect on direct infection is observed. Preliminary biochemical characterization demonstrates that the component seems to be large (>100kDa), heat and proteinase K resistant, binds in a α1-3 mannose independent manner and is highly variant between individuals. Immunoprecipitation using DC-SIGN-Fc coated agarose beads followed by mass spectrometry indicated lactoferrin (fragments) and its receptor (intelectin-1) as candidates. Using ELISA we showed that lactoferrin levels within CM correlate with DC-SIGN binding capacity. In conclusion, CM can bind the C-type lectin DC-SIGN and block HIV-1 trans-infection of both CCR5 and CXCR4 using HIV-1 strains. Furthermore, our data indicate that lactoferrin is a DC-SIGN binding component of CM. These results indicate that CM has the potential to interfere with pathogen transmission and modulate immune responses at the colorectal mucosa.

  3. Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans-Splicing Induces Selective Killing of HIV-Producing Cells

    Directory of Open Access Journals (Sweden)

    Carin K. Ingemarsdotter

    2017-06-01

    Full Text Available Antiviral strategies targeting hijacked cellular processes are less easily evaded by the virus than viral targets. If selective for viral functions, they can have a high therapeutic index. We used RNA trans-splicing to deliver the herpes simplex virus thymidine kinase-ganciclovir (HSV-tk/GCV cell suicide system into HIV-producing cells. Using an extensive in silico bioinformatics and RNA structural analysis approach, ten HIV RNA trans-splicing constructs were designed targeting eight different HIV splice donor or acceptor sites and were tested in cells expressing HIV. Trans-spliced mRNAs were identified in HIV-expressing cells using qRT-PCR with successful detection of fusion RNA transcripts between HIV RNA and the HSV-tk RNA transcripts from six of ten candidate RNA trans-splicing constructs. Conventional PCR and Sanger sequencing confirmed RNA trans-splicing junctions. Measuring cell viability in the presence or absence of GCV expression of HSV-tk by RNA trans-splicing led to selective killing of HIV-producing cells using either 3′ exon replacement or 5′ exon replacement in the presence of GCV. Five constructs targeting four HIV splice donor and acceptor sites, D4, A5, A7, and A8, involved in regulating the generation of multiple HIV RNA transcripts proved to be effective for trans-splicing mediated selective killing of HIV-infected cells, within which individual constructs targeting D4 and A8 were the most efficient.

  4. Rhesus macaque and chimpanzee DC-SIGN act as HIV/SIV gp120 trans-receptors, similar to human DC-SIGN

    NARCIS (Netherlands)

    Geijtenbeek, T. B.; Koopman, G.; van Duijnhoven, G. C.; van Vliet, S. J.; van Schijndel, A. C.; Engering, A.; Heeney, J. L.; van Kooyk, Y.

    2001-01-01

    Dendritic cells (DC) have been implicated in the pathogenesis of both human and simian immunodeficiency viruses (HIV and SIV, respectively). The DC-specific HIV-1 trans-receptor DC-SIGN is thought to be essential for viral dissemination by DC. Abundant expression in lymphoid tissues also implies a

  5. Design of Trypanosoma rangeli sialidase mutants with improved trans-sialidase activity

    DEFF Research Database (Denmark)

    Nyffenegger, Christian; Nordvang, Rune Thorbjørn; Jers, Carsten

    2017-01-01

    were analyzed via kinetics for their ability to carry out trans-sialidase reaction using CGMP and D-lactose as substrates. The sialidase variants with 15 and 16 mutations, respectively, exhibited significantly improved trans-sialidase activity for D-lactose sialylation. Our results corroborate......, that computational studies of trans-glycosylation can be a valuable input in the design of novel trans-glycosidases, but also highlight the importance of experimental validation in order to assess the performance. In conclusion, two of the seven mutants displayed a dramatic switch in specificity from hydrolysis...

  6. It All Starts with a Sandwich: Identification of Sialidases with Trans-Glycosylation Activity

    DEFF Research Database (Denmark)

    Nordvang, Rune Thorbjørn; Nyffenegger, Christian; Holck, Jesper

    2016-01-01

    structure of two amino acids proximal to the active site of the T. cruzi trans-sialidase infers trans-sialidase activity. On this basis, four enzymes with putative trans-sialidase activity were identified through an iterative alignment from 2909 native sialidases available in GenBank, which were cloned...... and expressed in Escherichia coli. Of these, one enzyme, SialH, derived from Haemophilus parasuis had an aromatic sandwich structure on the protein surface facing the end of the catalytic site (Phe168; Trp366), and was indeed found to exhibit trans-sialidase activity. SialH catalyzed production of the human...... provided data that help understand structure-function relations of trans-sialidases....

  7. Formation of trans-caffeoyl-CoA from trans-4-coumaroyl-CoA by Zn2+-dependent enzymes in cultured plant cells and its activation by an elicitor-induced pH shift

    NARCIS (Netherlands)

    Kneusel, R.; Matern, U.; Nicolaij, K.

    1989-01-01

    A novel hydroxylase activity catalyzing the formation of trans-caffeoyl-CoA from trans-4-coumaroyl-CoA was identified in crude extracts from cultured parsley cells. The extracts were less active (Vmax/Km) in converting trans-4-coumaric to trans-caffeic acid. Optimal hydroxylase activity was found at

  8. Design of Trypanosoma rangeli sialidase mutants with improved trans-sialidase activity.

    Directory of Open Access Journals (Sweden)

    Christian Nyffenegger

    Full Text Available A sialidase (EC 3.2.1.18 from the non-pathogenic Trypanosoma rangeli, TrSA, has been shown to exert trans-sialidase activity after mutation of five specific amino acids in the active site (M96V, A98P, S120Y, G249Y, Q284P to form the so-called TrSA5mut enzyme. By computational and hypothesis driven approaches additional mutations enhancing the trans-sialidase activity have been suggested. In the present work, we made a systematic combination of these mutations leading to seven new variants of the T. rangeli sialidase, having 6-16 targeted amino acid mutations. The resulting enzyme variants were analyzed via kinetics for their ability to carry out trans-sialidase reaction using CGMP and D-lactose as substrates. The sialidase variants with 15 and 16 mutations, respectively, exhibited significantly improved trans-sialidase activity for D-lactose sialylation. Our results corroborate, that computational studies of trans-glycosylation can be a valuable input in the design of novel trans-glycosidases, but also highlight the importance of experimental validation in order to assess the performance. In conclusion, two of the seven mutants displayed a dramatic switch in specificity from hydrolysis towards trans-sialylation and constitute the most potent trans-sialidase mutants of TrSA described in literature to date.

  9. A theoretically based evaluation of HIV/AIDS prevention campaigns along the trans-Africa highway in Kenya.

    Science.gov (United States)

    Witte, K; Cameron, K A; Lapinski, M K; Nzyuko, S

    1998-01-01

    Print HIV/AIDS prevention campaign materials (e.g., posters, pamphlets, stickers) from 10 public health organizations in Kenya were evaluated according to the Extended Parallel Process Model (EPPM), a health behavior change theory based on the fear appeal literature, at various sites along the Trans-Africa Highway in Kenya. Three groups each of commercial sex workers (CSWs), truck drivers (TDs) and their assistants (ASSTs), and young men (YM) who live and work at the truck stops participated in focus group discussions where reactions to the campaign materials were gathered according to this theoretical base. Reactions to campaign materials varied substantially, according to the poster or pamphlet viewed. Overall, most participants wanted more detailed information about (a) the proper way to use condoms, (b) ideas for how to negotiate condom use with reluctant partners, and (c) accurate information on symptoms of AIDS and what to do once one contracted HIV. Both quantitative and qualitative analyses of the campaign materials are reported.

  10. Brugia malayi Antigen (BmA Inhibits HIV-1 Trans-Infection but Neither BmA nor ES-62 Alter HIV-1 Infectivity of DC Induced CD4+ Th-Cells.

    Directory of Open Access Journals (Sweden)

    Emily E I M Mouser

    Full Text Available One of the hallmarks of HIV-1 disease is the association of heightened CD4+ T-cell activation with HIV-1 replication. Parasitic helminths including filarial nematodes have evolved numerous and complex mechanisms to skew, dampen and evade human immune responses suggesting that HIV-1 infection may be modulated in co-infected individuals. Here we studied the effects of two filarial nematode products, adult worm antigen from Brugia malayi (BmA and excretory-secretory product 62 (ES-62 from Acanthocheilonema viteae on HIV-1 infection in vitro. Neither BmA nor ES-62 influenced HIV-1 replication in CD4+ enriched T-cells, with either a CCR5- or CXCR4-using virus. BmA, but not ES-62, had the capacity to bind the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN thereby inhibiting HIV-1 trans-infection of CD4+ enriched T-cells. As for their effect on DCs, neither BmA nor ES-62 could enhance or inhibit DC maturation as determined by CD83, CD86 and HLA-DR expression, or the production of IL-6, IL-10, IL-12 and TNF-α. As expected, due to the unaltered DC phenotype, no differences were found in CD4+ T helper (Th cell phenotypes induced by DCs treated with either BmA or ES-62. Moreover, the HIV-1 susceptibility of the Th-cell populations induced by BmA or ES-62 exposed DCs was unaffected for both CCR5- and CXCR4-using HIV-1 viruses. In conclusion, although BmA has the potential capacity to interfere with HIV-1 transmission or initial viral dissemination through preventing the virus from interacting with DCs, no differences in the Th-cell polarizing capacity of DCs exposed to BmA or ES-62 were observed. Neither antigenic source demonstrated beneficial or detrimental effects on the HIV-1 susceptibility of CD4+ Th-cells induced by exposed DCs.

  11. Forms of Safety and Their Impact on Health: An Exploration of HIV/AIDS-Related Risk and Resilience Among Trans Women in Lebanon.

    Science.gov (United States)

    Kaplan, Rachel L; Wagner, Glenn J; Nehme, Simon; Aunon, Frances; Khouri, Danielle; Mokhbat, Jacques

    2015-01-01

    Using minority stress theory, the authors investigated risk behaviors of transgender women (trans women) in Lebanon. Using semistructured interviews, the authors explored six areas: relationships with family and friends; openness about gender and sexuality; experiences with stigma; sexual behavior; attitudes and behaviors regarding HIV testing; and perceived HIV-related norms among transgender peers. Participants voiced the importance of different forms of safety: social/emotional, physical, sexual, and financial. Strategies for obtaining safety were negotiated differently depending on social, behavioral, and structural factors in the environment. In this article, we provide study findings from the perspectives of trans women, their exposure to stigma, and the necessary navigation of environments characterized by transphobia.

  12. HIV-1 Reservoir Association with Immune Activation

    Directory of Open Access Journals (Sweden)

    Alejandro Vallejo

    2015-09-01

    Full Text Available In this issue of EBioMedicine, Ruggiero and colleagues describe immune activation biomarkers associated with the size of the HIV reservoir in a carefully designed cross-sectional study. The cohort consists of a homogeneous sample of HIV-1-infected patients with long-term plasma HIV-1 RNA suppression under antiretroviral treatment (ART. It is crucial to explore the potential utility of biomarkers that are easier (less labor intensive, less expensive to measure than integrated HIV DNA load, in order to quickly and accurately quantify cellular reservoirs of HIV.

  13. Dehalogenation Activity of Selected Fungi Toward δ-Iodo-γ-Lactone Derived from trans,trans-Farnesol.

    Science.gov (United States)

    Gliszczyńska, Anna; Gładkowski, Witold; Świtalska, Marta; Wietrzyk, Joanna; Szumny, Antoni; Gębarowska, Elżbieta; Wawrzeńczyk, Czesław

    2016-04-01

    Time-course of biotransformation of racemic trans-4-((E)-4',8'-dimethylnona-3',7'-dien-1-yl)-5-iodomethyl-4-methyldihydrofuran-2-one (1) in fungal and yeast cultures was investigated. In these conditions, the substrate 1 was enantioselectively dehalogenated yielding 4-((E)-4',8'-dimethylnona-3',7'-dien-1-yl)-4-methyl-5-methylenedihydrofuran-2-one (2) and its structure was established based on the spectroscopic data. The most effective biocatalyst used was Didymosphaeria igniaria, which catalyzed the process with highest rate and enantioselectivity (ee of product = 76%). The antiproliferative activity of δ-iodo-γ-lactone 1, product of its biotransformation 2, and starting substrate (farnesol) were evaluated toward two cancer cell lines: A549 (human lung adenocarcinoma) and HL-60 (human promyelocytic leukemia). © 2016 Verlag Helvetica Chimica Acta AG, Zürich.

  14. Benzoic Acid Derivatives with Trypanocidal Activity: Enzymatic Analysis and Molecular Docking Studies toward Trans-Sialidase

    Directory of Open Access Journals (Sweden)

    Muhammad Kashif

    2017-10-01

    Full Text Available Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, trans-sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic acid derivatives as trans-sialidase (TS inhibitors and anti-trypanosomal agents. Three compounds (14, 18, and 19 sharing a para-aminobenzoic acid moiety showed more potent trypanocidal activity than the commercially available drugs nifurtimox and benznidazole in both strains: the lysis concentration of 50% of the population (LC50 was <0.15 µM on the NINOA strain, and LC50 < 0.22 µM on the INC-5 strain. Additionally, compound 18 showed a moderate inhibition (47% on the trans-sialidase enzyme and a binding model similar to DANA (pattern A.

  15. Can we conserve trans-resveratrol content and antioxidant activity during industrial production of chocolate?

    Science.gov (United States)

    Salvador, Izabela; Massarioli, Adna P; Silva, Anna Paula S; Malaguetta, Heloísa; Melo, Priscilla S; Alencar, Severino M

    2018-05-23

    Cocoa exhibits high content of phenolic compounds, among which trans-resveratrol stands out, associated with several bioactive activities such as antioxidant properties. Chocolate contains reduced amounts of these bioactive compounds due to losses during the production process. Therefore, this study aimed to assess changes in total phenolic content and specifically trans-resveratrol, as well as in the antioxidant activity of cocoa and its products during industrial production of chocolate. A total of ten different cocoa products were analyzed. The processes of fermentation and roasting caused significant loss of total phenolic compounds and antioxidant activity. However, due to high temperature, roasting had a major influence on this loss (71% for total phenolic compounds and 53% to 77% for antioxidant activity), except for trans-resveratrol. The content of trans-resveratrol formed after fermentation (9.8 μg kg -1 ) showed little variation during the processes, and it was detected in higher concentrations both in natural (11.4 μg kg -1 ) and in alkalized cocoa powder (13.5 μg kg -1 ). Alkalization of cocoa products led to loss of capacity of deactivating superoxide radical. These findings contribute to the optimization of the production process of chocolate and other food products containing cocoa and its derivatives aiming to better preserve their bioactive compounds. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  16. Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells

    International Nuclear Information System (INIS)

    Tada, Hiroomi; Lashgari, M.; Amini, S.; Khalili, K.; Rappaport, J.; Wong-Staal, F.

    1990-01-01

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC virus (JCV), a human papovavirus. PML is a relatively rare disease seen predominantly in immunocompromised individuals and is a frequent complication observed in AIDS patients. The significantly higher incidence of PML in AIDS patients than in other immunosuppressive disorders has suggested that the presence of human immunodeficiency virus type 1 (HIV-1) in the brain may directly or indirectly contribute to the pathogenesis of this disease. In the present study the authors have examined the expression of the JCV genome in both glial and non-glial cells in the presence of HIV-1 regulatory proteins. They find that the HIV-1-encoded trans-regulatory protein tat increases the basal activity of the JCV late promoter, JCV L , in glial cells. They conclude that the presence of the HIV-1-encoded tat protein may positively affect the JCV lytic cycle in glial cells by stimulating JCV gene expression. The results suggest a mechanism for the relatively high incidence of PML in AIDS patients than in other immunosuppressive disorders. Furthermore, the findings indicate that the HIV-1 regulatory protein tat may stimulate other viral and perhaps cellular promoters, in addition to its own

  17. Medical UV exposures and HIV activation

    International Nuclear Information System (INIS)

    Zmudzka, B.Z.; Miller, S.A.; Jacobs, M.E.; Beer, J.Z.

    1996-01-01

    This paper presents the first attempt to evaluate the potential of clinical UV exposures to induce the human immunodeficiency (HIV) promoter and, thus, to upregulate HIV growth in those skin cells that are directly affected by the exposure. Using the data for HIV promoter activation in vitro, we computed UVB and psoralen plus UVA (PUVA) doses that produce 50% of the maximal promoter activation (AD 50 ). Then, using (a) literature data for UV transmittance in the human skin, (b) a composite action spectrum for HIV promoter and pyrimidine dimer induction by UVB and (c) an action spectrum for DNA synthesis inhibition by PUVA, we estimated the distribution of medical UVB and PUVA doses in the skin. This allowed us to estimate how deep into the skin the HIV-activating doses might penetrate in an initial and an advanced stge of UVB and PUVA therapy. Such analysis was done for normal type II skin and for single exposures. For UVB we found that, when the incident dose on the surface of the skin is 500 J/m 2 (290-320 nm) (initial stage of the therapy), the dose producing 50% of the maximal HIV promoter activation (AD 50 UVB ) is limited to the stratum corneum. For PUVA we found that, when the incident UVA doses are 25 or 100 kJ/m 2 (320-400 nm) (an initial and an advanced stage of therapy, respectively), and the 8-methoxypsoralen concentration in the blood is 0.1 μg/mL (the desired level), the combined doses to the mid epidermis (and some areas of the upper dermis) are well below the 50% HIV promoter-activating PUVA dose (AD 50 PUVA ). These results suggest that the probability of HIV activation in the epidermis by direct mechanisms is higher for UVB than for PUVA treatment. However, complexities of the UV-inducible HIV activation and immunomodulatory phenomena are such that our results by themselves should not be taken as an indication that UVB therapy carries a high risk than PUVA therapy when administered to HIV-infected patients. (Author)

  18. Structural and mechanistic analysis of trans-3-chloroacrylic acid dehalogenase activity

    Energy Technology Data Exchange (ETDEWEB)

    Pegan, Scott D., E-mail: pegan@uic.edu [Center of Pharmaceutical Biotechnology and the Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago (United States); Serrano, Hector; Whitman, Christian P. [Division of Medicinal Chemistry, College of Pharmacy, The University of Texas, Austin (United States); Mesecar, Andrew D., E-mail: pegan@uic.edu [Center of Pharmaceutical Biotechnology and the Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago (United States)

    2008-12-01

    The X-ray structure of a noncovalently modified trans-3-chloroacrylic acid dehalogenase with a substrate-homolog acetate bound in the active site has been determined to 1.7 Å resolution. Elucidation of catalytically important water is reported and multiple conformations of the catalytic residue αGlu52 are observed. Trans-3-chloroacrylic acid dehalogenase (CaaD) is a critical enzyme in the trans-1, 3-dichloropropene (DCP) degradation pathway in Pseudomonas pavonaceae 170. This enzyme allows bacteria to use trans-DCP, a common component in commercially produced fumigants, as a carbon source. CaaD specifically catalyzes the fourth step of the pathway by cofactor-independent dehalogenation of a vinyl carbon–halogen bond. Previous studies have reported an X-ray structure of CaaD under acidic conditions with a covalent modification of the catalytic βPro1 residue. Here, the 1.7 Å resolution X-ray structure of CaaD under neutral (pH 6.5) conditions is reported without the presence of the covalent adduct. In this new structure, a substrate-like acetate molecule is bound within the active site in a position analogous to the putative substrate-binding site. Additionally, a catalytically important water molecule was identified, consistent with previously proposed reaction schemes. Finally, flexibility of the catalytically relevant side chain αGlu52 is observed in the structure, supporting its role in the catalytic mechanism.

  19. Trans-methylation reactions in plants: focus on the activated methyl cycle.

    Science.gov (United States)

    Rahikainen, Moona; Alegre, Sara; Trotta, Andrea; Pascual, Jesús; Kangasjärvi, Saijaliisa

    2018-02-01

    Trans-methylation reactions are vital in basic metabolism, epigenetic regulation, RNA metabolism, and posttranslational control of protein function and therefore fundamental in determining the physiological processes in all living organisms. The plant kingdom is additionally characterized by the production of secondary metabolites that undergo specific hydroxylation, oxidation and methylation reactions to obtain a wide array of different chemical structures. Increasing research efforts have started to reveal the enzymatic pathways underlying the biosynthesis of complex metabolites in plants. Further engineering of these enzymatic machineries offers significant possibilities in the development of bio-based technologies, but necessitates deep understanding of their potential metabolic and regulatory interactions. Trans-methylation reactions are tightly coupled with the so-called activated methyl cycle (AMC), an essential metabolic circuit that maintains the trans-methylation capacity in all living cells. Tight regulation of the AMC is crucial in ensuring accurate trans-methylation reactions in different subcellular compartments, cell types, developmental stages and environmental conditions. This review addresses the organization and posttranslational regulation of the AMC and elaborates its critical role in determining metabolic regulation through modulation of methyl utilization in stress-exposed plants. © 2017 Scandinavian Plant Physiology Society.

  20. Fighting for Trans* Kids: Academic Parent Activism in the 21st Century

    Directory of Open Access Journals (Sweden)

    Kimberley Manning

    2015-12-01

    Full Text Available In this article we explore some of the affective and ethical dimensions that we have faced as parent academic-activists seeking to understand and undo some of the structural transphobia that currently exists in Canadian society.  Informed by critical feminist, critical race and black feminist thought, trans* scholarship, queer theory, and anti-oppression analysis, we discuss how our academic-activism assumes complex configurations of privilege and vulnerability.

  1. Picomolar dichotomous activity of gnidimacrin against HIV-1.

    Directory of Open Access Journals (Sweden)

    Li Huang

    Full Text Available Highly active antiretroviral therapy (HAART has offered a promising approach for controlling HIV-1 replication in infected individuals. However, with HARRT, HIV-1 is suppressed rather than eradicated due to persistence of HIV-1 in latent viral reservoirs. Thus, purging the virus from latent reservoirs is an important strategy toward eradicating HIV-1 infection. In this study, we discovered that the daphnane diterpene gnidimacrin, which was previously reported to have potent anti-cancer cell activity, activated HIV-1 replication and killed persistently-infected cells at picomolar concentrations. In addition to its potential to purge HIV-1 from latently infected cells, gnidimacrin potently inhibited a panel of HIV-1 R5 virus infection of peripheral blood mononuclear cells (PBMCs at an average concentration lower than 10 pM. In contrast, gnidimacrin only partially inhibited HIV-1 ×4 virus infection of PBMCs. The strong anti-HIV-1 R5 virus activity of gnidimacrin was correlated with its effect on down-regulation of the HIV-1 coreceptor CCR5. The anti-R5 virus activity of gnidimacrin was completely abrogated by a selective protein kinase C beta inhibitor enzastaurin, which suggests that protein kinase C beta plays a key role in the potent anti-HIV-1 activity of gnidimacrin in PBMCs. In summary, these results suggest that gnidimacrin could activate latent HIV-1, specifically kill HIV-1 persistently infected cells, and inhibit R5 viruses at picomolar concentrations.

  2. Constitutively Active MAVS Inhibits HIV-1 Replication via Type I Interferon Secretion and Induction of HIV-1 Restriction Factors.

    Directory of Open Access Journals (Sweden)

    Sachin Gupta

    Full Text Available Type I interferon is known to inhibit HIV-1 replication through the induction of interferon stimulated genes (ISG, including a number of HIV-1 restriction factors. To better understand interferon-mediated HIV-1 restriction, we constructed a constitutively active form of the RIG-I adapter protein MAVS. Constitutive MAVS was generated by fusion of full length MAVS to a truncated form of the Epstein Barr virus protein LMP1 (ΔLMP1. Supernatant from ΔLMP1-MAVS-transfected 293T cells contained high levels of type I interferons and inhibited HIV replication in both TZM-bl and primary human CD4+ T cells. Supernatant from ΔLMP1-MAVS-transfected 293T cells also inhibited replication of VSV-G pseudotyped single cycle SIV in TZM-bl cells, suggesting restriction was post-entry and common to both HIV and SIV. Gene array analysis of ΔLMP1-MAVS-transfected 293T cells and trans-activated CD4+ T cells showed significant upregulation of ISG, including previously characterized HIV restriction factors Viperin, Tetherin, MxB, and ISG56. Interferon blockade studies implicated interferon-beta in this response. In addition to direct viral inhibition, ΔLMP1-MAVS markedly enhanced secretion of IFN-β and IL-12p70 by dendritic cells and the activation and maturation of dendritic cells. Based on this immunostimulatory activity, an adenoviral vector (Ad5 expressing ΔLMP1-MAVS was tested as a molecular adjuvant in an HIV vaccine mouse model. Ad5-Gag antigen combined with Ad5-ΔLMP1-MAVS enhanced control of vaccinia-gag replication in a mouse challenge model, with 4/5 animals showing undetectable virus following challenge. Overall, ΔLMP1-MAVS is a promising reagent to inhibit HIV-1 replication in infected tissues and enhance vaccine-mediated immune responses, while avoiding toxicity associated with systemic type I interferon administration.

  3. Human Ubc9 is involved in intracellular HIV-1 Env stability after trafficking out of the trans-Golgi network in a Gag dependent manner.

    Directory of Open Access Journals (Sweden)

    Christopher R Bohl

    Full Text Available The cellular E2 Sumo conjugase, Ubc9 interacts with HIV-1 Gag, and is important for the assembly of infectious HIV-1 virions. In the previous study we demonstrated that in the absence of Ubc9, a defect in virion assembly was associated with decreased levels of mature intracellular Envelope (Env that affected Env incorporation into virions and virion infectivity. We have further characterized the effect of Ubc9 knockdown on HIV Env processing and assembly. We found that gp160 stability in the endoplasmic reticulum (ER and its trafficking to the trans-Golgi network (TGN were unaffected, indicating that the decreased intracellular mature Env levels in Ubc9-depleted cells were due to a selective degradation of mature Env gp120 after cleavage from gp160 and trafficked out of the TGN. Decreased levels of Gag and mature Env were found to be associated with the plasma membrane and lipid rafts, which suggest that these viral proteins were not trafficked correctly to the assembly site. Intracellular gp120 were partially rescued when treated with a combination of lysosome inhibitors. Taken together our results suggest that in the absence of Ubc9, gp120 is preferentially degraded in the lysosomes likely before trafficking to assembly sites leading to the production of defective virions. This study provides further insight in the processing and packaging of the HIV-1 gp120 into mature HIV-1 virions.

  4. The HIV-1 transcriptional activator Tat has potent nucleic acid chaperoning activities in vitro.

    Science.gov (United States)

    Kuciak, Monika; Gabus, Caroline; Ivanyi-Nagy, Roland; Semrad, Katharina; Storchak, Roman; Chaloin, Olivier; Muller, Sylviane; Mély, Yves; Darlix, Jean-Luc

    2008-06-01

    The human immunodeficiency virus type 1 (HIV-1) is a primate lentivirus that causes the acquired immunodeficiency syndrome (AIDS). In addition to the virion structural proteins and enzyme precursors, that are Gag, Env and Pol, HIV-1 encodes several regulatory proteins, notably a small nuclear transcriptional activator named Tat. The Tat protein is absolutely required for virus replication since it controls proviral DNA transcription to generate the full-length viral mRNA. Tat can also regulate mRNA capping and splicing and was recently found to interfere with the cellular mi- and siRNA machinery. Because of its extensive interplay with nucleic acids, and its basic and disordered nature we speculated that Tat had nucleic acid-chaperoning properties. This prompted us to examine in vitro the nucleic acid-chaperoning activities of Tat and Tat peptides made by chemical synthesis. Here we report that Tat has potent nucleic acid-chaperoning activities according to the standard DNA annealing, DNA and RNA strand exchange, RNA ribozyme cleavage and trans-splicing assays. The active Tat(44-61) peptide identified here corresponds to the smallest known sequence with DNA/RNA chaperoning properties.

  5. Screening of the target genes trans-activated by HLA-HA8 in hepatocytes

    Directory of Open Access Journals (Sweden)

    Qi WANG

    2011-06-01

    Full Text Available Objective To clone and identify the target genes trans-activated by human minor histocompatibility antigen HLA-HA8 in hepatocytes with suppression subtractive hybridization(SSH and bioinfomatics technique.Methods mRNA was isolated from HepG2 cells transfected by pcDNA3.1(--HLA-HA8 and pcDNA3.1(- empty vector,and then used to synthesize the double-stranded cDNA(marked as Tester and Driver,respectively by reverse transcription.After being digested with restriction enzyme Rsa I,the tester cDNA was divided into two parts and ligated to the specific adaptor 1 and adaptor 2,respectively,and then hybridized with driver cDNA twice and underwent PCR twice.The production was subcloned into pEGM-Teasy plasmid vectors to set up the subtractive library.The library was then amplified by transfection into E.coli strain DH5α.The cDNA was sequenced and analyzed in GenBank with Blast search after PCR amplification.Results The subtractive library of genes trans-activated by HLA-HA8 was constructed successfully.The amplified library contained 101 positive clones.Colony PCR showed that all these clones contained 200-1000bp inserts.Twenty eight clones were selected randomly to analyze the sequences.The result of homologous analysis showed that altogether 16 coding sequences were gotten,of which 4 sequences were with unknown function.Conclusions The obtained sequences trans-activated by HLA-HA8 may code different proteins and play important roles in cell growth and metabolism,energy synthesis and metabolism,material transport and signal transduction.This finding will bring some new clues for the studies not only on the biological functions of HLA-HA8,but also on the HBV infection mechanism.

  6. Colorectal mucus binds DC-SIGN and inhibits HIV-1 trans-infection of CD4+ T-lymphocytes

    NARCIS (Netherlands)

    Stax, Martijn J.; Mouser, Emily E. I. M.; van Montfort, Thijs; Sanders, Rogier W.; de Vries, Henry J. C.; Dekker, Henk L.; Herrera, Carolina; Speijer, Dave; Pollakis, Georgios; Paxton, William A.

    2015-01-01

    Bodily secretions, including breast milk and semen, contain factors that modulate HIV-1 infection. Since anal intercourse caries one of the highest risks for HIV-1 transmission, our aim was to determine whether colorectal mucus (CM) also contains factors interfering with HIV-1 infection and

  7. Comparing Trans-Spectrum and Same-Sex-Attracted Youth in Australia: Increased Risks, Increased Activisms

    Science.gov (United States)

    Jones, Tiffany; Hillier, Lynne

    2013-01-01

    Tran-spectrum youth include those who are gender questioning, transgender, intersex, genderqueer, and androgynous. Drawing on data from an Australian study of more than 3,000 same-sex-attracted and trans-spectrum youth aged 14 to 21, this article compares a group of 91 trans-spectrum youth from the study to "cisgender" same-sex-attracted…

  8. Lectins with Anti-HIV Activity: A Review

    Directory of Open Access Journals (Sweden)

    Ouafae Akkouh

    2015-01-01

    Full Text Available Lectins including flowering plant lectins, algal lectins, cyanobacterial lectins, actinomycete lectin, worm lectins, and the nonpeptidic lectin mimics pradimicins and benanomicins, exhibit anti-HIV activity. The anti-HIV plant lectins include Artocarpus heterophyllus (jacalin lectin, concanavalin A, Galanthus nivalis (snowdrop agglutinin-related lectins, Musa acuminata (banana lectin, Myrianthus holstii lectin, Narcissus pseudonarcissus lectin, and Urtica diocia agglutinin. The anti-HIV algal lectins comprise Boodlea coacta lectin, Griffithsin, Oscillatoria agardhii agglutinin. The anti-HIV cyanobacterial lectins are cyanovirin-N, scytovirin, Microcystis viridis lectin, and microvirin. Actinohivin is an anti-HIV actinomycete lectin. The anti-HIV worm lectins include Chaetopterus variopedatus polychaete marine worm lectin, Serpula vermicularis sea worm lectin, and C-type lectin Mermaid from nematode (Laxus oneistus. The anti-HIV nonpeptidic lectin mimics comprise pradimicins and benanomicins. Their anti-HIV mechanisms are discussed.

  9. Development of a GAL4-VP16/UAS trans-activation system for tissue specific expression in Medicago truncatula.

    Directory of Open Access Journals (Sweden)

    Amélie Sevin-Pujol

    Full Text Available Promoters with tissue-specific activity are very useful to address cell-autonomous and non cell autonomous functions of candidate genes. Although this strategy is widely used in Arabidopsis thaliana, its use to study tissue-specific regulation of root symbiotic interactions in legumes has only started recently. Moreover, using tissue specific promoter activity to drive a GAL4-VP16 chimeric transcription factor that can bind short upstream activation sequences (UAS is an efficient way to target and enhance the expression of any gene of interest. Here, we developed a collection of promoters with different root cell layers specific activities in Medicago truncatula and tested their abilities to drive the expression of a chimeric GAL4-VP16 transcription factor in a trans-activation UAS: β-Glucuronidase (GUS reporter gene system. By developing a binary vector devoted to modular Golden Gate cloning together with a collection of adapted tissue specific promoters and coding sequences we could test the activity of four of these promoters in trans-activation GAL4/UAS systems and compare them to "classical" promoter GUS fusions. Roots showing high levels of tissue specific expression of the GUS activity could be obtained with this trans-activation system. We therefore provide the legume community with new tools for efficient modular Golden Gate cloning, tissue specific expression and a trans-activation system. This study provides the ground work for future development of stable transgenic lines in Medicago truncatula.

  10. Synthesis and anticancer activity of N-substituted 2-arylquinazolinones bearing trans-stilbene scaffold.

    Science.gov (United States)

    Mahdavi, Mohammad; Pedrood, Keyvan; Safavi, Maliheh; Saeedi, Mina; Pordeli, Mahboobeh; Ardestani, Sussan Kabudanian; Emami, Saeed; Adib, Mehdi; Foroumadi, Alireza; Shafiee, Abbas

    2015-05-05

    A novel series of 2-arylquinazolinones 7a-o bearing trans-stilbene moiety were designed, synthesized, and evaluated against human breast cancer cell lines including human breast adenocarcinoma (MCF-7 and MDA-MB-231) and human ductal breast epithelial tumor (T-47D). Among the tested compounds, the sec-butyl derivative 7h showed the best profile of activity (IC50 < 5 μM) against all cell lines, being 2-fold more potent than standard drug, etoposide. Our investigation revealed that the cytotoxic activity was significantly affected by N3-alkyl substituents. Furthermore, the morphological analysis by acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that the prototype compound 7h can induce apoptosis in MCF-7 and MDA-MB-231 cells. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. Chemical Composition and Biological Activities of Trans-Himalayan Alga Spirogyra porticalis (Muell.) Cleve

    Science.gov (United States)

    Kumar, Jatinder; Dhar, Priyanka; Tayade, Amol B.; Gupta, Damodar; Chaurasia, Om P.; Upreti, Dalip K.; Toppo, Kiran; Arora, Rajesh; Suseela, M. R.; Srivastava, Ravi B.

    2015-01-01

    The freshwater alga Spirogyra porticalis (Muell.) Cleve, a filamentous charophyte, collected from the Indian trans-Himalayan cold desert, was identified on the basis of morpho-anatomical characters. Extracts of this alga were made using solvents of varying polarity viz. n-hexane, acetonitrile, methanol and water. The antioxidant capacities and phenolic profile of the extracts were estimated. The methanol extract showing highest antioxidant capacity and rich phenolic attributes was further investigated and phytochemical profiling was conducted by gas chromatography-mass spectrometry (GC/MS) hyphenated technique. The cytotoxic activity of methanol extract was evaluated on human hepatocellular carcinoma HepG2 and colon carcinoma RKO cell lines. The anti-hypoxic effect of methanol extract of the alga was tested on in vivo animal system to confirm its potential to ameliorate oxidative stress. The antioxidant assays viz. ferric reducing antioxidant power (FRAP), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), 1,1-diphenyl-2-picrylhydrazyl (DPPH) and nitric oxide (NO) radical scavenging capacities, β-carotene-linoleic acid bleaching property and lipid peroxidation exhibited analogous results, wherein the algal extracts showed significantly high antioxidant potential. The extracts were also found to possess high content of total proanthocyanidin, flavonoid and polyphenol. GC/MS analysis revealed the presence of thirteen chemotypes in the methanol extract representing different phytochemical groups like fatty acid esters, sterols, unsaturated alcohols, alkynes etc. with substantial phyto-pharmaceutical importance. The methanol extract was observed to possess anticancer activity as revealed from studies on HepG2 and RKO cell lines. In the present study, S. porticalis methanol extract also provided protection from hypoxia-induced oxidative stress and accelerated the onset of adaptative changes in rats during exposure to hypobaric hypoxia. The

  12. Contribution to the investigation of the p53 in vivo and in vitro trans-activation activity

    International Nuclear Information System (INIS)

    Meiller, A.

    2004-03-01

    Among the body's defence mechanisms, the programmed cellular death or apoptosis is an important safeguard way which allows the body to get rid of the injured cells before they acquire steady genetic modifications leading to an anarchistic multiplication. As p53 tumor suppressor gene plays a predominant role within this process, this research report first presents the p53 protein, its structure, its activities as a transcription factor, its modifications and the implications on its functional activities, its biological activities, and describes the p53 intracellular rate regulation and the use of this protein in radiology, particularly in 'in vivo' investigations on irradiated mice. It also presents the p53 family. Then, the author reports experimental investigations on possible other genes which could be trans-activated by p53. A gene is identified as a new target gene. She also demonstrates a new p53 activation path induced by another member of the p53 family, the p73 alpha protein

  13. All-trans retinoic acid negatively regulates cytotoxic activities of nature killer cell line 92

    International Nuclear Information System (INIS)

    Li Ang; He Meilan; Wang Hui; Qiao Bin; Chen Ping; Gu Hua; Zhang Mengjie; He Shengxiang

    2007-01-01

    NK cells are key components of innate immune systems and their activities are regulated by cytokines and hormones. All-trans retinoic acid (ATRA), as a metabolite of vitamin A and an immunomodulatory hormone, plays an important role in regulating immune responses. In the present study, we investigated the effect of ATRA on human NK cell line NK92. We found that ATRA dose-dependently suppressed cytotoxic activities of NK92 cells without affecting their proliferation. To explore the mechanisms underlying the ATRA influence on NK92 cells, we examined the production of cytokines (TNF-α, IFN-γ), gene expression of cytotoxic-associated molecules (perforin, granzyme B, nature killer receptors (NCRs), and NKG2D), and the activation of NF-κB pathways related with immune response. Our results demonstrated that ATRA suppressed NF-κB activity and prevented IκBα degradation in a dose-dependent way, inhibited IFN-γ production and gene expression of granzyme B and NKp46. Our findings suggest that ATRA is a negative regulator of NK92 cell activation and may act as a potential regulator of anti-inflammatory functions in vivo

  14. In vitro modeling of HIV proviral activity in microglia.

    Science.gov (United States)

    Campbell, Lee A; Richie, Christopher T; Zhang, Yajun; Heathward, Emily J; Coke, Lamarque M; Park, Emily Y; Harvey, Brandon K

    2017-12-01

    Microglia, the resident macrophages of the brain, play a key role in the pathogenesis of HIV-associated neurocognitive disorders (HAND) due to their productive infection by HIV. This results in the release of neurotoxic viral proteins and pro-inflammatory compounds which negatively affect the functionality of surrounding neurons. Because models of HIV infection within the brain are limited, we aimed to create a novel microglia cell line with an integrated HIV provirus capable of recreating several hallmarks of HIV infection. We utilized clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology and integrated a modified HIV provirus into CHME-5 immortalized microglia to create HIV-NanoLuc CHME-5. In the modified provirus, the Gag-Pol region is replaced with the coding region for NanoLuciferase (NanoLuc), which allows for the rapid assay of HIV long terminal repeat activity using a luminescent substrate, while still containing the necessary genetic material to produce established neurotoxic viral proteins (e.g. tat, nef, gp120). We confirmed that HIV-NanoLuc CHME-5 microglia express NanoLuc, along with the HIV viral protein Nef. We subsequently exposed these cells to a battery of experiments to modulate the activity of the provirus. Proviral activity was enhanced by treating the cells with pro-inflammatory factors lipopolysaccharide (LPS) and tumor necrosis factor alpha and by overexpressing the viral regulatory protein Tat. Conversely, genetic modification of the toll-like receptor-4 gene by CRISPR/Cas9 reduced LPS-mediated proviral activation, and pharmacological application of NF-κB inhibitor sulfasalazine similarly diminished proviral activity. Overall, these data suggest that HIV-NanoLuc CHME-5 may be a useful tool in the study of HIV-mediated neuropathology and proviral regulation. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  15. Tryptophan as a Molecular Shovel in the Glycosyl Transfer Activity of Trypanosoma cruzi Trans-sialidase

    Science.gov (United States)

    Mitchell, Felicity L.; Miles, Steven M.; Neres, João; Bichenkova, Elena V.; Bryce, Richard A.

    2010-01-01

    Abstract Molecular dynamics investigations into active site plasticity of Trypanosoma cruzi trans-sialidase, a protein implicated in Chagas disease, suggest that movement of the Trp312 loop plays an important role in the enzyme's sialic acid transfer mechanism. The observed Trp312 flexibility equates to a molecular shovel action, which leads to the expulsion of the donor aglycone leaving group from the catalytic site. These computational simulations provide detailed structural insights into sialyl transfer by the trans-sialidase and may aid the design of inhibitors effective against this neglected tropical disease. PMID:20441732

  16. Alterations in HIV-1 LTR promoter activity during AIDS progression

    International Nuclear Information System (INIS)

    Hiebenthal-Millow, Kirsten; Greenough, Thomas C.; Bretttler, Doreen B.; Schindler, Michael; Wildum, Steffen; Sullivan, John L.; Kirchhoff, Frank

    2003-01-01

    HIV-1 variants evolving in AIDS patients frequently show increased replicative capacity compared to those present during early asymptomatic infection. It is known that late stage HIV-1 variants often show an expanded coreceptor tropism and altered Nef function. In the present study we investigated whether enhanced HIV-1 LTR promoter activity might also evolve during disease progression. Our results demonstrate increased LTR promoter activity after AIDS progression in 3 of 12 HIV-1-infected individuals studied. Further analysis revealed that multiple alterations in the U3 core-enhancer and in the transactivation-response (TAR) region seem to be responsible for the enhanced functional activity. Our findings show that in a subset of HIV-1-infected individuals enhanced LTR transcription contributes to the increased replicative potential of late stage virus isolates and might accelerate disease progression

  17. HIV/AIDS Prevention Activities of Faith-Based Christian ...

    African Journals Online (AJOL)

    Based on these findings, it was recommended that the faith-based Christian organizations should collaborate with relevant agencies, community based workers and non-formal education providers to improve HIV/AIDS prevention service delivery in the study area. Keywords: Prevention, Activities, HIV/AIDS, Empowerment, ...

  18. Molecular Mechanisms in Activation of Latent HIV-1

    NARCIS (Netherlands)

    H. Rafati (Haleh)

    2014-01-01

    markdownabstract__Abstract__ Finding a cure for the human immunodeficiency virus type 1 (HIV-1) is extremely challenging. Development of highly active anti-retroviral therapy (HAART), transformed HIV-1 infection from an acute syndrome into chronic disease. Although using HAART results in

  19. Immunological Response of Hiv-Infected Children to Highly Active ...

    African Journals Online (AJOL)

    BACKGROUND: The effectiveness of highly active antiretroviral therapy (HAART) in children has not been well studied specially in developing countries where the burden of HIV is high. This study was aimed to assess the immunologic response of HIV-infected children to HAART at Pediatric ART Clinic Gondar University ...

  20. Synthesis of trans-disubstituted alkenes by cobalt-catalyzed reductive coupling of terminal alkynes with activated alkenes.

    Science.gov (United States)

    Mannathan, Subramaniyan; Cheng, Chien-Hong

    2012-09-10

    A cobalt-catalyzed reductive coupling of terminal alkynes, RC≡CH, with activated alkenes, R'CH=CH(2), in the presence of zinc and water to give functionalized trans-disubstituted alkenes, RCH=CHCH(2)CH(2)R', is described. A variety of aromatic terminal alkynes underwent reductive coupling with activated alkenes including enones, acrylates, acrylonitrile, and vinyl sulfones in the presence of a CoCl(2)/P(OMe)(3)/Zn catalyst system to afford 1,2-trans-disubstituted alkenes with high regio- and stereoselectivity. Similarly, aliphatic terminal alkynes also efficiently participated in the coupling reaction with acrylates, enones, and vinyl sulfone, in the presence of the CoCl(2)/P(OPh)(3)/Zn system providing a mixture of 1,2-trans- and 1,1-disubstituted functionalized terminal alkene products in high yields. The scope of the reaction was also extended by the coupling of 1,3-enynes and acetylene gas with alkenes. Furthermore, a phosphine-free cobalt-catalyzed reductive coupling of terminal alkynes with enones, affording 1,2-trans-disubstituted alkenes as the major products in a high regioisomeric ratio, is demonstrated. In the reactions, less expensive and air-stable cobalt complexes, a mild reducing agent (Zn) and a simple hydrogen source (water) were used. A possible reaction mechanism involving a cobaltacyclopentene as the key intermediate is proposed. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. A mutant sialidase having trans-sialidase activity for use in production of sialylated glycans

    DEFF Research Database (Denmark)

    2014-01-01

    galacto-oligosaccharides (GOS), fructo-oligosaccharides (FOS), malto-oligosaccharides (MOS), isomalto-oligosaccarides (IMO), lactulose, melibiose, maltose, glycosyl sucrose, lactosucrose and fucose. Trans-sialidated mono- and oligo- saccharides, produced with the mutant enzyme, are useful in preparing...

  2. Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation

    Science.gov (United States)

    Lee, Eun-Jae; Lee, Hyejin; Huang, Tzyy-Nan; Chung, Changuk; Shin, Wangyong; Kim, Kyungdeok; Koh, Jae-Young; Hsueh, Yi-Ping; Kim, Eunjoon

    2015-01-01

    Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Zinc (Zn) is a nutritional factor implicated in ASDs, but evidence for a strong association and linking mechanism is largely lacking. Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation. PMID:25981743

  3. Brain-targeted delivery of trans-activating transcriptor-conjugated magnetic PLGA/lipid nanoparticles.

    Directory of Open Access Journals (Sweden)

    Xiangru Wen

    Full Text Available Magnetic poly (D,L-lactide-co-glycolide (PLGA/lipid nanoparticles (MPLs were fabricated from PLGA, L-α-phosphatidylethanolamine (DOPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino (polyethylene glycol (DSPE-PEG-NH2, and magnetic nanoparticles (NPs, and then conjugated to trans-activating transcriptor (TAT peptide. The TAT-MPLs were designed to target the brain by magnetic guidance and TAT conjugation. The drugs hesperidin (HES, naringin (NAR, and glutathione (GSH were encapsulated in MPLs with drug loading capacity (>10% and drug encapsulation efficiency (>90%. The therapeutic efficacy of the drug-loaded TAT-MPLs in bEnd.3 cells was compared with that of drug-loaded MPLs. The cells accumulated higher levels of TAT-MPLs than MPLs. In addition, the accumulation of QD-loaded fluorescein isothiocyanate (FITC-labeled TAT-MPLs in bEnd.3 cells was dose and time dependent. Our results show that TAT-conjugated MPLs may function as an effective drug delivery system that crosses the blood brain barrier to the brain.

  4. Uncoupling of Protease trans-Cleavage and Helicase Activities in Pestivirus NS3.

    Science.gov (United States)

    Zheng, Fengwei; Lu, Guoliang; Li, Ling; Gong, Peng; Pan, Zishu

    2017-11-01

    The nonstructural protein NS3 from the Flaviviridae family is a multifunctional protein that contains an N-terminal protease and a C-terminal helicase, playing essential roles in viral polyprotein processing and genome replication. Here we report a full-length crystal structure of the classical swine fever virus (CSFV) NS3 in complex with its NS4A protease cofactor segment (PCS) at a 2.35-Å resolution. The structure reveals a previously unidentified ∼2,200-Å 2 intramolecular protease-helicase interface comprising three clusters of interactions, representing a "closed" global conformation related to the NS3-NS4A cis -cleavage event. Although this conformation is incompatible with protease trans -cleavage, it appears to be functionally important and beneficial to the helicase activity, as the mutations designed to perturb this conformation impaired both the helicase activities in vitro and virus production in vivo Our work reveals important features of protease-helicase coordination in pestivirus NS3 and provides a key basis for how different conformational states may explicitly contribute to certain functions of this natural protease-helicase fusion protein. IMPORTANCE Many RNA viruses encode helicases to aid their RNA genome replication and transcription by unwinding structured RNA. Being naturally fused to a protease participating in viral polyprotein processing, the NS3 helicases encoded by the Flaviviridae family viruses are unique. Therefore, how these two enzyme modules coordinate in a single polypeptide is of particular interest. Here we report a previously unidentified conformation of pestivirus NS3 in complex with its NS4A protease cofactor segment (PCS). This conformational state is related to the protease cis -cleavage event and is optimal for the function of helicase. This work provides an important basis to understand how different enzymatic activities of NS3 may be achieved by the coordination between the protease and helicase through different

  5. USE OF TRANS-CONTEXTUAL MODEL-BASED PHYSICAL ACTIVITY COURSE IN DEVELOPING LEISURE-TIME PHYSICAL ACTIVITY BEHAVIOR OF UNIVERSITY STUDENTS.

    Science.gov (United States)

    Müftüler, Mine; İnce, Mustafa Levent

    2015-08-01

    This study examined how a physical activity course based on the Trans-Contextual Model affected the variables of perceived autonomy support, autonomous motivation, determinants of leisure-time physical activity behavior, basic psychological needs satisfaction, and leisure-time physical activity behaviors. The participants were 70 Turkish university students (M age=23.3 yr., SD=3.2). A pre-test-post-test control group design was constructed. Initially, the participants were randomly assigned into an experimental (n=35) and a control (n=35) group. The experimental group followed a 12 wk. trans-contextual model-based intervention. The participants were pre- and post-tested in terms of Trans-Contextual Model constructs and of self-reported leisure-time physical activity behaviors. Multivariate analyses showed significant increases over the 12 wk. period for perceived autonomy support from instructor and peers, autonomous motivation in leisure-time physical activity setting, positive intention and perceived behavioral control over leisure-time physical activity behavior, more fulfillment of psychological needs, and more engagement in leisure-time physical activity behavior in the experimental group. These results indicated that the intervention was effective in developing leisure-time physical activity and indicated that the Trans-Contextual Model is a useful way to conceptualize these relationships.

  6. Trans* Leadership.

    Science.gov (United States)

    Jourian, T J; Simmons, Symone L

    2017-06-01

    Focusing on emerging literature on trans* and gender-nonconforming students and their leadership, this chapter outlines the ways trans* students are engaged in leadership in educational institutions and outside of them and discusses implications for staff and faculty regarding how to support and engage these students and their leadership. © 2017 Wiley Periodicals, Inc., A Wiley Company.

  7. Anti-HIV-1 activity of flavonoid myricetin on HIV-1 infection in a dual-chamber in vitro model.

    Directory of Open Access Journals (Sweden)

    Silvana Pasetto

    Full Text Available HIV infection by sexual transmission remains an enormous global health concern. More than 1 million new infections among women occur annually. Microbicides represent a promising prevention strategy that women can easily control. Among emerging therapies, natural small molecules such as flavonoids are an important source of new active substances. In this study we report the in vitro cytotoxicity and anti-HIV-1 and microbicide activity of the following flavonoids: Myricetin, Quercetin and Pinocembrin. Cytotoxicity tests were conducted on TZM-bl, HeLa, PBMC, and H9 cell cultures using 0.01-100 µM concentrations. Myricetin presented the lowest toxic effect, with Quercetin and Pinocembrin relatively more toxic. The anti-HIV-1 activity was tested with TZM-bl cell plus HIV-1 BaL (R5 tropic, H9 and PBMC cells plus HIV-1 MN (X4 tropic, and the dual tropic (X4R5 HIV-1 89.6. All flavonoids showed anti-HIV activity, although Myricetin was more effective than Quercetin or Pinocembrin. In TZM-bl cells, Myricetin inhibited ≥90% of HIV-1 BaL infection. The results were confirmed by quantification of HIV-1 p24 antigen in supernatant from H9 and PBMC cells following flavonoid treatment. In H9 and PBMC cells infected by HIV-1 MN and HIV-1 89.6, Myricetin showed more than 80% anti-HIV activity. Quercetin and Pinocembrin presented modest anti-HIV activity in all experiments. Myricetin activity was tested against HIV-RT and inhibited the enzyme by 49%. Microbicide activities were evaluated using a dual-chamber female genital tract model. In the in vitro microbicide activity model, Myricetin showed promising results against different strains of HIV-1 while also showing insignificant cytotoxic effects. Further studies of Myricetin should be performed to identify its molecular targets in order to provide a solid biological foundation for translational research.

  8. Building coalitions: The interconnections between feminism and trans* activism in Spain.

    Science.gov (United States)

    Lucas Platero, R; Ortega-Arjonilla, Esther

    2016-01-01

    What made current Spanish feminism shift toward transfeminism? Based on in-depth interviews and literature reviews, we explore what factors facilitated the participation of trans* women in Spanish feminism. Tracing the history through relevant events such as the National Feminist Conferences, it becomes clear that trans* women participated in the 1993, 2000, and 2009 conferences, posing relevant issues regarding prostitution, transgenderism, and the political subject of feminism. Our research allows a break with global oppositional narratives, in which these movements are in conflict, and highlights the importance of understanding the vernacular nuances that take place in a particular geopolitical context.

  9. Frontotemporal dementia with trans-activation response DNA-binding protein 43 presenting with catatonic syndrome.

    Science.gov (United States)

    Watanabe, Ryohei; Kawakami, Ito; Onaya, Mitsumoto; Higashi, Shinji; Arai, Nobutaka; Akiyama, Haruhiko; Hasegawa, Masato; Arai, Tetsuaki

    2017-11-07

    Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder. At the age of 58, the patient had a sudden onset of disorganized behavior and meaningless speech. Psychotropic drugs were effective for catatonic symptoms. However, after remission apathy, hyperorality, socially inappropriate behavior, hoarding, and an instinctive grasp reaction appeared and persisted. Brain MRI showed significant atrophy of the bilateral fronto-temporal lobes. A neuropathological examination revealed extensive trans-activation response DNA-binding protein 43 (TDP-43) positive neurocytoplasmic inclusions and dystrophic neurites in the brain, including the cerebral cortex, basal ganglia, and brainstem. Pathological diagnosis was frontotemporal lobar degeneration (FTLD) with TDP-43 (FTLD-TDP) type C, which was also confirmed by the band pattern of C-terminal fragments of TDP-43 on western blotting of sarkosyl-insoluble fractions extracted from the frozen brain. Dysfunction of the thalamus, globus pallidus, supplementary motor area, amygdala and cingulate cortex have been said to be related to the catatonic syndrome. In this case, these areas were affected, showing abnormal TDP-43-positive structures. Further studies are expected to confirm further clinical - pathological correlations to FTLD. © 2017 Japanese Society of Neuropathology.

  10. Innate immune recognition and activation during HIV infection

    Directory of Open Access Journals (Sweden)

    Larsen Carsten S

    2010-06-01

    Full Text Available Abstract The pathogenesis of HIV infection, and in particular the development of immunodeficiency, remains incompletely understood. Whichever intricate molecular mechanisms are at play between HIV and the host, it is evident that the organism is incapable of restricting and eradicating the invading pathogen. Both innate and adaptive immune responses are raised, but they appear to be insufficient or too late to eliminate the virus. Moreover, the picture is complicated by the fact that the very same cells and responses aimed at eliminating the virus seem to play deleterious roles by driving ongoing immune activation and progressive immunodeficiency. Whereas much knowledge exists on the role of adaptive immunity during HIV infection, it has only recently been appreciated that the innate immune response also plays an important part in HIV pathogenesis. In this review, we present current knowledge on innate immune recognition and activation during HIV infection based on studies in cell culture, non-human primates, and HIV-infected individuals, and discuss the implications for the understanding of HIV immunopathogenesis.

  11. Evolving trade policy and the Trans-Pacific Partnership Agreement: does it threaten Vietnam's access to medicine and its progress towards scaling up HIV prevention, treatment and care?

    Science.gov (United States)

    Linh, Nguyen Nhat; Huong, Nguyen Thanh; Thuy, Hua Thanh

    2015-01-01

    The Trans-Pacific Partnership Agreement (TPP) has undergone 18 rounds of secretive negotiation between the USA and 11 Asia-Pacific countries. Aiming at a free trade area, this multilateral trade proposal covers all aspects of commercial relations among the countries involved. Despite some anticipated positive impacts in trade, specific articles in this proposal's intellectual property and transparency chapters might negatively impact access to medicine, in general, and to antiretroviral (ARV) drugs, in particular, in Vietnam. Drawing on a desk review and qualitative in-depth interviews with 20 key informants from government, academia, hospitals and civil society, we analyse various provisions of the proposal being negotiated leaked after the 14th round of negotiations in September 2012. Findings suggest that the TPP could lead to increased monopoly protection and could limit technological advancements within the local pharmaceutical manufacturing industry, resulting in higher medicine prices in Vietnam. This outcome would have a significant impact on Vietnam's ability to achieve goals for HIV prevention, treatment and care, and create barriers to universal health-care coverage. This research provides unique evidence for Vietnam to advocate for more equitable pharmaceutical provisions in and to raise awareness of the implications of the TPP among the pharmaceutical stakeholder community in Vietnam.

  12. Trans-1,4 selective polymerization of 1,3-butadiene with symmetry pincer chromium complexes activated by MMAO

    KAUST Repository

    Gong, Dirong; Jia, Xiaoyu; Wang, Baolin; Zhang, Xuequan; Huang, Kuo-Wei

    2014-01-01

    Tridentate chromium complexes (Cr1-Cr7) incorporated with symmetrical pincer ligand bis(arylimino)pyridine and bis(pyrzaolyl)pyridine have been synthesized and characterized by elemental analyis, FT-IR as well as ESI-MS. X-ray diffraction reveals solids-state structures of Cr2, Cr4 and Cr6 all adopt pseudo-octahedral coordination environment with respect to metal center. All complexes have been tested in stereoregulated polymerization of butadiene under various polymerization conditions. The trans-1,4 and cis-1,4 enchainment of resultant polymer are found to be dependent on the structure of ligand and amount of activator used. Under the optimized condition, free ortho-substitutes Cr catalysts Cr1, Cr3, Cr4 and Cr6 are capable of initiating high trans-1,4 selectivity (trans-1,4: 89.2%-92.0%) with good polymer yields (71.5%-78.0%), while counterparts with ortho-positioned alkyl groups Cr2, Cr5 and Cr7 display mixed selectivities with moderate polymer yields. The sterical effect of ligand and amount of MMAO on the catalytic performance, in particular, the stereoselectivity and polymer yield, has been also elucidated by conjugated diene polymerization mechanism. © 2014 Elsevier B.V. All rights reserved.

  13. Trans-1,4 selective polymerization of 1,3-butadiene with symmetry pincer chromium complexes activated by MMAO

    KAUST Repository

    Gong, Dirong

    2014-09-01

    Tridentate chromium complexes (Cr1-Cr7) incorporated with symmetrical pincer ligand bis(arylimino)pyridine and bis(pyrzaolyl)pyridine have been synthesized and characterized by elemental analyis, FT-IR as well as ESI-MS. X-ray diffraction reveals solids-state structures of Cr2, Cr4 and Cr6 all adopt pseudo-octahedral coordination environment with respect to metal center. All complexes have been tested in stereoregulated polymerization of butadiene under various polymerization conditions. The trans-1,4 and cis-1,4 enchainment of resultant polymer are found to be dependent on the structure of ligand and amount of activator used. Under the optimized condition, free ortho-substitutes Cr catalysts Cr1, Cr3, Cr4 and Cr6 are capable of initiating high trans-1,4 selectivity (trans-1,4: 89.2%-92.0%) with good polymer yields (71.5%-78.0%), while counterparts with ortho-positioned alkyl groups Cr2, Cr5 and Cr7 display mixed selectivities with moderate polymer yields. The sterical effect of ligand and amount of MMAO on the catalytic performance, in particular, the stereoselectivity and polymer yield, has been also elucidated by conjugated diene polymerization mechanism. © 2014 Elsevier B.V. All rights reserved.

  14. Serum Adenosine Deaminase (ADA) Activity: A Novel Screening Test to Differentiate HIV Monoinfection From HIV-HBV and HIV-HCV Coinfections.

    Science.gov (United States)

    Abdi, Mohammad; Rahbari, Rizgar; Khatooni, Zahed; Naseri, Nima; Najafi, Adel; Khodadadi, Iraj

    2016-05-01

    CD4(+) cell count, the common HIV infection screening test, is costly and unable to differentiate HIV monoinfection from its concurrent infection with hepatitis B or C virus. We aimed to ascertain diagnostic value of serum adenosine deaminase (ADA) activity as a useful tool to differentiate HIV mono- and co-infection. Blood samples were collected from 30 HIV-HBV and 30 HIV-HCV coinfected patients, 33 HIV positive subjects, and 72 controls. CD4(+) cell count, serum total ADA (tADA), and ADA1, and ADA2 isoenzyme activities were determined and their sensitivity and specificity were computed. tADA and ADA2 activities were significantly higher and CD4(+) counts were markedly lower in all patients compared with controls. Strong inverse agreements between CD4(+) cell counts and both tADA and ADA2 activities were observed. Serum tADA and ADA1 activities showed the highest specificity and the highest sensitivity, respectively, for differentiating HIV monoinfection from HIV-HBV and HIV-HCV coinfections. We showed strong agreement and correlation between CD4(+) cell count and ADA enzyme activity. Based on high ADA sensitivity and specificity, it is concluded that determination of ADA activity might be a novel diagnostic tool to distinguish of HIV monoinfection from its coinfection with HBV or HCV. © 2015 Wiley Periodicals, Inc.

  15. Anti-HIV activity in cervical-vaginal secretions from HIV-positive and -negative women correlate with innate antimicrobial levels and IgG antibodies.

    Directory of Open Access Journals (Sweden)

    Mimi Ghosh

    2010-06-01

    Full Text Available We investigated the impact of antimicrobials in cervicovaginal lavage (CVL from HIV(+ and HIV(- women on target cell infection with HIV. Since female reproductive tract (FRT secretions contain a spectrum of antimicrobials, we hypothesized that CVL from healthy HIV(+ and (- women inhibit HIV infection.CVL from 32 HIV(+ healthy women with high CD4 counts and 15 healthy HIV(- women were collected by gently washing the cervicovaginal area with 10 ml of sterile normal saline. Following centrifugation, anti-HIV activity in CVL was determined by incubating CVL with HIV prior to addition to TZM-bl cells. Antimicrobials and anti-gp160 HIV IgG antibodies were measured by ELISA. When CXCR4 and CCR5 tropic HIV-1 were incubated with CVL from HIV(+ women prior to addition to TZM-bl cells, anti-HIV activity in CVL ranged from none to 100% inhibition depending on the viral strains used. CVL from HIV(- controls showed comparable anti-HIV activity. Analysis of CH077.c (clone of an R5-tropic, mucosally-transmitted founder virus viral inhibition by CVL was comparable to laboratory strains. Measurement of CVL for antimicrobials HBD2, trappin-2/elafin, SLPI and MIP3alpha indicated that each was present in CVL from HIV(+ and HIV(- women. HBD2 and MIP3alpha correlated with anti-HIV activity as did anti-gp160 HIV IgG antibodies in CVL from HIV(+ women.These findings indicate that CVL from healthy HIV(+ and HIV(- women contain innate and adaptive defense mechanisms that inhibit HIV infection. Our data suggest that innate endogenous antimicrobials and HIV-specific IgG in the FRT can act in concert to contribute toward the anti-HIV activity of the CVL and may play a role in inhibition of HIV transmission to women.

  16. Degradative pro-vitamin A active compounds of all- trans -&beta ...

    African Journals Online (AJOL)

    Dark green leafy vegetables (DGLV) are rich source of pro-vitamin A carotenoids, with all-trans-b-carotene as the main compound contributing over 90% of the vitamin A content. The other pro-vitamin A carotenoids present in DGLV are the cis isomers of b-carotene; the 9-cis and the 13-cis, and a-carotene in some ...

  17. Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

    Science.gov (United States)

    Cysique, Lucette A; Jugé, Lauriane; Gates, Thomas; Tobia, Michael; Moffat, Kirsten; Brew, Bruce J; Rae, Caroline

    2018-01-01

    To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Seventy-three HIV+ virally suppressed men and 35 HIV- men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy ( 1 H-MRS) at baseline and after and 23 ± 5 months. 1 H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N -acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo -Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls ( p < 0.002). In addition, relative to the HIV- group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV- groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p < 0.001), decreased PCC NAA and CA NAA (both p < 0.05) and PCC mI increase ( p < 0.05). HIV duration and historical HAND had modest effects on metabolite changes. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing

  18. Cortisol patterns are associated with T cell activation in HIV.

    Directory of Open Access Journals (Sweden)

    Sarah Patterson

    Full Text Available The level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.We studied 128 HIV-infected adults who were not on treatment and had a CD4(+ T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.Lower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4(+ T cells (r = -0.26, p = 0.006. Participants with lower waking cortisol also showed a trend toward greater activation on CD8(+ T cells (r = -0.17, p = 0.08. A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4(+ (r = 0.24, p = 0.018 and CD8(+ (r = 0.24, p = 0.017 activation.These data suggest that the hypothalamic-pituitary-adrenal (HPA axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV.

  19. Experimentally calibrated computational chemistry of tryptophan hydroxylase: Trans influence, hydrogen-bonding, and 18-electron rule govern O-2-activation

    DEFF Research Database (Denmark)

    Haahr, Lærke Tvedebrink; Kepp, Kasper Planeta; Boesen, Jane

    2010-01-01

    with the experimental value (0.25 mm/s) which we propose as the structure of the hydroxylating intermediate, with the tryptophan substrate well located for further reaction 3.5 Å from the ferryl group. Based on the optimized transition states, the activation barriers for the two paths (glu and his) are similar, so......Insight into the nature of oxygen activation in tryptophan hydroxylase has been obtained from density functional computations. Conformations of O2-bound intermediates have been studied with oxygen trans to glutamate and histidine, respectively. An O2-adduct with O2 trans to histidine (Ohis...... towards the cofactor and a more activated O–O bond (1.33 Å) than in Oglu (1.30 Å). It is shown that the cofactor can hydrogen bond to O2 and activate the O–O bond further (from 1.33 to 1.38 Å). The Ohis intermediate leads to a ferryl intermediate (Fhis) with an isomer shift of 0.34 mm/s, also consistent...

  20. Trans-Binding Mechanism of Ubiquitin-like Protein Activation Revealed by a UBA5-UFM1 Complex

    Directory of Open Access Journals (Sweden)

    Walaa Oweis

    2016-09-01

    Full Text Available Modification of proteins by ubiquitin or ubiquitin-like proteins (UBLs is a critical cellular process implicated in a variety of cellular states and outcomes. A prerequisite for target protein modification by a UBL is the activation of the latter by activating enzymes (E1s. Here, we present the crystal structure of the non-canonical homodimeric E1, UBA5, in complex with its cognate UBL, UFM1, and supporting biochemical experiments. We find that UBA5 binds to UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 dimer. This binding mechanism requires a region C-terminal to the adenylation domain that brings UFM1 to the active site of the adjacent UBA5 subunit. We also find that transfer of UFM1 from UBA5 to the E2, UFC1, occurs via a trans mechanism, thereby requiring a homodimer of UBA5. These findings explicitly elucidate the role of UBA5 dimerization in UFM1 activation.

  1. Dopamine receptor activation increases HIV entry into primary human macrophages.

    Directory of Open Access Journals (Sweden)

    Peter J Gaskill

    Full Text Available Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

  2. Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

    Science.gov (United States)

    Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

    2014-01-01

    Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers. PMID:25268786

  3. Similarities and differences in the nucleic acid chaperone activity of HIV-2 and HIV-1 nucleocapsid proteins in vitro.

    Science.gov (United States)

    Pachulska-Wieczorek, Katarzyna; Stefaniak, Agnieszka K; Purzycka, Katarzyna J

    2014-07-03

    The nucleocapsid domain of Gag and mature nucleocapsid protein (NC) act as nucleic acid chaperones and facilitate folding of nucleic acids at critical steps of retroviral replication cycle. The basic N-terminus of HIV-1 NC protein was shown most important for the chaperone activity. The HIV-2 NC (NCp8) and HIV-1 NC (NCp7) proteins possess two highly conserved zinc fingers, flanked by basic residues. However, the NCp8 N-terminal domain is significantly shorter and contains less positively charged residues. This study characterizes previously unknown, nucleic acid chaperone activity of the HIV-2 NC protein. We have comparatively investigated the in vitro nucleic acid chaperone properties of the HIV-2 and HIV-1 NC proteins. Using substrates derived from the HIV-1 and HIV-2 genomes, we determined the ability of both proteins to chaperone nucleic acid aggregation, annealing and strand exchange in duplex structures. Both NC proteins displayed comparable, high annealing activity of HIV-1 TAR DNA and its complementary nucleic acid. Interesting differences between the two NC proteins were discovered when longer HIV substrates, particularly those derived from the HIV-2 genome, were used in chaperone assays. In contrast to NCp7, NCp8 weakly facilitates annealing of HIV-2 TAR RNA to its complementary TAR (-) DNA. NCp8 is also unable to efficiently stimulate tRNALys3 annealing to its respective HIV-2 PBS motif. Using truncated NCp8 peptide, we demonstrated that despite the fact that the N-terminus of NCp8 differs from that of NCp7, this domain is essential for NCp8 activity. Our data demonstrate that the HIV-2 NC protein displays reduced nucleic acid chaperone activity compared to that of HIV-1 NC. We found that NCp8 activity is limited by substrate length and stability to a greater degree than that of NCp7. This is especially interesting in light of the fact that the HIV-2 5'UTR is more structured than that of HIV-1. The reduced chaperone activity observed with NCp8 may

  4. Full trans-activation mediated by the immediate-early protein of equine herpesvirus 1 requires a consensus TATA box, but not its cognate binding sequence.

    Science.gov (United States)

    Kim, Seong K; Shakya, Akhalesh K; O'Callaghan, Dennis J

    2016-01-04

    The immediate-early protein (IEP) of equine herpesvirus 1 (EHV-1) has extensive homology to the IEP of alphaherpesviruses and possesses domains essential for trans-activation, including an acidic trans-activation domain (TAD) and binding domains for DNA, TFIIB, and TBP. Our data showed that the IEP directly interacted with transcription factor TFIIA, which is known to stabilize the binding of TBP and TFIID to the TATA box of core promoters. When the TATA box of the EICP0 promoter was mutated to a nonfunctional TATA box, IEP-mediated trans-activation was reduced from 22-fold to 7-fold. The IEP trans-activated the viral promoters in a TATA motif-dependent manner. Our previous data showed that the IEP is able to repress its own promoter when the IEP-binding sequence (IEBS) is located within 26-bp from the TATA box. When the IEBS was located at 100 bp upstream of the TATA box, IEP-mediated trans-activation was very similar to that of the minimal IE(nt -89 to +73) promoter lacking the IEBS. As the distance from the IEBS to the TATA box decreased, IEP-mediated trans-activation progressively decreased, indicating that the IEBS located within 100 bp from the TATA box sequence functions as a distance-dependent repressive element. These results indicated that IEP-mediated full trans-activation requires a consensus TATA box of core promoters, but not its binding to the cognate sequence (IEBS). Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Antimalarial activity of HIV-1 protease inhibitor in chromone series.

    Science.gov (United States)

    Lerdsirisuk, Pradith; Maicheen, Chirattikan; Ungwitayatorn, Jiraporn

    2014-12-01

    Increasing parasite resistance to nearly all available antimalarial drugs becomes a serious problem to human health and necessitates the need to continue the search for new effective drugs. Recent studies have shown that clinically utilized HIV-1 protease (HIV-1 PR) inhibitors can inhibit the in vitro and in vivo growth of Plasmodium falciparum. In this study, a series of chromone derivatives possessing HIV-1 PR inhibitory activity has been tested for antimalarial activity against P. falciparum (K1 multi-drug resistant strain). Chromone 15, the potent HIV-1 PR inhibitor (IC50=0.65μM), was found to be the most potent antimalarial compound with IC50=0.95μM while primaquine and tafenoquine showed IC50=2.41 and 1.95μM, respectively. Molecular docking study of chromone compounds against plasmepsin II, an aspartic protease enzyme important in hemoglobin degradation, revealed that chromone 15 exhibited the higher binding affinity (binding energy=-13.24kcal/mol) than the known PM II inhibitors. Thus, HIV-1 PR inhibitor in chromone series has the potential to be a new class of antimalarial agent. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. HIV Serosorting, Status Disclosure, and Strategic Positioning Among Highly Sexually Active Gay and Bisexual Men.

    Science.gov (United States)

    Grov, Christian; Rendina, H Jonathon; Moody, Raymond L; Ventuneac, Ana; Parsons, Jeffrey T

    2015-10-01

    Researchers have identified harm reduction strategies that gay, bisexual, and other men who have sex with men (GBMSM) use to reduce HIV transmission--including serosorting, status disclosure, and strategic positioning. We report on patterns of these behaviors among 376 highly sexually active (i.e., 9+partners, positioning; however, rates varied based on the participant's HIV status. HIV-positive and HIV-negative men both engaged in sex with men of similar status more often than they engaged in sex with men known to be a different HIV status (i.e., serosorting). However, HIV-negative men disclosed their HIV-status with about half of their partners, whereas HIV-positive participants disclosed with only about one-third. With regard to strategic positioning, HIV-positive participants were the receptive partner about half the time with their HIV-negative partners and with their HIV-positive partners. In contrast, strategic positioning was very common among HIV-negative participants-they rarely bottomed with HIV-positive partners, bottomed about one-third of the time with status-unknown partners, and 42% of the time (on average) with HIV-negative partners. Highly sexually active GBMSM are a critical population in which to both investigate HIV prevention strategies as well as develop effective intervention programs. Providers and clinicians might be well served to include a wide range of behavioral harm reduction strategies in addition to condom use and biomedical approaches to reduce onward HIV transmission.

  7. Approaching an experimental electron density model of the biologically active trans -epoxysuccinyl amide group-Substituent effects vs. crystal packing

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Ming W.; Stewart, Scott G.; Sobolev, Alexandre N.; Dittrich, Birger; Schirmeister, Tanja; Luger, Peter; Hesse, Malte; Chen, Yu-Sheng; Spackman, Peter R.; Spackman, Mark A.; Grabowsky, Simon (Heinrich-Heine); (Freie); (UC); (Bremen); (JG-UM); (UWA)

    2017-01-24

    The trans-epoxysuccinyl amide group as a biologically active moiety in cysteine protease inhibitors such as loxistatin acid E64c has been used as a benchmark system for theoretical studies of environmental effects on the electron density of small active ingredients in relation to their biological activity. Here, the synthesis and the electronic properties of the smallest possible active site model compound are reported to close the gap between the unknown experimental electron density of trans-epoxysuccinyl amides and the well-known function of related drugs. Intramolecular substituent effects are separated from intermolecular crystal packing effects on the electron density, which allows us to predict the conditions under which an experimental electron density investigation on trans-epoxysuccinyl amides will be possible. In this context, the special importance of the carboxylic acid function in the model compound for both crystal packing and biological activity is revealed through the novel tool of model energy analysis.

  8. Direct interaction of TFIIB and the IE protein of equine herpesvirus 1 is required for maximal trans-activation function

    International Nuclear Information System (INIS)

    Albrecht, Randy A.; Jang, Hyung K.; Kim, Seong K.; O'Callaghan, Dennis J.

    2003-01-01

    Recently, we reported that the immediate-early (IE) protein of equine herpesvirus 1 (EHV-1) associates with transcription factor TFIIB [J. Virol. 75 (2001), 10219]. In the current study, the IE protein purified as a glutathione-S-transferase (GST) fusion protein was shown to interact directly with purified TFIIB in GST-pulldown assays. A panel of TFIIB mutants employed in protein-binding assays revealed that residues 125 to 174 within the first direct repeat of TFIIB mediate its interaction with the IE protein. This interaction is physiologically relevant as transient transfection assays demonstrated that (1) exogenous native TFIIB did not perturb IE protein function, and (2) ectopic expression of a TFIIB mutant that lacked the IE protein interactive domain significantly diminished the ability of the IE protein to trans-activate EHV-1 promoters. These results suggest that an interaction of the IE protein with TFIIB is an important aspect of the regulatory role of the IE protein in the trans-activation of EHV-1 promoters

  9. Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy

    Science.gov (United States)

    Solomon, Ajantha; Ghneim, Khader; Ahlers, Jeffrey; Cameron, Mark J.; Smith, Miranda Z.; Spelman, Tim; McMahon, James; Velayudham, Pushparaj; Brown, Gregor; Roney, Janine; Watson, Jo; Prince, Miles H.; Hoy, Jennifer F.; Chomont, Nicolas; Fromentin, Rémi; Procopio, Francesco A.; Zeidan, Joumana; Palmer, Sarah; Odevall, Lina; Johnstone, Ricky W.; Martin, Ben P.; Sinclair, Elizabeth; Deeks, Steven G.; Hazuda, Daria J.; Cameron, Paul U.; Sékaly, Rafick-Pierre; Lewin, Sharon R.

    2014-01-01

    Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. Trial Registration ClinicalTrials.gov NCT01365065 PMID:25393648

  10. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Julian H Elliott

    2014-10-01

    Full Text Available Human immunodeficiency virus (HIV persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART. The primary endpoint was change in cell associated unspliced (CA-US HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065. Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90% with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1. CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.ClinicalTrials.gov NCT01365065.

  11. Psychometric Factors Affecting Female Employees Physical Activity Status: Applying Trans-Theoretical Model and Theory of Planned Behavior

    Directory of Open Access Journals (Sweden)

    M. Shafieinia

    2015-01-01

    Full Text Available Introduction & Objective: Sedentary women are at risk for problems such as obesity, diabetes, depression and cardiovascular disease. Meanwhile, due to long working hours and excessive travel time from home to work and vice versa the employees have minimal physical activity .The purpose of this study was to investigate the effective psychometric factors on physical activity of female employees, according to the Trans-theoretical Model and theory of planned behavior. Materials & Methods: In this cross-sectional study, 95 female staff of Tehran University was selected through a call. In order to collect data, a questionnaire with acceptable, reliability and validity, including demographic data, and constructs of planned behavior theory as well as Trans-theoretical Model was used. The data was analyzed using SPSS version 21 statisti-cal tests; correlation and stepwise regression were also performed. Results: In this study, 72% of the population was in the inactive stages (pre-contemplation, contemplation and preparation and only 28% of patients had regular physical activity. There was a significant positive correlation between the behavioral intention and attitude scores (P = 0.02, perceived behavioral control (P = 0.000, self-efficacy (P = 0.000 and stage of change (P = 0.000, but subjective norms score (P = 0.605 was irrelevant. Conclusion: The results of this study showed that self-efficacy and perceived behavioral con-trol can affect female employees’ intention and physical activity behaviors. So, the authori-ties should seriously consider these factors in educational planning for this stratum of society, remove barriers for the participation of more employees in sporting activities, and offer fa-cilitators at the community level. (Sci J Hamadan Univ Med Sci 2015; 21(4:350-359

  12. The organization of HIV and other health activities within urban religious congregations.

    Science.gov (United States)

    Palar, Kartika; Mendel, Peter; Derose, Kathryn Pitkin

    2013-10-01

    Most religious congregations in the USA are involved with some type of social service activity, including health activities. However, relatively few formally engage with people with HIV, and many have reported barriers to introducing HIV prevention activities. We conducted a qualitative case study of HIV involvement among 14 urban congregations in Los Angeles County in 2007. In-depth qualitative interviews of lay leaders and clergy were analyzed for themes related to HIV and other health activities, including types of health issues addressed, types of activities conducted, how activities were organized, and the relationship between HIV and other health activities. We identified three primary models representing how congregations organized HIV and other health activities: (1) embedded (n = 7), where HIV activities were contained within other health activities; (2) parallel (n = 5), where HIV and other health activities occurred side by side and were organizationally distinct; (3) overlap (n = 2), where HIV and non-HIV health efforts were conducted by distinct groups, but shared some members and organization. We discuss implications of each model for initiating and sustaining HIV activities within urban congregations over time.

  13. Syndemics and gender affirmation: HIV sexual risk in female-to-male trans masculine adults reporting sexual contact with cisgender males.

    Science.gov (United States)

    Reisner, Sari L; White Hughto, Jaclyn M; Pardee, Dana; Sevelius, Jae

    2016-10-01

    Female-to-male trans masculine adults who have sex with cisgender (non-transgender) males (TMSM) represent an understudied population in relation to HIV/sexually transmitted infection (STI) risk. This study examined the role of syndemic conditions and social gender affirmation processes (living full-time in one's identified gender) in potentiating sexual risk among TMSM adults in Massachusetts, US. Cross-sectional data were restricted to TMSM who reported lifetime sexual behaviour with a cisgender male (n = 173; mean age = 29.4, SD = 9.6; 18.5% people of colour; 93.1% non-heterosexual identity; 56.1% hormones/surgery). Sexual risk outcomes were: lifetime STI diagnoses, three or more sexual partners in the previous six months, and condomless anal/vaginal sex at last encounter with a cisgender male. Age- and survey mode-adjusted logistic regression models regressed sexual risk outcomes on the main effect of syndemics (six indicators summed: binge drinking, substance use, depression, anxiety, childhood abuse, intimate partner violence), followed by the interaction of syndemics and social gender affirmation. Syndemics were associated with increased odds of all sexual risk indicators (adjusted odds ratios [aORs] = 1.32-1.55; p < 0.0001). Social gender affirmation moderated the association between syndemics and condomless anal/vaginal sex at last encounter with a cisgender male (p < 0.0001). Syndemics were associated with sexual risk in TMSM who had socially affirmed their gender (aOR = 1.79; 95% CI = 1.42-2.25; p < 0.001), but not among those TMSM who had not (aOR = 0.86; 95% CI = 0.63-1.19; p = 0.37). Findings suggest that syndemic pathways to sexual risk are similar for TMSM who have socially gender affirmed as for cisgender MSM. Integration of syndemics and gender affirmation frameworks is recommended in interventions to address TMSM sexual risk. © The Author(s) 2016.

  14. High levels of T lymphocyte activation in Leishmania-HIV-1 co-infected individuals despite low HIV viral load

    Directory of Open Access Journals (Sweden)

    Grinsztejn Beatriz

    2010-12-01

    Full Text Available Abstract Background Concomitant infections may influence HIV progression by causing chronic activation leading to decline in T-cell function. In the Americas, visceral (AVL and tegumentary leishmaniasis (ATL have emerged as important opportunistic infections in HIV-AIDS patients and both of those diseases have been implicated as potentially important co-factors in disease progression. We investigated whether leishmaniasis increases lymphocyte activation in HIV-1 co-infected patients. This might contribute to impaired cellular immune function. Methods To address this issue we analyzed CD4+ T absolute counts and the proportion of CD8+ T cells expressing CD38 in Leishmania/HIV co-infected patients that recovered after anti-leishmanial therapy. Results We found that, despite clinical remission of leishmaniasis, AVL co-infected patients presented a more severe immunossupression as suggested by CD4+ T cell counts under 200 cells/mm3, differing from ATL/HIV-AIDS cases that tends to show higher lymphocytes levels (over 350 cells/mm3. Furthermore, five out of nine, AVL/HIV-AIDS presented low CD4+ T cell counts in spite of low or undetectable viral load. Expression of CD38 on CD8+ T lymphocytes was significantly higher in AVL or ATL/HIV-AIDS cases compared to HIV/AIDS patients without leishmaniasis or healthy subjects. Conclusions Leishmania infection can increase the degree of immune system activation in individuals concomitantly infected with HIV. In addition, AVL/HIV-AIDS patients can present low CD4+ T cell counts and higher proportion of activated T lymphocytes even when HIV viral load is suppressed under HAART. This fact can cause a misinterpretation of these laboratorial markers in co-infected patients.

  15. In vitro separation and expansion of CD4 lymphocytes from HIV-infected individuals without activation of HIV infection

    DEFF Research Database (Denmark)

    Nielsen, S D; Nielsen, Jens Ole; Hansen, J E

    1997-01-01

    In order to offer a gene therapy-based treatment against AIDS, it is likely to be necessary to harvest and culture CD4 cells from HIV-positive patients without activating the HIV infection. We have used a magnetic cell sorting (MACS) system to enrich CD4 cells. Using positive selection, CD4 cells...

  16. The Effect of Trans-Chalcone on Amylase Activity, Blood Glucose and Lipid Levels in Diabetic and Non Diabetic Rats

    Directory of Open Access Journals (Sweden)

    M Najafian

    2011-04-01

    Full Text Available Introduction & Objective: Alpha amylase is the most important decomposing enzyme in starch. Digestion and absorption of starch in the intestine can be prevented and also the blood sugar levels can be controlled by restrain and control of alpha amylase. The aim of this study was to evaluate the effect of trans-chalcone on amylase activity, blood glucose and lipid levels in diabetic and non diabetic rats. Materials & Methods: This experimental study was conducted in 1388 at Tehran University of Medical Sciences. Sixty rats were randomly divided to ten equal groups: non diabetic control, diabetic control, four non diabetic experiments and four diabetic experiments. Control groups received grape seed oil and experimental groups received 2, 8,16 and 32 mg/kg of body weight in a period of 24 days with a gastric cannula. Blood sugar, every two days, serum insulin levels in days 0,12, and 24 and at the end of the experiment, lipoproteins and alpha amylase activity were measured.The data were analyzed by one way analysis of variance, ANOVA, followed by Turkey,s test with SPSS soft ware . Results: On average Chalcone reduced 25.5% of blood sugar in normal and diabetic rats. IT also decreased the serum insulin level. On average, chalcone decreased 34.9% of alpha amylase activity in normal and diabetic rats. Following disturbances in lipids metabolism caused by diabetes, this drug improved lipoproteins metabolism and reduced water, food and urine volume. Conclusion: This study shows that trans-Chalcone reduces blood sugar and body weight via inhibition of alpha amylas. Moreover, improvement of lipoprotein metabolism may happen via the inhibitory effect of this drug on hydroxyl methyl glutaryl -COA reductase and phosphodiesterase.

  17. Synthesis, Crystal Structure, and Biological Activity of cis/trans Amide Rotomers of (Z-N′-(2-Oxoindolin-3-ylideneformohydrazide

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    Hatem A. Abdel-Aziz

    2014-01-01

    Full Text Available (Z-N′-(2-Oxoindolin-3-ylideneformohydrazide (2 was synthesized by the reaction of (Z-3-hydrazonoindolin-2-one (1 with formic acid under reflux. The structure of 2 was characterized by IR, Mass, 1H NMR, and X-ray crystal structure determination. Interestingly, compound 2 appeared in DMSO-d6 as cis and trans amide rotomers in 25% and 75%, respectively. The X-ray analysis showed the Z geometrical isomer of 2 around –C=N– for cis and trans amide rotomers. The crystal of 2 belongs to monoclinic, space group P21/c, with a=4.5206 (1 Å, b=22.4747 (7 Å, c=17.3637 (5 Å, β=103.752 (1°, Z=8, V=1713.57 (8 Å3, Dc=1.467 Mg m−3, μ=0.11 mm−1, F(000=784, R=0.047, and wR=0.123 for 3798 observed reflections with I>2σ(I. Compound 2 exhibited a moderate activity in its antimicrobial evaluation against E. coli and P. aeruginosa and a good activity against S. aureus close to that of the standard drug ciprofloxacin. The in vitro anticancer activity of 2 was evaluated against two human tumor cell lines, namely, HepG2 hepatocellular carcinoma and MCF-7 breast cancer. HepG2 cancer cell line was more susceptible to compound 2 than MCF-7.

  18. Stigma, activism, and well-being among people living with HIV.

    Science.gov (United States)

    Earnshaw, Valerie A; Rosenthal, Lisa; Lang, Shawn M

    2016-01-01

    Evidence demonstrates that HIV stigma undermines the psychological and physical health of people living with HIV (PLWH). Yet, PLWH describe engaging in HIV activism to challenge stigma, and research suggests that individuals may benefit from activism. We examine associations between experiences of HIV stigma and HIV activism, and test whether HIV activists benefit from greater well-being than non-activists. Participants include 93 PLWH recruited from drop-in centers, housing programs, and other organizations providing services to PLWH in the Northeastern USA between 2012 and 2013 (mean age = 50 years; 56% Black, 20% White, 18% Other; 61% non-Latino(a), 39% Latino(a); 59% male, 38% female, 3% transgender; 82% heterosexual, 15% sexual minority). Participants completed a cross-sectional written survey. Results of regression analyses suggest that PLWH who experienced greater enacted stigma engaged in greater HIV activism. Anticipated, internalized, and perceived public stigma, however, were unrelated to HIV activism. Moreover, results of a multivariate analysis of variance suggest that HIV activists reported greater social network integration, greater social well-being, greater engagement in active coping with discrimination, and greater meaning in life than non-activists. Yet, HIV activists also reported somewhat greater depressive symptoms than non-activists, suggesting that the association between HIV activism and well-being is complex. By differentiating between HIV stigma mechanisms, the current study provides a more nuanced understanding of which experiences of HIV stigma may be associated with HIV activism. It further suggests that engagement in activism may offer benefits to PLWH, while raising the possibility that activists could experience greater depressive symptoms than non-activists. Given the preliminary nature of this study, future research should continue to examine these complex associations between HIV stigma, activism, and well-being among PLWH

  19. International trade law, plain packaging and tobacco industry political activity: the Trans-Pacific Partnership

    Science.gov (United States)

    Fooks, Gary; Gilmore, Anna B

    2014-01-01

    Tobacco companies are increasingly turning to trade and investment agreements to challenge measures aimed at reducing tobacco use. This study examines their efforts to influence the Trans-Pacific Partnership (TPP), a major trade and investment agreement which may eventually cover 40% of the world's population; focusing on how these efforts might enhance the industry's power to challenge the introduction of plain packaging. Specifically, the paper discusses the implications for public health regulation of Philip Morris International's interest in using the TPP to: shape the bureaucratic structures and decision-making processes of business regulation at the national level; introduce a higher standard of protection for trademarks than is currently provided under the Agreement on Trade Related Aspects of Intellectual Property Rights; and expand the coverage of Investor-State Dispute Settlement which empowers corporations to litigate directly against governments where they are deemed to be in breach of investment agreements. The large number of countries involved in the TPP underlines its risk to the development of tobacco regulation globally. PMID:23788606

  20. International trade law, plain packaging and tobacco industry political activity: the Trans-Pacific Partnership.

    Science.gov (United States)

    Fooks, Gary; Gilmore, Anna B

    2014-01-01

    Tobacco companies are increasingly turning to trade and investment agreements to challenge measures aimed at reducing tobacco use. This study examines their efforts to influence the Trans-Pacific Partnership (TPP), a major trade and investment agreement which may eventually cover 40% of the world's population; focusing on how these efforts might enhance the industry's power to challenge the introduction of plain packaging. Specifically, the paper discusses the implications for public health regulation of Philip Morris International's interest in using the TPP to: shape the bureaucratic structures and decision-making processes of business regulation at the national level; introduce a higher standard of protection for trademarks than is currently provided under the Agreement on Trade Related Aspects of Intellectual Property Rights; and expand the coverage of Investor-State Dispute Settlement which empowers corporations to litigate directly against governments where they are deemed to be in breach of investment agreements. The large number of countries involved in the TPP underlines its risk to the development of tobacco regulation globally.

  1. Program collaboration and service integration activities among HIV programs in 59 U.S. health departments.

    Science.gov (United States)

    Fitz Harris, Lauren F; Toledo, Lauren; Dunbar, Erica; Aquino, Gustavo A; Nesheim, Steven R

    2014-01-01

    We identified the level and type of program collaboration and service integration (PCSI) among HIV prevention programs in 59 CDC-funded health department jurisdictions. Annual progress reports (APRs) completed by all 59 health departments funded by CDC for HIV prevention activities were reviewed for collaborative and integrated activities reported by HIV programs for calendar year 2009. We identified associations between PCSI activities and funding, AIDS diagnosis rate, and organizational integration. HIV programs collaborated with other health department programs through data-related activities, provider training, and providing funding for sexually transmitted disease (STD) activities in 24 (41%), 31 (53%), and 16 (27%) jurisdictions, respectively. Of the 59 jurisdictions, 57 (97%) reported integrated HIV and STD testing at the same venue, 39 (66%) reported integrated HIV and tuberculosis testing, and 26 (44%) reported integrated HIV and viral hepatitis testing. Forty-five (76%) jurisdictions reported providing integrated education/outreach activities for HIV and at least one other disease. Twenty-six (44%) jurisdictions reported integrated partner services among HIV and STD programs. Overall, the level of PCSI activities was not associated with HIV funding, AIDS diagnoses, or organizational integration. HIV programs in health departments collaborate primarily with STD programs. Key PCSI activities include integrated testing, integrated education/outreach, and training. Future assessments are needed to evaluate PCSI activities and to identify the level of collaboration and integration among prevention programs.

  2. Synthesis, DFT and antimicrobial activity assays in vitro for novel cis/trans-but-2-enedioic acid esters

    Science.gov (United States)

    Ma, Yan-Long; Zhou, Ru-Jin; Zeng, Xing-Ye; An, Ya-Xiong; Qiu, Song-Shan; Nie, Li-Jun

    2014-04-01

    Six novel cis/trans-but-2-enedioic acid esters had been synthesized to discover the new bioactive molecules that could kill food-related bacteria and fungi. Their structures were analyzed by melting point, LC-MS, 1H NMR and 13C NMR. 4-(Methoxycarbonyl) phenyl ethyl fumarate (6b) was also characterized by single-crystal X-ray diffraction. Their antimicrobial activities were evaluated in vitro by measuring the minimal inhibitory concentration (MIC). Compared with the single monomethyl fumarate and methyl 4-hydroxybenzoate, these compounds had stronger antimicrobial activity against all the eight microorganisms. Among the antibacterial and antifungal compounds, 4-(methoxycarbonyl) phenyl methyl fumarate (6a) showed the best antimicrobial activity. The electronic properties of these compounds were calculated by the density functional theory (DFT) method with 6-31G (d, p) basis set. DFT studies indicated that molecular electrostatic potential (MEP) map, ELUMO, energy gap, electronegativity and electrophilicity index could be helpful to understand the various antimicrobial activities among these compounds. The antimicrobial activity of compound 6a was evaluated in vitro against Salmonellacholeraesuis subsp. choleraesuis, Lactococcus lactis subsp. lactis and Saccharomyces cerevisiae by time-kill, and it was found that compound 6a exhibited significant microbiocidal activity against the three microorganisms.

  3. Dyslipidemia in HIV Infected Children Receiving Highly Active Antiretroviral Therapy.

    Science.gov (United States)

    Mandal, Anirban; Mukherjee, Aparna; Lakshmy, R; Kabra, Sushil K; Lodha, Rakesh

    2016-03-01

    To assess the prevalence of dyslipidemia and lipodystrophy in Indian children receiving non-nucleoside reverse transcriptase inhibitor (NNRTI) based highly active antiretroviral therapy (HAART) and to determine the associated risk factors for the same. The present cross-sectional study was conducted at a Pediatric Clinic of a tertiary care teaching center in India, from May 2011 through December 2012. HIV infected children aged 5-15 y were enrolled if they did not have any severe disease or hospital admission within last 3 mo or receive any medications known to affect the lipid profile. Eighty-one children were on highly active antiretroviral therapy (HAART) for at least 6 mo and 16 were receiving no antiretroviral therapy (ART). Participants' sociodemographic, nutritional, clinical, and laboratory data were recorded in addition to anthropometry and evidence of lipodystrophy. Fasting lipid profile, apolipoprotein A1 and B levels were done for all the children. Among the children on highly active antiretroviral therapy (HAART), 38.3 % had dyslipidemia and 80.2 % had lipodystrophy, while 25 % antiretroviral therapy (ART) naïve HIV infected children had dyslipidemia. No clinically significant risk factors could be identified that increased the risk of dyslipidemia or lipodystrophy in children on highly active antiretroviral therapy (HAART). There is a high prevalence of dyslipidemia and lipodystrophy in Indian children with HIV infection with an imminent need to establish facilities for testing and treatment of these children for metabolic abnormalities.

  4. Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling

    Science.gov (United States)

    Sears, James C.; Broadie, Kendal

    2018-01-01

    Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. The disease arises through loss of fragile X mental retardation protein (FMRP), which normally exhibits peak expression levels in early-use critical periods, and is required for activity-dependent synaptic remodeling during this transient developmental window. FMRP canonically binds mRNA to repress protein translation, with targets that regulate cytoskeleton dynamics, membrane trafficking, and trans-synaptic signaling. We focus here on recent advances emerging in these three areas from the Drosophila disease model. In the well-characterized central brain mushroom body (MB) olfactory learning/memory circuit, FMRP is required for activity-dependent synaptic remodeling of projection neurons innervating the MB calyx, with function tightly restricted to an early-use critical period. FMRP loss is phenocopied by conditional removal of FMRP only during this critical period, and rescued by FMRP conditional expression only during this critical period. Consistent with FXS hyperexcitation, FMRP loss defects are phenocopied by heightened sensory experience and targeted optogenetic hyperexcitation during this critical period. FMRP binds mRNA encoding Drosophila ESCRTIII core component Shrub (human CHMP4 homolog) to restrict Shrub translation in an activity-dependent mechanism only during this same critical period. Shrub mediates endosomal membrane trafficking, and perturbing Shrub expression is known to interfere with neuronal process pruning. Consistently, FMRP loss and Shrub overexpression targeted to projection neurons similarly causes endosomal membrane trafficking defects within synaptic boutons, and genetic reduction of Shrub strikingly rescues Drosophila FXS model defects. In parallel work on the well-characterized giant fiber (GF) circuit, FMRP limits iontophoretic dye loading into central interneurons, demonstrating an FMRP role controlling core neuronal properties through the

  5. Systemic Immune Activation and HIV Shedding in the Female Genital Tract.

    Science.gov (United States)

    Spencer, LaShonda Y; Christiansen, Shawna; Wang, Chia-Hao H; Mack, Wendy J; Young, Mary; Strickler, Howard D; Anastos, Kathryn; Minkoff, Howard; Cohen, Mardge; Geenblatt, Ruth M; Karim, Roksana; Operskalski, Eva; Frederick, Toni; Homans, James D; Landay, Alan; Kovacs, Andrea

    2016-02-01

    Plasma HIV RNA is the most significant determinant of cervical HIV shedding. However, shedding is also associated with sexually transmitted infections (STIs) and cervical inflammation. The mechanism by which this occurs is poorly understood. There is evidence that systemic immune activation promotes viral entry, replication, and HIV disease progression. We hypothesized that systemic immune activation would be associated with an increase in HIV genital shedding. Clinical assessments, HIV RNA in plasma and genital secretions, and markers of immune activation (CD38(+)DR(+) and CD38(-)DR(-)) on CD4(+) and CD8(+) T cells in blood were evaluated in 226 HIV+ women enrolled in the Women's Interagency HIV Study. There were 569 genital evaluations of which 159 (28%) exhibited HIV RNA shedding, defined as HIV viral load >80 copies per milliliter. We tested associations between immune activation and shedding using generalized estimating equations with logit link function. In the univariate model, higher levels of CD4(+) and CD8(+) T-cell activation in blood were significantly associated with genital tract shedding. However, in the multivariate model adjusting for plasma HIV RNA, STIs, and genital tract infections, only higher levels of resting CD8(+) T cells (CD38(-)DR(-)) were significantly inversely associated with HIV shedding in the genital tract (odds ratios = 0.44, 95% confidence interval: 0.21 to 0.9, P = 0.02). The association of systemic immune activation with genital HIV shedding is multifactorial. Systemic T-cell activation is associated with genital tract shedding in univariate analysis but not when adjusting for plasma HIV RNA, STIs, and genital tract infections. In addition, women with high percentage of resting T cells are less likely to have HIV shedding compared with those with lower percentages. These findings suggest that a higher percentage of resting cells, as a result of maximal viral suppression with treatment, may decrease local genital activation, HIV

  6. HIV-induced immune activation - pathogenesis and clinical relevance

    Directory of Open Access Journals (Sweden)

    Stellbrink HJ

    2010-01-01

    Full Text Available Abstract This manuscript is communicated by the German AIDS Society (DAIG http://www.daignet.de. It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V..

  7. Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-Neuronal–Glial Stimulation of Excitatory GABA Circuits

    Science.gov (United States)

    Haam, Juhee; Halmos, Katalin C.; Di, Shi

    2014-01-01

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal–glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal–glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal–glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

  8. HIV Risk Behavior and Access to Services: What Predicts HIV Testing among Heterosexually Active Homeless Men?

    Science.gov (United States)

    Wenzel, Suzanne L.; Rhoades, Harmony; Tucker, Joan S.; Golinelli, Daniela; Kennedy, David P.; Zhou, Annie; Ewing, Brett

    2012-01-01

    HIV is a serious epidemic among homeless persons, where rates of infection are estimated to be three times higher than in the general population. HIV testing is an effective tool for reducing HIV transmission and for combating poor HIV/AIDS health outcomes that disproportionately affect homeless persons, however, little is known about the HIV…

  9. Hili Inhibits HIV Replication in Activated T Cells.

    Science.gov (United States)

    Peterlin, B Matija; Liu, Pingyang; Wang, Xiaoyun; Cary, Daniele; Shao, Wei; Leoz, Marie; Hong, Tian; Pan, Tao; Fujinaga, Koh

    2017-06-01

    P-element-induced wimpy-like (Piwil) proteins restrict the replication of mobile genetic elements in the germ line. They are also expressed in many transformed cell lines. In this study, we discovered that the human Piwil 2 (Hili) protein can also inhibit HIV replication, especially in activated CD4 + T cells that are the preferred target cells for this virus in the infected host. Although resting cells did not express Hili, its expression was rapidly induced following T cell activation. In these cells and transformed cell lines, depletion of Hili increased levels of viral proteins and new viral particles. Further studies revealed that Hili binds to tRNA. Some of the tRNAs represent rare tRNA species, whose codons are overrepresented in the viral genome. Targeting tRNA Arg (UCU) with an antisense oligonucleotide replicated effects of Hili and also inhibited HIV replication. Finally, Hili also inhibited the retrotransposition of the endogenous intracysternal A particle (IAP) by a similar mechanism. Thus, Hili joins a list of host proteins that inhibit the replication of HIV and other mobile genetic elements. IMPORTANCE Piwil proteins inhibit the movement of mobile genetic elements in the germ line. In their absence, sperm does not form and male mice are sterile. This inhibition is thought to occur via small Piwi-interacting RNAs (piRNAs). However, in some species and in human somatic cells, Piwil proteins bind primarily to tRNA. In this report, we demonstrate that human Piwil proteins, especially Hili, not only bind to select tRNA species, including rare tRNAs, but also inhibit HIV replication. Importantly, T cell activation induces the expression of Hili in CD4 + T cells. Since Hili also inhibited the movement of an endogenous retrovirus (IAP), our finding shed new light on this intracellular resistance to exogenous and endogenous retroviruses as well as other mobile genetic elements. Copyright © 2017 American Society for Microbiology.

  10. Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2.

    Directory of Open Access Journals (Sweden)

    Bin Jia

    2009-05-01

    Full Text Available Tetherin, also known as BST2, CD317 or HM1.24, was recently identified as an interferon-inducible host-cell factor that interferes with the detachment of virus particles from infected cells. HIV-1 overcomes this restriction by expressing an accessory protein, Vpu, which counteracts tetherin. Since lentiviruses of the SIV(smm/mac/HIV-2 lineage do not have a vpu gene, this activity has likely been assumed by other viral gene products. We found that deletion of the SIV(mac239 nef gene significantly impaired virus release in cells expressing rhesus macaque tetherin. Virus release could be restored by expressing Nef in trans. However, Nef was unable to facilitate virus release in the presence of human tetherin. Conversely, Vpu enhanced virus release in the presence of human tetherin, but not in the presence of rhesus tetherin. In accordance with the species-specificity of Nef in mediating virus release, SIV Nef downregulated cell-surface expression of rhesus tetherin, but did not downregulate human tetherin. The specificity of SIV Nef for rhesus tetherin mapped to four amino acids in the cytoplasmic domain of the molecule that are missing from human tetherin, whereas the specificity of Vpu for human tetherin mapped to amino acid differences in the transmembrane domain. Nef alleles of SIV(smm, HIV-2 and HIV-1 were also able to rescue virus release in the presence of both rhesus macaque and sooty mangabey tetherin, but were generally ineffective against human tetherin. Thus, the ability of Nef to antagonize tetherin from these Old World primates appears to be conserved among the primate lentiviruses. These results identify Nef as the viral gene product of SIV that opposes restriction by tetherin in rhesus macaques and sooty mangabeys, and reveal species-specificity in the activities of both Nef and Vpu in overcoming tetherin in their respective hosts.

  11. Analysis of serum adenosine deaminase (ADA) and ADA1 and ADA2 isoenzyme activities in HIV positive and HIV-HBV co-infected patients.

    Science.gov (United States)

    Khodadadi, Iraj; Abdi, Mohammad; Ahmadi, Abbas; Wahedi, Mohammad Saleh; Menbari, Shahoo; Lahoorpour, Fariba; Rahbari, Rezgar

    2011-08-01

    To determine adenosine deaminase (ADA) activity as a possible diagnostic marker in HIV and HIV-HBV co-infected patients. Blood samples were collected from 72 healthy, 33 HIV positive and 30 HIV-HBV co-infected subjects. Blood CD4+ cell count was recorded and serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total ADA, and ADA1 and ADA2 isoenzyme activities were determined. Serum ALT, AST, total ADA and ADA2 isoenzyme activities were significantly higher in HIV positive and HIV-HBV co-infected groups compare to the control (pADA activities (R(2)=0.589, pADA was significantly increased in HIV and HIV-HBV co-infections. Therefore, because of its low cost and simplicity to perform, ADA activity might be considered as a useful diagnostic tool among the other markers in these diseases. Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  12. CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection

    DEFF Research Database (Denmark)

    Buggert, Marcus; Frederiksen, Juliet Wairimu; Lund, Ole

    2016-01-01

    cells are linked to such outcome. DESIGN: HIV-seronegative (n=25), HIV-1 (n?=?33), HIV-2 (n?=?39, of whom 26 were aviremic), and HIV-1/2 dually (HIV-D) (n?=?13) infected subjects were enrolled from an occupational cohort in Guinea-Bissau. METHODS:: CD4+ T cell differentiation, activation, exhaustion......, senescence, and transcription factors were assessed by polychromatic flow cytometry. Multidimensional clustering bioinformatic tools were used to identify CD4+ T cell subpopulations linked to infection type and disease stage. RESULTS: HIV-2-infected individuals had early- and late-differentiated CD4+ T cell...... clusters with lower activation (CD38+HLA-DR+) and exhaustion (PD-1) than HIV-1 and HIV-D-infected subjects. We also noted that aviremic HIV-2-infected individuals possessed fewer CD4+ T cells with pathological signs compared to other HIV-infected groups. Still, compared to HIV-seronegatives, aviremic HIV-2...

  13. A trans-activator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNA

    International Nuclear Information System (INIS)

    Caselmann, W.H.; Meyer, M.; Kekule, A.S.; Lauer, U.; Hofschneider, P.H.; Koshy, R.

    1990-01-01

    The X gene of wild-type hepatitis B virus or integrated DNA has recently been shown to stimulate transcription of a variety of enhancers and promoters. To further delineate the viral sequences responsible for trans-activation in hepatomas, the authors cloned the single hepatitis B virus insert from human hepatocellular carcinoma DNA M1. The plasmid pM1 contains 2004 base of hepatitis B virus DNA subtype adr, including truncated preS/S sequences and the enhancer element. The X promoter and 422 nucleotides of the X coding region are present. The entire preC/C gene is deleted. In transient cotransfection assays using Chang liver cells (CCL 13), pM1 DNA exerts a 6- to 10-fold trans-activating effect on the expression of the pSV2CAT reporter plasmid. The transactivation occurs by stimulation of transcription and is dependent on the simian virus 40 enhancer in the reporter plasmid. Deletion analysis of pM1 subclones reveals that the transactivator is encoded by preS/S and not by X sequences. A frameshift mutation within the preS2 open reading frame shows that this portion is indispensable for the trans-activating function. Initiation of transcription has been mapped to the S1 promoter. A comparable trans-activating effect is also observed with cloned wild-type hepatitis B virus sequences similarly truncated. These results show that a transcriptional trans-activator function not present in the intact gene is generated by 3' truncation of integrated hepatitis B virus DNA preS/S sequences

  14. Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

    International Nuclear Information System (INIS)

    Iordanskiy, Sergey; Van Duyne, Rachel; Sampey, Gavin C; Woodson, Caitlin M; Fry, Kelsi; Saifuddin, Mohammed; Guo, Jia; Wu, Yuntao; Romerio, Fabio; Kashanchi, Fatah

    2015-01-01

    The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4"+ T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4"+ T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4"+ T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells. - Highlights: • X-ray irradiation (IR) increases

  15. Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

    Energy Technology Data Exchange (ETDEWEB)

    Iordanskiy, Sergey [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Van Duyne, Rachel [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Sampey, Gavin C; Woodson, Caitlin M; Fry, Kelsi; Saifuddin, Mohammed; Guo, Jia; Wu, Yuntao [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Romerio, Fabio [Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Kashanchi, Fatah, E-mail: fkashanc@gmu.edu [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States)

    2015-11-15

    The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4{sup +} T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4{sup +} T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4{sup +} T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells. - Highlights: • X-ray irradiation

  16. Noninvasive High-Throughput Single-Cell Analysis of HIV Protease Activity Using Ratiometric Flow Cytometry

    Directory of Open Access Journals (Sweden)

    Rok Gaber

    2013-11-01

    Full Text Available To effectively fight against the human immunodeficiency virus infection/ acquired immunodeficiency syndrome (HIV/AIDS epidemic, ongoing development of novel HIV protease inhibitors is required. Inexpensive high-throughput screening assays are needed to quickly scan large sets of chemicals for potential inhibitors. We have developed a Förster resonance energy transfer (FRET-based, HIV protease-sensitive sensor using a combination of a fluorescent protein pair, namely mCerulean and mCitrine. Through extensive in vitro characterization, we show that the FRET-HIV sensor can be used in HIV protease screening assays. Furthermore, we have used the FRET-HIV sensor for intracellular quantitative detection of HIV protease activity in living cells, which more closely resembles an actual viral infection than an in vitro assay. We have developed a high-throughput method that employs a ratiometric flow cytometry for analyzing large populations of cells that express the FRET-HIV sensor. The method enables FRET measurement of single cells with high sensitivity and speed and should be used when subpopulation-specific intracellular activity of HIV protease needs to be estimated. In addition, we have used a confocal microscopy sensitized emission FRET technique to evaluate the usefulness of the FRET-HIV sensor for spatiotemporal detection of intracellular HIV protease activity.

  17. Noninvasive High-Throughput Single-Cell Analysis of HIV Protease Activity Using Ratiometric Flow Cytometry

    Science.gov (United States)

    Gaber, Rok; Majerle, Andreja; Jerala, Roman; Benčina, Mojca

    2013-01-01

    To effectively fight against the human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) epidemic, ongoing development of novel HIV protease inhibitors is required. Inexpensive high-throughput screening assays are needed to quickly scan large sets of chemicals for potential inhibitors. We have developed a Förster resonance energy transfer (FRET)-based, HIV protease-sensitive sensor using a combination of a fluorescent protein pair, namely mCerulean and mCitrine. Through extensive in vitro characterization, we show that the FRET-HIV sensor can be used in HIV protease screening assays. Furthermore, we have used the FRET-HIV sensor for intracellular quantitative detection of HIV protease activity in living cells, which more closely resembles an actual viral infection than an in vitro assay. We have developed a high-throughput method that employs a ratiometric flow cytometry for analyzing large populations of cells that express the FRET-HIV sensor. The method enables FRET measurement of single cells with high sensitivity and speed and should be used when subpopulation-specific intracellular activity of HIV protease needs to be estimated. In addition, we have used a confocal microscopy sensitized emission FRET technique to evaluate the usefulness of the FRET-HIV sensor for spatiotemporal detection of intracellular HIV protease activity. PMID:24287545

  18. The Determination of Physical Activity among Girl Adolescents based on Trans-theoretical model (TTM

    Directory of Open Access Journals (Sweden)

    Masoumeh Alidosti

    2017-07-01

    Full Text Available Background It has been proved that physical activity has positive effects for all people. However, low activity is common among adolescents especially girl teenagers. The present study aimed to determine the condition of physical activity among girl adolescents by use of the stages of change derived from Trantheoretical model (TTM. Materials and Methods: This descriptive- analytical investigation was done (in 2016 and 2017 school year in the first – round girl high school among 324 students studying in state schools of Shahrekord city (Western Iran. They were selected through clustering method. The data were collected by researcher-made questionnaires including demographic characteristics, knowledge construct and the stages of change (pre-contemplation, contemplation, preparation, action and maintenance. The collected data were analyzed by SPSS (version 18.0. Results The mean age of participants was 13.69+ 1.95 years old. The mean score of girls' knowledge about types of physical activity was 53.18± 21.82 (a total of 100 scores, which represents the average level of knowledge among them. The study of physical activity in students based on stages of change showed that 165 ones (43 %, 102 ones (26.6 % and only 22 ones (5.7 % of the studied students were in precontemplation, contemplation and maintenance stages, respectively. There was a significant relation between students' knowledge level and their mothers' age (P

  19. A Trans-Theoretical Approach to Physical Activity Profile in General Population of Mashhad

    Science.gov (United States)

    Shaye, Zahra Abbasi; Bazzaz, Mojtaba Mousavi; Vakili, Veda

    2015-01-01

    Regular physical-activity is necessity for a healthy lifestyle. Despite public health efforts, a minority of population are involved in healthy levels of physical-activity. This study provides evidence about exercise patterns and predictors of Mashhad-Iran population according to TTM change stages. In this cross-sectional study, we surveyed a total number of 564 participants from Mashhad in 2014 by using stages of change questionnaire. Analysis showed 23.4% of participants were in pre-contemplation stage, 18 in contemplation, 24.6% in preparation, 8.10% in action, 14.4% in maintenance and 11.5% were in termination phase. Age, gender, BMI, alcohol consumption, sleep duration, having compeer and encouragement were identified as predictors of pre-contemplation stage. Genders, having company and using bicycle for transportation were predictors of termination phase. Tailor interventions based on the predictors to enhance the physical activity among specific subgroups would be of interest. PMID:26153203

  20. Increased catalase activity by all-trans retinoic acid and its effect on radiosensitivity in rat glioma cells

    International Nuclear Information System (INIS)

    Jin, Hua; Jeon, Ha Yeun; Park, Woo Yoon; Kim, Won Dong; Ahn, Hee Yul; Yu, Jae Ran

    2005-01-01

    It has been reported that all-trans retinoic acid (ATRA) can inhibit glioma growing in vitro. However, clinical trials with ATRA alone in gliomas revealed modest results. ATRA has been shown to increase radiosensitivity in other tumor types, so combining radiation and ATRA would be one of alternatives to increase therapeutic efficacy in malignant gliomas. Thus, we intended to know the role of catalase, which is induced by ATRA, for radiosensitivity. If radiation-reduced reactive oxygen species (ROS) is removed by catalase, the effect of radiation will be reduced. A rat glioma cell line (36B10) was used for this study. The change of catalase activity and radiosensitivity by ATRA, with or without 3-amino-1, 2, 4-triazole (ATZ), a chemical inhibitor of catalase were measured. Catalase activity was measured by the decomposition of H 2 O 2 spectrophotometrically. Radiosensitivity was measured with clonogenic assay. Also ROS was measured using a 2, 7-dichlorofluores-cein diacetate spectrophotometrically. When 36B10 cells were exposed to 10, 25 and 50 μ M of ATRA for 48 h, the expression of catalase activity were increased with increasing concentration and incubation time of ATRA. Catalase activity was decreased with increasing the concentration of AT (1, 10 mM) dose-dependently. ROS was increased with ATRA and it was augmented with the combination of ATRA and radiation. ATZ decreased ROS production and increased cell survival in combination of ATRA and radiation despite the reduction of catalase. The increase of ROS is one of the reasons for the increased radiosensitivity in combination with ATRA. The catalase that is induced by ATRA doesn't decrease ROS production and radiosensitivity

  1. AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer.

    Science.gov (United States)

    Tian, Ying; Wang, Genjie; Hu, Qingzhu; Xiao, Xichun; Chen, Shuxia

    2018-04-01

    The AML1/ETO onco-fusion protein is crucial for the genesis of t(8;21) acute myeloid leukemia (AML) and is well documented as a transcriptional repressor through dominant-negative effect. However, little is known about the transactivation mechanism of AML1/ETO. Through large cohort of patient's expression level data analysis and a series of experimental validation, we report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. Gene expression analyses verify that c-KIT expression is significantly high in t(8;21) AML. Further ChIP-seq analysis and motif scanning identify two regulatory regions located in the promoter and intronic enhancer region of c-KIT, respectively. Both regions are enriched by co-factors of AML1/ETO, such as AML1, CEBPe, c-Jun, and c-Fos. Further luciferase reporter assays show that AML1/ETO trans-activates c-KIT promoter activity through directly recognizing the AML1 motif and the co-existence of co-factors. The induction of c-KIT promoter activity is reinforced with the existence of intronic enhancer region. Furthermore, ChIP-3C-qPCR assays verify that AML1/ETO mediates the formation of DNA-looping between the c-KIT promoter and intronic enhancer region through the long-range interaction. Collectively, our data uncover a novel transcriptional activity mechanism of AML1/ETO and enrich our knowledge of the onco-fusion protein mediated transcription regulation. © 2017 Wiley Periodicals, Inc.

  2. Creating Trans-Inclusive Schools: Introductory Activities That Enhance the Critical Consciousness of Future Educators

    Science.gov (United States)

    De Pedro, Kris Tunac; Jackson, Christopher; Campbell, Erin; Gilley, Jade; Ciarelli, Brock

    2016-01-01

    The Lawrence King murder and other tragedies surrounding transgender youth have prompted a national discussion about the need for schools to be more supportive and inclusive of transgender students. In this multi-authored reflection, the authors describe a series of three introductory activities in an undergraduate educational studies course aimed…

  3. Imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV-1.

    Science.gov (United States)

    Gudmundsson, Kristjan S; Boggs, Sharon D; Catalano, John G; Svolto, Angilique; Spaltenstein, Andrew; Thomson, Michael; Wheelan, Pat; Jenkinson, Stephen

    2009-11-15

    Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several compounds with low nanomolar anti-HIV activity and oral bioavailability are described.

  4. Resveratrol Reactivates Latent HIV through Increasing Histone Acetylation and Activating Heat Shock Factor 1.

    Science.gov (United States)

    Zeng, Xiaoyun; Pan, Xiaoyan; Xu, Xinfeng; Lin, Jian; Que, Fuchang; Tian, Yuanxin; Li, Lin; Liu, Shuwen

    2017-06-07

    The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on "shock and kill" strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC). However, latent HIV was reactivated by resveratrol mediated through increasing histone acetylation and activation of heat shock factor 1 (HSF1). Additionally, synergistic activation of the latent HIV reservoirs was observed under cotreatment with resveratrol and conventional LRAs. Collectively, this research reveals that resveratrol is a natural LRA and shows promise for HIV therapy.

  5. Hypoglycemic and Hypotensive Activity of a Root Extract of Smilax aristolochiifolia, Standardized on N-trans-Feruloyl-Tyramine

    Directory of Open Access Journals (Sweden)

    Carol Arely Botello Amaro

    2014-07-01

    Full Text Available The metabolic syndrome (MS is a condition consisting of various metabolic abnormalities that are risk factors for developing kidney failure, cardiovascular, vascular and cerebrovascular diseases, among others. The prevalence of this syndrome shows a marked increase. The aim of this study was to investigate the pharmacological effect of Smilax aristolochiifolia root on some components of MS and obtain some of the active principle using chromatographic techniques. The compound isolated was N-trans-feruloyl tyramine NTF (1, and its structure was determined by spectroscopic and spectrometric analyses. The whole extract and the standardized fractions were able to control the weight gain around 30%; the fraction rich in NTF was able to decrease the hypertriglyceridemia by 60%. The insulin resistance decreased by approximately 40%; the same happened with blood pressure, since the values of systolic and diastolic pressure fell on average 31% and 37% respectively, to levels comparable to normal value. The treatment also had an immunomodulatory effect on the low-grade inflammation associated with obesity, since it significantly decreased the relative production of pro-inflammatory cytokines regarding anti-inflammatory cytokines, both kidney and adipose tissue. Therefore it can be concluded that the extract and fractions of Smilax aristolochiifolia root with NTF are useful to counteract some symptoms of MS in animal models.

  6. Direct trans-activation of the human cyclin D2 gene by the oncogene product Tax of human T-cell leukemia virus type I.

    Science.gov (United States)

    Huang, Y; Ohtani, K; Iwanaga, R; Matsumura, Y; Nakamura, M

    2001-03-01

    Cyclins are one of the pivotal determinants regulating cell cycle progression. We previously reported that the trans-activator Tax of human T-cell leukemia virus type I (HTLV-I) induces endogenous cyclin D2 expression along with cell cycle progression in a resting human T-cell line, Kit 225, suggesting a role of cyclin D2 in Tax-mediated cell cycle progression. The cyclin D2 gene has a typical E2F binding element, raising the possibility that induction of cyclin D2 expression is a consequence of cell cycle progression. In this study, we examined the role and molecular mechanism of induction of the endogenous human cyclin D2 gene by Tax. Introduction of p19(INK4d), a cyclin dependent kinase (CDK) inhibitor of the INK4 family specific for D-type CDK, inhibited Tax-mediated activation of E2F, indicating requirement of D-type CDK in Tax-mediated activation of E2F. Previously indicated E2F binding element and two NF-kappaB-like binding elements in the 1.6 kbp cyclin D2 promoter fragment had little, if any, effect on responsiveness to Tax. We found that trans-activation of the cyclin D2 promoter by Tax was mainly mediated by a newly identified NF-kappaB-like element with auxiliary contribution of a CRE-like element residing in sequences downstream of -444 which were by themselves sufficient for trans-activation by Tax. These results indicate that Tax directly trans-activates the cyclin D2 gene, resulting in growth promotion and perhaps leukemogenesis through activation of D-type CDK.

  7. Natural Plant Alkaloid (Emetine Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity

    Directory of Open Access Journals (Sweden)

    Ana Luiza Chaves Valadão

    2015-06-01

    Full Text Available Ipecac alkaloids are secondary metabolites produced in the medicinal plant Psychotria ipecacuanha. Emetine is the main alkaloid of ipecac and one of the active compounds in syrup of Ipecac with emetic property. Here we evaluated emetine’s potential as an antiviral agent against Human Immunodeficiency Virus. We performed in vitro Reverse Transcriptase (RT Assay and Natural Endogenous Reverse Transcriptase Activity Assay (NERT to evaluate HIV RT inhibition. Emetine molecular docking on HIV-1 RT was also analyzed. Phenotypic assays were performed in non-lymphocytic and in Peripheral Blood Mononuclear Cells (PBMC with HIV-1 wild-type and HIV-harboring RT-resistant mutation to Nucleoside Reverse Transcriptase Inhibitors (M184V. Our results showed that HIV-1 RT was blocked in the presence of emetine in both models: in vitro reactions with isolated HIV-1 RT and intravirion, measured by NERT. Emetine revealed a strong potential of inhibiting HIV-1 replication in both cellular models, reaching 80% of reduction in HIV-1 infection, with low cytotoxic effect. Emetine also blocked HIV-1 infection of RT M184V mutant. These results suggest that emetine is able to penetrate in intact HIV particles, and bind and block reverse transcription reaction, suggesting that it can be used as anti-HIV microbicide. Taken together, our findings provide additional pharmacological information on the potential therapeutic effects of emetine.

  8. A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects.

    Directory of Open Access Journals (Sweden)

    Ece A Mutlu

    2014-02-01

    Full Text Available HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy.

  9. Unraveling the relationship between microbial translocation and systemic immune activation in HIV infection

    Science.gov (United States)

    Shan, Liang; Siliciano, Robert F.

    2014-01-01

    Chronic immune activation is a key factor in HIV-1 disease progression. The translocation of microbial products from the intestinal lumen into the systemic circulation occurs during HIV-1 infection and is associated closely with immune activation; however, it has not been determined conclusively whether microbial translocation drives immune activation or occurs as a consequence of HIV-1 infection. In an important study in this issue of the JCI, Kristoff and colleagues describe the role of microbial translocation in producing immune activation in an animal model of HIV-1 infection, SIV infection of pigtailed macaques. Blocking translocation of intestinal bacterial LPS into the circulation dramatically reduced T cell activation and proliferation, production of proinflammatory cytokines, and plasma SIV RNA levels. This study directly demonstrates that microbial translocation promotes the systemic immune activation associated with HIV-1/SIV infection. PMID:24837427

  10. Antiviral activity of Justicia gendarussa Burm.f. leaves against HIV ...

    African Journals Online (AJOL)

    Backgrounds: Justicia gendarussa Burm.f. has been known to have anti-HIV activity. This study was conducted to evaluate the effect of incubation time on the antiviral activity of the J. gendarussa leaves extract on HIV-infected MT-4 cells in vitro. Molecular docking test was also conducted to determine the interaction of ...

  11. Risk Factors of Active Tuberculosis in People Living with HIV/AIDS ...

    African Journals Online (AJOL)

    BACKGROUND: Determinants of active tuberculosis among People Living with HIV/AIDS (PLHA) are not well elucidated in countries with limited resources. The objective of this study was to assess distal and proximate determinants of active tuberculosis among people living with HIV/AIDS in southwest. Ethiopia.

  12. Persistent Inflammation and Endothelial Activation in HIV-1 Infected Patients after 12 Years of Antiretroviral Therapy

    DEFF Research Database (Denmark)

    Rönsholt, Frederikke F; Ullum, Henrik; Katzenstein, Terese L

    2013-01-01

    The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART).......The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART)....

  13. HIV enhancing activity of semen impairs the antiviral efficacy of microbicides

    Science.gov (United States)

    Zirafi, Onofrio; Kim, Kyeong-Ae; Roan, Nadia R.; Kluge, Silvia F.; Müller, Janis A.; Jiang, Shibo; Mayer, Benjamin; Greene, Warner C.; Kirchhoff, Frank; Münch, Jan

    2015-01-01

    Topically applied microbicides potently inhibit HIV in vitro but have largely failed to exert protective effects in clinical trials. One possible reason for this discrepancy is that the preclinical testing of microbicides does not faithfully reflect the conditions of HIV sexual transmission. Here, we report that candidate microbicides that target HIV components show greatly reduced antiviral efficacy in the presence of semen, the main vector for HIV transmission. This diminished antiviral activity was dependent on the ability of amyloid fibrils in semen to enhance the infectivity of HIV. Thus, the anti-HIV efficacy of microbicides determined in the absence of semen greatly underestimated the drug concentrations needed to block semen-exposed virus. One notable exception was Maraviroc. This HIV entry inhibitor targets the host cell CCR5 coreceptor and was highly active against both untreated and semen-exposed HIV. These data help explain why microbicides have failed to protect against HIV in clinical trials and suggest that antiviral compounds targeting host factors hold promise for further development. These findings also suggest that the in vitro efficacy of candidate microbicides should be determined in the presence of semen to identify the best candidates for the prevention of HIV sexual transmission. PMID:25391483

  14. Artistic activities and cultural activism as responses to HIV/AIDS in Harare, Zimbabwe.

    Science.gov (United States)

    Pietrzyk, Susan

    2009-12-01

    Over the last two decades both the number and types of civil-society-led organisations involved in addressing HIV and AIDS have increased dramatically. In many cases, the work undertaken is thoughtfully researched, appropriately focused, and as a result produces positive outcomes. Yet questions can be raised about what civil society engagements involve, particularly at a micro level. An important element concerns the role of the arts in efforts to understand and address HIV and AIDS. This article examines ways that insight, analysis, and action around HIV and AIDS have unfolded through the purview of artistic activities undertaken by cultural activists in Harare, Zimbabwe-that is, arts-oriented engagements occurring beyond the boundaries of formally structured organisations. Artistic expressions, which often concern lived experiences, make clear the complex circumstances surrounding HIV and AIDS, and at the same time seek to act upon those circumstances. Understanding and addressing HIV and AIDS requires more than one form of knowledge. Drawing on data from 21 months of ethnographic research in Harare, I examine artistic expressions as legitimate forms of knowledge and as strategies for intervention.

  15. Unraveling the differences of the hydrolytic activity of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase: a quantum mechanics-molecular mechanics modeling study.

    Science.gov (United States)

    Bueren-Calabuig, Juan A; Pierdominici-Sottile, Gustavo; Roitberg, Adrian E

    2014-06-05

    Chagas' disease, also known as American trypanosomiasis, is a lethal, chronic disease that currently affects more than 10 million people in Central and South America. The trans-sialidase from Trypanosoma cruzi (T. cruzi, TcTS) is a crucial enzyme for the survival of this parasite: sialic acids from the host are transferred to the cell surface glycoproteins of the trypanosome, thereby evading the host's immune system. On the other hand, the sialidase of T. rangeli (TrSA), which shares 70% sequence identity with TcTS, is a strict hydrolase and shows no trans-sialidase activity. Therefore, TcTS and TrSA represent an excellent framework to understand how different catalytic activities can be achieved with extremely similar structures. By means of combined quantum mechanics-molecular mechanics (QM/MM, SCC-DFTB/Amberff99SB) calculations and umbrella sampling simulations, we investigated the hydrolysis mechanisms of TcTS and TrSA and computed the free energy profiles of these reactions. The results, together with our previous computational investigations, are able to explain the catalytic mechanism of sialidases and describe how subtle differences in the active site make TrSA a strict hydrolase and TcTS a more efficient trans-sialidase.

  16. Fumigant Activity of 6 Selected Essential Oil Compounds and Combined Effect of Methyl Salicylate And Trans-Cinnamaldehyde Against Culex pipiens pallens.

    Science.gov (United States)

    Ma, Wei-Bin; Feng, Jun-Tao; Jiang, Zhi-Li; Zhang, Xing

    2014-09-01

    We studied the knockdown activity and lethal toxicity of 6 essential oil compounds-methyl salicylate, linalool, 2-phenethyl alcohol, eugenol, β-citronellol, and trans-cinnamaldehyde-as fumigants against adult female Culex pipiens pallens in the laboratory. Of the 6 products tested, trans-cinnamaldehyde was the most toxic (LC50  =  0.26 µl/l air, 24 h) with a slow knockdown time (KT95  =  176.5 min at 0.5 µl/l air). Methyl salicylate displayed a lower toxicity (LC50  =  1.17 µl/l air, 24 h) but the fastest knockdown activity (KT95  =  16.8 min) at the sublethal concentration 0.5 µl/l air. Furthermore, the binary mixture of methyl salicylate and trans-cinnamaldehyde exhibited a combined effect of fast knockdown activity and high toxicity against Cx. p. pallens adults, showing potential for development as natural fumigants for mosquito control.

  17. Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. II. Effects after intrathecal administration

    Science.gov (United States)

    Alique, M; Lucio, F J; Herrero, J F

    2006-01-01

    Background and purpose: In our previous study (see accompanying paper) we observed that all-trans retinoic acid (ATRA) p.o. induces changes in spinal cord neuronal responses similar to those observed in inflammation-induced sensitization. In the present study we assessed the it. effects of ATRA, and its mechanisms of action. Experimental approach: The effects of all drugs were studied after it. administration in nociceptive withdrawal reflexes using behavioural tests in awake male Wistar rats. Key results: The administration of ATRA in normal rats induced a dose-dependent enhancement of nociceptive responses to noxious mechanical and thermal stimulation, as well as responses to innocuous stimulation. The intensity of the responses was similar to that observed in non-treated animals after carrageenan-induced inflammation. The effect induced by ATRA was fully prevented by the previous administration of the retinoic acid receptor (RAR) pan-antagonist LE540 but not by the retinoid X receptor (RXR) pan-antagonist HX531, suggesting a selective action on spinal cord RARs. The COX inhibitor dexketoprofen and the interleukin-1 receptor antagonist IL-1ra inhibited ATRA effect. The results indicate that COX and interleukin-1 are involved in the effects of ATRA in the spinal cord, similar to that seen in inflammation. Conclusions and implications: In conclusion, ATRA induces changes in the spinal cord similar to those observed in inflammation. The sensitization-like effect induced by ATRA was mediated by RARs and associated with a modulation of COX-2 and interleukin-1 activities. ATRA might be involved in the mechanisms underlying the initiation and/or maintenance of sensitization in the spinal cord. PMID:16847438

  18. HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes.

    Directory of Open Access Journals (Sweden)

    Beth S Zha

    Full Text Available HIV protease inhibitors (PI are core components of Highly Active Antiretroviral Therapy (HAART, the most effective treatment for HIV infection currently available. However, HIV PIs have now been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease and metabolic syndrome. Our previous studies have shown that HIV PIs activate endoplasmic reticulum (ER stress and disrupt lipid metabolism in hepatocytes and macrophages. Yet, little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome.Cultured and primary mouse adipocytes and human adipocytes were used to examine the effect of frequently used HIV PIs in the clinic, lopinavir/ritonavir, on adipocyte differentiation and further identify the underlying molecular mechanism of HIV PI-induced dysregulation of lipid metabolism in adipocytes. The results indicated that lopinavir alone or in combination with ritonavir, significantly activated the ER stress response, inhibited cell differentiation, and induced cell apoptosis in adipocytes. In addition, HIV PI-induced ER stress was closely linked to inhibition of autophagy activity. We also identified through the use of primary adipocytes of CHOP(-/- mice that CHOP, the major transcriptional factor of the ER stress signaling pathway, is involved in lopinavir/ritonavir-induced inhibition of cell differentiation in adipocytes. In addition, lopinavir/ritonavir-induced ER stress appears to be associated with inhibition of autophagy activity in adipocytes.Activation of ER stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV patients.

  19. Erectile Dysfunction Among HIV Patients Undergoing Highly Active Antiretroviral Therapy: Dyslipidemia as a Main Risk Factor

    Directory of Open Access Journals (Sweden)

    Gustavo Romero‐Velez, MD

    2014-04-01

    Conclusions: ED is highly prevalent in HIV patients. Dyslipidemia should be considered as a risk factor for ED in HIV patients. Romero‐Velez G, Lisker‐Cervantes A, Villeda‐Sandoval CI, Sotomayor de Zavaleta M, Olvera‐Posada D, Sierra‐Madero JG, Arreguin‐Camacho LO, and Castillejos‐Molina RA. Erectile dysfunction among HIV patients undergoing highly active antiretroviral therapy: Dyslipidemia as a main risk factor. Sex Med 2014;2:24–30.

  20. Structural Elucidation of cis / trans Dicaffeoylquinic Acid Photoisomerization Using Ion Mobility Spectrometry-Mass Spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Xueyun; Renslow, Ryan S.; Makola, Mpho M.; Webb, Ian K.; Deng, Liulin; Thomas, Dennis G.; Govind, Niranjan; Ibrahim, Yehia M.; Kabanda, Mwadham M.; Dubery, Ian A.; Heyman, Heino M.; Smith, Richard D.; Madala, Ntakadzeni E.; Baker, Erin S.

    2017-03-15

    Due to the recently uncovered health benefits and anti-HIV activities of dicaffeoylquinic acids (diCQAs), understanding their structures and functions is of great interest for drug discovery efforts. DiCQAs are analytically challenging to identify and quantify since they commonly exist as a diverse mixture of positional and geometric (cis/trans) isomers. In this work, we utilized ion mobility spectrometry coupled with mass spectrometry to separate the various isomers before and after UV irradiation. The experimental collision cross sections were then compared with theoretical structures to differentiate and identify the diCQA isomers. Our analyses found that naturally the diCQAs existed predominantly as trans/trans isomers, but after 3 h of UV irradiation, cis/cis, cis/trans, trans/cis, and trans/trans isomers were all present in the mixture. This is the first report of successful differentiation of cis/trans diCQA isomers individually, which shows the great promise of IMS coupled with theoretical calculations for determining the structure and activity relationships of different isomers in drug discovery studies.

  1. Monocyte activation in HIV/HCV coinfection correlates with cognitive impairment.

    Directory of Open Access Journals (Sweden)

    Hans Rempel

    Full Text Available Coinfection with human immunodeficiency virus (HIV and hepatitis C virus (HCV challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS. Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects' GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be

  2. Weak anti-HIV CD8+ T-cell effector activity in HIV primary infection

    Science.gov (United States)

    Dalod, Marc; Dupuis, Marion; Deschemin, Jean-Christophe; Goujard, Cécile; Deveau, Christiane; Meyer, Laurence; Ngo, Nicole; Rouzioux, Christine; Guillet, Jean-Gérard; Delfraissy, Jean-François; Sinet, Martine; Venet, Alain

    1999-01-01

    HIV-specific CD8+ T cells play a major role in the control of virus during HIV primary infection (PI) but do not completely prevent viral replication. We used IFN-γ enzyme-linked immunospot assay and intracellular staining to characterize the ex vivo CD8+ T-cell responses to a large variety of HIV epitopic peptides in 24 subjects with early HIV PI. We observed HIV-specific responses in 71% of subjects. Gag and Nef peptides were more frequently recognized than Env and Pol peptides. The number of peptides recognized was low (median 2, range 0–6). In contrast, a much broader response was observed in 30 asymptomatic subjects with chronic infection: all were responders with a median of 5 peptides recognized (range 1–13). The frequency of HIV-specific CD8+ T cells among PBMC for a given peptide was of the same order of magnitude in both groups. The proportion of HIV-specific CD8+CD28– terminally differentiated T cells was much lower in PI than at the chronic stage of infection. The weakness of the immune response during HIV PI could partially account for the failure to control HIV. These findings have potential importance for defining immunotherapeutic strategies and establishing the goals for effective vaccination. J. Clin. Invest. 104:1431–1439 (1999). PMID:10562305

  3. Remission of HIV-associated myelopathy after highly active antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Fernandez-Fernandez F

    2004-07-01

    Full Text Available HIV-associated myelopathy is the leading cause of spinal cord disease in HIV-infected patients. Typically, it affects individuals with low CD4 T cell counts, presenting with slowly progressive spastic paraparesis associated with dorsal column sensory loss as well as urinary disturbances. Other aetiologies must be first ruled out before establishing the diagnosis. We report here the case of a 37-year-old woman with advanced HIV disease, who developed HIV-associated myelopathy. The patient showed a gradual improvement after beginning with highly active antiretroviral therapy and, finally, she achieved a complete functional recovery. In addition, neuroimaging and neurophysiological tests normalized.

  4. Oxidized lipoproteins are associated with markers of inflammation and immune activation in HIV-1 infection

    Science.gov (United States)

    Kelesidis, T; Jackson, N; McComsey, GA; Wang, X; Elashoff, D; Dube, MP; Brown, TT; Yang, OO; Stein, JH; Currier, JS

    2016-01-01

    Objective The pathogenesis of immune dysfunction in chronic HIV-1 infection is unclear, and a potential role for oxidized lipids has been suggested. We hypothesize that both oxidized low- and high-density lipoproteins (HDLox, LDLox) contribute to HIV-1 related immune dysfunction. Study In the AIDS Clinical Trials Group (ACTG) A5260, 234 HIV-infected antiretroviral therapy (ART)-naïve participants were randomized to receive tenofovir-emtricitabine plus protease inhibitors or raltegravir and had HIV-1 RNA lipoproteins may contribute to persistent immune activation on ART. PMID:27603288

  5. Polyomavirus JCV excretion and genotype analysis in HIV-infected patients receiving highly active antiretroviral therapy

    Science.gov (United States)

    Lednicky, John A.; Vilchez, Regis A.; Keitel, Wendy A.; Visnegarwala, Fehmida; White, Zoe S.; Kozinetz, Claudia A.; Lewis, Dorothy E.; Butel, Janet S.

    2003-01-01

    OBJECTIVE: To assess the frequency of shedding of polyomavirus JC virus (JCV) genotypes in urine of HIV-infected patients receiving highly active antiretroviral therapy (HAART). METHODS: Single samples of urine and blood were collected prospectively from 70 adult HIV-infected patients and 68 uninfected volunteers. Inclusion criteria for HIV-infected patients included an HIV RNA viral load < 1000 copies, CD4 cell count of 200-700 x 106 cells/l, and stable HAART regimen. PCR assays and sequence analysis were carried out using JCV-specific primers against different regions of the virus genome. RESULTS: JCV excretion in urine was more common in HIV-positive patients but not significantly different from that of the HIV-negative group [22/70 (31%) versus 13/68 (19%); P = 0.09]. HIV-positive patients lost the age-related pattern of JCV shedding (P = 0.13) displayed by uninfected subjects (P = 0.01). Among HIV-infected patients significant differences in JCV shedding were related to CD4 cell counts (P = 0.03). Sequence analysis of the JCV regulatory region from both HIV-infected patients and uninfected volunteers revealed all to be JCV archetypal strains. JCV genotypes 1 (36%) and 4 (36%) were the most common among HIV-infected patients, whereas type 2 (77%) was the most frequently detected among HIV-uninfected volunteers. CONCLUSION: These results suggest that JCV shedding is enhanced by modest depressions in immune function during HIV infection. JCV shedding occurred in younger HIV-positive persons than in the healthy controls. As the common types of JCV excreted varied among ethnic groups, JCV genotypes associated with progressive multifocal leukoencephalopathy may reflect demographics of those infected patient populations.

  6. Oxaliplatin antagonizes HIV-1 latency by activating NF-κB without causing global T cell activation

    International Nuclear Information System (INIS)

    Zhu, Xiaoli; Liu, Sijie; Wang, Pengfei; Qu, Xiying; Wang, Xiaohui; Zeng, Hanxian; Chen, Huabiao; Zhu, Huanzhang

    2014-01-01

    Highlights: • The chemotherapeutic drug oxaliplatin reactivates latent HIV-1 in this cell line model of HIV-1 latency. • Reactivation is synergized when oxaliplatin is used in combination with valproic acid. • Oxaliplatin reactivates latent HIV-1 through activation of NF-kB and does not induce T cell activation. - Abstract: Reactivation of latent HIV-1 is a promising strategy for the clearance of the viral reservoirs. Because of the limitations of current agents, identification of new latency activators is urgently required. Using an established model of HIV-1 latency, we examined the effect of Oxaliplatin on latent HIV-1 reactivation. We showed that Oxaliplatin, alone or in combination with valproic acid (VPA), was able to reactivate HIV-1 without inducing global T cell activation. We also provided evidence that Oxaliplatin reactivated HIV-1 expression by inducing nuclear factor kappa B (NF-κB) nuclear translocation. Our results indicated that Oxaliplatin could be a potential drug candidate for anti-latency therapies

  7. Oxaliplatin antagonizes HIV-1 latency by activating NF-κB without causing global T cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Xiaoli; Liu, Sijie; Wang, Pengfei; Qu, Xiying; Wang, Xiaohui; Zeng, Hanxian [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China); Chen, Huabiao [Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139 (United States); Zhu, Huanzhang, E-mail: hzzhu@fudan.edu.cn [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433 (China)

    2014-07-18

    Highlights: • The chemotherapeutic drug oxaliplatin reactivates latent HIV-1 in this cell line model of HIV-1 latency. • Reactivation is synergized when oxaliplatin is used in combination with valproic acid. • Oxaliplatin reactivates latent HIV-1 through activation of NF-kB and does not induce T cell activation. - Abstract: Reactivation of latent HIV-1 is a promising strategy for the clearance of the viral reservoirs. Because of the limitations of current agents, identification of new latency activators is urgently required. Using an established model of HIV-1 latency, we examined the effect of Oxaliplatin on latent HIV-1 reactivation. We showed that Oxaliplatin, alone or in combination with valproic acid (VPA), was able to reactivate HIV-1 without inducing global T cell activation. We also provided evidence that Oxaliplatin reactivated HIV-1 expression by inducing nuclear factor kappa B (NF-κB) nuclear translocation. Our results indicated that Oxaliplatin could be a potential drug candidate for anti-latency therapies.

  8. Mechanism of anti-HIV activity of succinylated human serum albumin

    NARCIS (Netherlands)

    Kuipers, ME; Berg, HVD; Swart, PJ; Laman, Jon; Meijer, DKF; Kopelman, MHGM; Huisman, H

    1999-01-01

    In the present study, we described the interaction of succinylated human serum albumin (Suc-HSA), a negatively charged anti-HIV-1 active protein, with HIV-1 gp120 and in detail with the third variable domain of gp120 (V3 loop). To this end, different assay formats were tested in which gp120- and

  9. Sexual activity and condom use among people living with HIV in ...

    African Journals Online (AJOL)

    However, the extent to which knowledge of one's HIV status contributes to behavioural change among people living with HIV (PLHIV) has not been comprehensively documented. Drawing on an analysis of 37 in-depth interviews and five focus group discussions with PLHIV, this paper examines the nature of sexual activity ...

  10. E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor

    International Nuclear Information System (INIS)

    Hiebert, S.W.; Lipp, M.; Nevins, J.R.

    1989-01-01

    E2F is a cellular transcription factor that binds to two sites in the adenovirus E2 promoter. Previous experiments have implicated E2F in the E1A-dependent transactivation of the E2 gene since levels of active E2F increase markedly during adenovirus infection in parallel with the increase in E2 transcription, and an E2F binding site can confer E1A inducibility to a heterologous promoter. Here the authors show that E2F binds to two sequence elements within the P2 promoter of the human MYC gene which are within a region that is critical for promoter activity. The MYC promoter can be trans-activated in an E1A-dependent manner and site-directed mutagenesis demonstrates that these E2F elements are essential for trans-activation. Finally, they also find that adenovirus infection of quiescent cells results in a stimulation of the endogenous MYC gene. They conclude that the activation of the E2F factor, which is likely responsible for the activation of viral E2 transcription, is also responsible for the E1A-dependent induction of MYC transcription

  11. CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells.

    Science.gov (United States)

    Abdel-Mohsen, Mohamed; Kuri-Cervantes, Leticia; Grau-Exposito, Judith; Spivak, Adam M; Nell, Racheal A; Tomescu, Costin; Vadrevu, Surya Kumari; Giron, Leila B; Serra-Peinado, Carla; Genescà, Meritxell; Castellví, Josep; Wu, Guoxin; Del Rio Estrada, Perla M; González-Navarro, Mauricio; Lynn, Kenneth; King, Colin T; Vemula, Sai; Cox, Kara; Wan, Yanmin; Li, Qingsheng; Mounzer, Karam; Kostman, Jay; Frank, Ian; Paiardini, Mirko; Hazuda, Daria; Reyes-Terán, Gustavo; Richman, Douglas; Howell, Bonnie; Tebas, Pablo; Martinez-Picado, Javier; Planelles, Vicente; Buzon, Maria J; Betts, Michael R; Montaner, Luis J

    2018-04-18

    The persistence of HIV reservoirs, including latently infected, resting CD4 + T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4 + T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4 + T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV + or SIV + subjects, we found that most of the circulating memory CD32 + CD4 + T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a T H 2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4 + T cells in peripheral blood or lymphoid tissue; isolated CD32 + resting CD4 + T cells accounted for less than 3% of the total HIV DNA in CD4 + T cells. Cell-associated HIV DNA and RNA loads in CD4 + T cells positively correlated with the frequency of CD32 + CD69 + CD4 + T cells but not with CD32 expression on resting CD4 + T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4 + T cells or of enriched HIV DNA-positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4 + T cells enriched for transcriptionally active HIV after long-term ART. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  12. EFFECT OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY ON VAGINAL Candida spp. ISOLATION IN HIV-INFECTED COMPARED TO HIV-UNINFECTED WOMEN

    Directory of Open Access Journals (Sweden)

    Silvia de Souza Dantas ALCZUK

    2015-04-01

    Full Text Available Vulvovaginal candidiasis (VVC in HIV-infected women contributed to the impairment of their quality of life. The aim of this study was to evaluate the effect of highly active antiretroviral therapy (HAART use on the vaginal Candida spp. isolation in HIV-infected compared to HIV-uninfected women. This cross-sectional study included 178 HIV-infected (HIV group and 200 HIV-uninfected women (control that were studied at the Specialized Assistance Service (SAE for sexually transmitted diseases (STD/AIDS of the city of Maringá, Brazil, from April 1 to October 30, 2011. The yeasts were isolated and identified by phenotypic and molecular methods. The in vitro antifungal susceptibility to fluconazole, itraconazole, nystatin and amphotericin B was tested by the reference microdilution method. Higher frequencies of total vaginal Candida spp. isolation were found in the HIV-infected group than in the control group. However, both groups showed a similar frequency of colonization and VVC. Although C. albicans was the most frequent and sensitive to azolics and polyenes in both HIV-infected and uninfected women, the emerging resistance of C. glabrata to amphotericin B in the HIV-infected women was observed. Although higher frequency of vaginal Candida spp. isolation had been observed in the HIV-infected than in HIV-uninfected women, colonization and VVC showed similar frequency in both groups, indicating that HAART appears to protect against vaginal colonization and VVC.

  13. Endothelial activation and cardiometabolic profiles of treated and never-treated HIV infected Africans.

    Science.gov (United States)

    Fourie, C M T; Schutte, A E; Smith, W; Kruger, A; van Rooyen, J M

    2015-05-01

    The role the human immunodeficiency virus (HIV) and antiretroviral treatment on endothelial activation, and the subsequent relationship with cardiovascular disease, is not well understood. We investigated endothelial activation, inflammatory and cardiometabolic profiles, and measures of vascular structure and function of 66 antiretroviral treated (ART), 78 never-treated (no-ART) HIV infected and 165 HIV free Africans. Blood samples were obtained for biochemical analysis and blood pressure, pulse wave velocity (PWV) and carotid intima-media thickness (IMT) measurements were performed. The HIV infection duration was at least five years and the treatment 2.86±0.13 years. The intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) levels were elevated in the HIV infected groups compared to the controls. The odds of higher adhesion molecule levels were increased when HIV infected (especially in the no-ART group); OR no-ART vs. no-HIV: ICAM 3.92 (2.2-7.0); VCAM 16.2 (7.5-35). ICAM and VCAM associated with HIV status and interleukin-6 (IL-6) in the total group (all pART: β=-0.28, p=0.01; ART: β=-0.22, p=0.07) and TC (no-ART: β=-0.36, pART: β=-0.27, p=0.03). The ART group had an unfavourable lipid profile compared to the no-ART group. The inflammatory markers (C-reactive protein (CRP) and IL-6), PWV and IMT did not differ between the three groups. HIV infected Africans showed endothelial activation when compared to HIV free controls. The endothelial activation was not accompanied by increased inflammation (as measured with CRP and IL-6), arterial stiffness or sub-clinical atherosclerosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Current practices around HIV disclosure to children on highly active ...

    African Journals Online (AJOL)

    Antiretroviral therapy (ART) is critical in the effective care and management of the ... that parents and caregivers of HIV-infected children face is disclosing HIV ... support a more open and comm uni cative approach to children with cancer in light of ... disclosure had occurred in 27 patients, while 73 were unaware of their HIV ...

  15. Effects of integration and replication on transcription of the HIV-1 long terminal repeat

    NARCIS (Netherlands)

    Jeang, K. T.; Berkhout, B.; Dropulic, B.

    1993-01-01

    The activity of a promoter is influenced by chromosomal and cell cycle/replication context. We analyzed the influences of integration and replication on transcription of the human immunodeficiency virus (HIV)-1 long terminal repeat (LTR). We found that one requirement for Tat trans-activated

  16. risk factors of active tuberculosis in people living with hiv/aids

    African Journals Online (AJOL)

    Abrham

    2011-07-02

    Jul 2, 2011 ... The objective of this study was to assess distal ... KEYWORDS: Active TB, HIV, risk factors, case control study, Southwest Ethiopia ... and Khat (stimulant plant from Chata Edulis), .... to live in a house made of a cement floor.

  17. Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity.

    Science.gov (United States)

    Lu, Zhenyu; Harper, Mary Kay; Pond, Christopher D; Barrows, Louis R; Ireland, Chris M; Van Wagoner, Ryan M

    2012-08-24

    As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large-scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey's method. The three compounds were evaluated for anti-HIV activity in both an HIV integrase inhibition assay and a cytoprotective cell-based assay. Compound 2 was active in both assays with IC(50) values of 39 and 78 μM, respectively. Compound 3 was active only in the cytoprotective cell-based assay, with an IC(50) value of 60 μM.

  18. Creation of chimeric human/rabbit APOBEC1 with HIV-1 restriction and DNA mutation activities

    Science.gov (United States)

    Ikeda, Terumasa; Ong, Eugene Boon Beng; Watanabe, Nobumoto; Sakaguchi, Nobuo; Maeda, Kazuhiko; Koito, Atsushi

    2016-01-01

    APOBEC1 (A1) proteins from lagomorphs and rodents have deaminase-dependent restriction activity against HIV-1, whereas human A1 exerts a negligible effect. To investigate these differences in the restriction of HIV-1 by A1 proteins, a series of chimeric proteins combining rabbit and human A1s was constructed. Homology models of the A1s indicated that their activities derive from functional domains that likely act in tandem through a dimeric interface. The C-terminal region containing the leucine-rich motif and the dimerization domains of rabbit A1 is important for its anti-HIV-1 activity. The A1 chimeras with strong anti-HIV-1 activity were incorporated into virions more efficiently than those without anti-HIV-1 activity, and exhibited potent DNA-mutator activity. Therefore, the C-terminal region of rabbit A1 is involved in both its packaging into the HIV-1 virion and its deamination activity against both viral cDNA and genomic RNA. This study identifies the novel molecular mechanism underlying the target specificity of A1.

  19. Targeted HIV-1 Latency Reversal Using CRISPR/Cas9-Derived Transcriptional Activator Systems.

    Directory of Open Access Journals (Sweden)

    Julia K Bialek

    Full Text Available CRISPR/Cas9 technology is currently considered the most advanced tool for targeted genome engineering. Its sequence-dependent specificity has been explored for locus-directed transcriptional modulation. Such modulation, in particular transcriptional activation, has been proposed as key approach to overcome silencing of dormant HIV provirus in latently infected cellular reservoirs. Currently available agents for provirus activation, so-called latency reversing agents (LRAs, act indirectly through cellular pathways to induce viral transcription. However, their clinical performance remains suboptimal, possibly because reservoirs have diverse cellular identities and/or proviral DNA is intractable to the induced pathways. We have explored two CRISPR/Cas9-derived activator systems as targeted approaches to induce dormant HIV-1 proviral DNA. These systems recruit multiple transcriptional activation domains to the HIV 5' long terminal repeat (LTR, for which we have identified an optimal target region within the LTR U3 sequence. Using this target region, we demonstrate transcriptional activation of proviral genomes via the synergistic activation mediator complex in various in culture model systems for HIV latency. Observed levels of induction are comparable or indeed higher than treatment with established LRAs. Importantly, activation is complete, leading to production of infective viral particles. Our data demonstrate that CRISPR/Cas9-derived technologies can be applied to counteract HIV latency and may therefore represent promising novel approaches in the quest for HIV elimination.

  20. Homogeneous conversion of methane to methanol. 2. Catalytic activation of methane by cis- and trans-platin: A density functional study of the Shilov type reaction

    Energy Technology Data Exchange (ETDEWEB)

    Mylvaganam, K.; Bacskay, G.B.; Hush, N.S.

    2000-03-08

    The C-H activation of methane catalyzed by cis- and trans-platin in aqueous solution has been studied by density functional based computational methods. By analogy with the Shilov reaction, the initial step is the replacement of an ammonia ligand by methane, followed by the formation of a methyl complex and the elimination o a proton. The computations utilize the B3LYP hybrid functionals, effective core potentials, and double-{zeta} to polarized double-{zeta} basis sets and include solvation effects by a dielectric continuum method. In contrast with the Shilov reaction studied by Seigbahn and Crabtree (J.Am.Chem.Soc. 1996, 118, 4443), in the platins the replacement of an ammonia ligand by methane is found to be effectively rate determining, in that the energy barriers to C-H activation are comparable with those of the initial substitution reaction, viz. {approximately} 34 and 44 kcal/mol for cis- and trans-platin, respectively. Several reaction pathways for C-H activation and subsequent proton elimination were identified. For cis-platin the energy barriers associated with the oxidative addition and {sigma}-bond metathesis type mechanisms were found to be comparable, while for trans-platin oxidative addition is predicted to be strongly preferred over {sigma}-bond metathesis, which, interestingly, also proceeds through a Pt(IV) methyl hydrido complex as reaction intermediate. In line with accepted ideas on trans influence, the methyl and hydride ligands in the Pt(IV) complexes that arise in the oxidative addition reactions were always found to be cis to each other. On the basis of the population analyses on the Pt(IV) complexes it is suggested that the Pt-H and Pt-CH{sub 3} bonds are best described as covalent bonds and, further, that the preference of the hydride and methyl anions to be cis to each other is a consequence of such covalent bonding. In light of these findings, the energies of several methyl Pt(IV) hydrido bisulfate complexes were also recalculated

  1. Promoter trans-activation of protooncogenes c-fos and c-myc, but not c-Ha-ras, by products of adenovirus early region 1A

    International Nuclear Information System (INIS)

    Sassone-Corsi, P.; Borrelli, E.

    1987-01-01

    The E1A (early region 1A) oncogene products of adenovirus type 2 trans-activate the other early viral transcription units, as well as some cellular promoters. Using a short-term cotransfection assay in murine NIH 3T3 fibroblasts, we show that c-fos and c-myc promoter activities are stimulated by the E1A proteins, whereas c-Ha-ras transcription is not affected. The product of E1A 13S mRNA is responsible for the trans-activation, whereas the 12S mRNA product has no effect. Analysis of the c-fos promoter sequences required for the E1A stimulation shows that responsive sequences are located between positions -402 and -240 upstream of the transcription initiation site. This same region also contains the c-fos serum-responsive element. Furthermore, transcription of the endogenous c-fos gene in HeLa cells is increased after E1A transfection

  2. Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Bestetti Arabella

    2010-06-01

    Full Text Available Abstract HIV-1 invades the central nervous system (CNS in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF. In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients. In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays ( Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury.

  3. PECULIARITIES OF PROLIFERATIVE ACTIVITY OF CERVICAL SQUAMOUS CANCER IN HIV INFECTION.

    Science.gov (United States)

    Lytvynenko, M; Shkolnikov, V; Bocharova, T; Sychova, L; Gargin, V

    2017-09-01

    Patients with human immunodeficiency virus (HIV) infection have a statistically significant increased risk of developing cervical cancer. The expression of the human Ki-67 protein is strictly associated with cell proliferation. The purpose of our work was detection of proliferative activity in cervical squamous cancer in women with HIV infection. We investigated 24 cases (12 patients with HIV and 12 patients without HIV infection) of cervical carcinoma, where biopsy had been performed before the treatment. According to histopathological diagnoses, well-differentiated, moderately and poorly differentiated squamous cell carcinoma (7, 13 and 4 cases respectively) was determined. Mean age of women in the group with HIV infection was 32.7 years, and 38.2 years in the group without HIV infection. Detection of protein Ki-67 expression was performed with nuclear staining in the intermediate and superficial cells. The results of this work show that proliferative activity of cervical squamous cancer in women with HIV infection is characterized by a higher level of Ki-67 with averaging level for all histological types of squamous cell carcinoma 62.5±5.6% that is one and half times higher than in group without HIV infection. Depending on a histological type, expression of Ki-67 has increased from 4.7±3.8% in well-differentiated squamous cell carcinoma up to 89.2±5.1% in poorly differentiated squamous cell carcinoma for group with HIV, and from 21.3±2.4% to 79.4±3.7 in group without HIV.

  4. Sulfated Polysaccharides in Marine Sponges: Extraction Methods and Anti-HIV Activity

    Directory of Open Access Journals (Sweden)

    Ana I. S. Esteves

    2011-01-01

    Full Text Available The extraction, fractionation and HIV-1 inhibition potential of polysaccharides extracted from three species of marine sponges, Erylus discophorus, Cliona celata and Stelletta sp., collected in the Northeastern Atlantic, is presented in this work. The anti-HIV activity of 23 polysaccharide pellets and three crude extracts was tested. Crude extracts prepared from Erylus discophorus specimens were all highly active against HIV-1 (90 to 95% inhibition. Cliona celata pellets showed low polysaccharide content (bellow 38.5% and almost no anti-HIV activity (<10% inhibition. Stelletta sp. pellets, although quite rich in polysaccharide (up to 97.3%, showed only modest bioactivity (<36% HIV-1 inhibition. Erylus discophorus pellets were among the richest in terms of polysaccharide content (up to 98% and the most active against HIV-1 (up to 95% inhibition. Chromatographic fractionation of the polysaccharide pellet obtained from a specimen of Erylus discophorus (B161 yielded only modestly active fractions. However, we could infer that the active molecule is most probably a high molecular weight sulfated polysaccharide (>2000 kDa, whose mechanism is possibly preventing viral attachment and entry (fusion inhibitor.

  5. Antiretroviral treatment is associated with increased attentional load-dependent brain activation in HIV patients.

    Science.gov (United States)

    Chang, L; Yakupov, R; Nakama, H; Stokes, B; Ernst, T

    2008-06-01

    The purpose of this paper was to determine whether antiretroviral medications, especially the nucleoside analogue reverse transcriptase inhibitors, lead to altered brain activation due to their potential neurotoxic effects in patients with human immunodeficiency virus (HIV) infection. Forty-two right-handed men were enrolled in three groups: seronegative controls (SN, n = 18), HIV subjects treated with antiretroviral medications (HIV+ARV, n = 12), or not treated with antiretroviral medications (HIV+NARV, n = 12). Each subject performed a set of visual attention tasks with increasing difficulty or load (tracking two, three or four balls) during functional magnetic resonance imaging. HIV subjects, both groups combined, showed greater load-dependent increases in brain activation in the right frontal regions compared to SN (p-corrected = 0.006). HIV+ARV additionally showed greater load-dependent increases in activation compared to SN in bilateral superior frontal regions (p-corrected = 0.032) and a lower percent accuracy on the performance of the most difficult task (tracking four balls). Region of interest analyses further demonstrated that SN showed load-dependent decreases (with repeated trials despite increasing difficulty), while HIV subjects showed load-dependent increases in activation with the more difficult tasks, especially those on ARVs. These findings suggest that chronic ARV treatments may lead to greater requirement of the attentional network reserve and hence less efficient usage of the network and less practice effects in these HIV patients. As the brain has a limited reserve capacity, exhausting the reserve capacity in HIV+ARV would lead to declined performance with more difficult tasks that require more attention.

  6. High early life stress and aberrant amygdala activity: risk factors for elevated neuropsychiatric symptoms in HIV+ adults.

    Science.gov (United States)

    Clark, Uraina S; Sweet, Lawrence H; Morgello, Susan; Philip, Noah S; Cohen, Ronald A

    2017-06-01

    Relative to HIV-negative adults, HIV+ adults report elevated levels of early life stress (ELS). In non-HIV samples, high ELS has been linked to abnormalities in brain structure and function, as well as increased risk of neuropsychiatric symptoms. Yet, little is known about the neural effects of high ELS, and their relation to elevated neuropsychiatric symptoms, in HIV+ adults. Recent studies have revealed combined effects of HIV and high ELS on amygdala morphometry. Aberrant amygdala activity is prominently implicated in studies of neuropsychiatric symptomology in non-HIV samples. Hence, this preliminary study examined: 1) the combined effects of HIV and high ELS on amygdala activity, and 2) the relation between amygdala activity and neuropsychiatric symptoms in HIV+ adults. We included 28 HIV+ adults and 25 demographically-matched HIV-negative control (HC) adults. ELS exposure was quantified using a retrospective ELS questionnaire, which defined four groups: HIV+ Low-ELS (N = 15); HIV+ High-ELS (N = 13); HC Low-ELS (N = 16); and HC High-ELS (N = 9). Participants completed a battery of neuropsychiatric measures. BOLD fMRI assessed amygdala reactivity during explicit observation of fearful/angry faces. High-ELS participants demonstrated reduced levels of amygdala reactivity relative to Low-ELS participants. HIV+ High-ELS participants reported higher levels of neuropsychiatric symptoms than all other groups. In the HIV+ group, lower amygdala responses were associated with higher neuropsychiatric symptoms, particularly depression, anxiety, and alexithymia. Collectively, these results suggest that high ELS exposure is a significant risk factor for neuropsychiatric symptoms in HIV+ adults. Furthermore, our results implicate ELS-related abnormalities in amygdala activity in the etiology of neuropsychiatric symptoms in HIV+ adults.

  7. New findings on the d(TGGGAG) sequence: Surprising anti-HIV-1 activity.

    Science.gov (United States)

    Romanucci, Valeria; Zarrelli, Armando; Liekens, Sandra; Noppen, Sam; Pannecouque, Christophe; Di Fabio, Giovanni

    2018-02-10

    The biological relevance of tetramolecular G-quadruplexes especially as anti-HIV agents has been extensively reported in the literature over the last years. In the light of our recent results regarding the slow G-quadruplex folding kinetics of ODNs based on d(TGGGAG) sequence, here we report a systematic anti-HIV screening to investigate the impact of the G-quadruplex folding on their anti-HIV activity. In particular, varying the single stranded concentrations of ODNs, it has been tested a pool of ODN sample solutions with different G-quadruplex concentrations. The anti-HIV assays have been designed favouring the limited kinetics involved in the tetramolecular G4-association based on the d(TGGGAG) sequence. Aiming to determine the stoichiometry of G-quadruplex structures in the same experimental conditions of the anti-HIV assays, a native gel electrophoresis was performed. The gel confirmed the G-quadruplex formation for almost all sample solutions while showing the formation of high order G4 structures for the more concentrated ODNs solutions. The most significant result is the discovery of a potent anti-HIV activity of the G-quadruplex formed by the natural d(TGGGAG) sequence (IC 50  = 14 nM) that, until now, has been reported to be completely inactive against HIV infection. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  8. Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides

    Directory of Open Access Journals (Sweden)

    Li Yun-Yao

    2006-10-01

    Full Text Available Abstract Background Evaluation of microbicides for prevention of HIV-1 infection in macaque models for vaginal infection has indicated that the concentrations of active compounds needed for protection by far exceed levels sufficient for complete inhibition of infection in vitro. These experiments were done in the absence of seminal plasma (SP, a vehicle for sexual transmission of the virus. To gain insight into the possible effect of SP on the performance of selected microbicides, their anti-HIV-1 activity in the presence, and absence of SP, was determined. Methods The inhibitory activity of compounds against the X4 virus, HIV-1 IIIB, and the R5 virus, HIV-1 BaL was determined using TZM-bl indicator cells and quantitated by measuring β-galactosidase induced by infection. The virucidal properties of cellulose acetate 1,2-benzene-dicarboxylate (CAP, the only microbicide provided in water insoluble, micronized form, in the presence of SP was measured. Results The HIV-1 inhibitory activity of the polymeric microbicides, poly(naphthalene sulfonate, cellulose sulfate, carrageenan, CAP (in soluble form and polystyrene sulfonate, respectively, was considerably (range ≈ 4 to ≈ 73-fold diminished in the presence of SP (33.3%. Formulations of micronized CAP, providing an acidic buffering system even in the presence of an SP volume excess, effectively inactivated HIV-1 infectivity. Conclusion The data presented here suggest that the in vivo efficacy of polymeric microbicides, acting as HIV-1 entry inhibitors, might become at least partly compromised by the inevitable presence of SP. These possible disadvantages could be overcome by combining the respective polymers with acidic pH buffering systems (built-in for formulations of micronized CAP or with other anti-HIV-1 compounds, the activity of which is not affected by SP, e.g. reverse transcriptase and zinc finger inhibitors.

  9. Both cis and trans Activities of Foot-and-Mouth Disease Virus 3D Polymerase Are Essential for Viral RNA Replication.

    Science.gov (United States)

    Herod, Morgan R; Ferrer-Orta, Cristina; Loundras, Eleni-Anna; Ward, Joseph C; Verdaguer, Nuria; Rowlands, David J; Stonehouse, Nicola J

    2016-08-01

    The Picornaviridae is a large family of positive-sense RNA viruses that contains numerous human and animal pathogens, including foot-and-mouth disease virus (FMDV). The picornavirus replication complex comprises a coordinated network of protein-protein and protein-RNA interactions involving multiple viral and host-cellular factors. Many of the proteins within the complex possess multiple roles in viral RNA replication, some of which can be provided in trans (i.e., via expression from a separate RNA molecule), while others are required in cis (i.e., expressed from the template RNA molecule). In vitro studies have suggested that multiple copies of the RNA-dependent RNA polymerase (RdRp) 3D are involved in the viral replication complex. However, it is not clear whether all these molecules are catalytically active or what other function(s) they provide. In this study, we aimed to distinguish between catalytically active 3D molecules and those that build a replication complex. We report a novel nonenzymatic cis-acting function of 3D that is essential for viral-genome replication. Using an FMDV replicon in complementation experiments, our data demonstrate that this cis-acting role of 3D is distinct from the catalytic activity, which is predominantly trans acting. Immunofluorescence studies suggest that both cis- and trans-acting 3D molecules localize to the same cellular compartment. However, our genetic and structural data suggest that 3D interacts in cis with RNA stem-loops that are essential for viral RNA replication. This study identifies a previously undescribed aspect of picornavirus replication complex structure-function and an important methodology for probing such interactions further. Foot-and-mouth disease virus (FMDV) is an important animal pathogen responsible for foot-and-mouth disease. The disease is endemic in many parts of the world with outbreaks within livestock resulting in major economic losses. Propagation of the viral genome occurs within

  10. Trans-Planckian wimpzillas

    CERN Document Server

    Kolb, E W; Tkachev, I I

    2007-01-01

    Two previously proposed conjectures--gravitational trans-Planckian particle creation in the expanding universe, and the existence of ultra-heavy stable particles with masses up to the Planck scale (wimpzillas)--are combined in a proposal for trans-Planckian particle creation of wimpzillas. It is shown that the trans-Planckian particle creation parameter should be rather small to avoid overproduction of such particles. This ensures that wimpzillas are mainly created at the end of primordial inflation. Conditions under which trans-Planckian wimpzillas can constitute the present dark matter are determined.

  11. Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection.

    Science.gov (United States)

    Hagberg, Lars; Cinque, Paola; Gisslen, Magnus; Brew, Bruce J; Spudich, Serena; Bestetti, Arabella; Price, Richard W; Fuchs, Dietmar

    2010-06-03

    HIV-1 invades the central nervous system (CNS) in the context of acute infection, persists thereafter in the absence of treatment, and leads to chronic intrathecal immunoactivation that can be measured by the macrophage activation marker, neopterin, in cerebrospinal fluid (CSF). In this review we describe our experience with CSF neopterin measurements in 382 untreated HIV-infected patients across the spectrum of immunosuppression and HIV-related neurological diseases, in 73 untreated AIDS patients with opportunistic CNS infections, and in 233 treated patients.In untreated patients, CSF neopterin concentrations are almost always elevated and increase progressively as immunosuppression worsens and blood CD4 cell counts fall. However, patients with HIV dementia exhibit particularly high CSF neopterin concentrations, above those of patients without neurological disease, though patients with CNS opportunistic infections, including CMV encephalitis and cryptococcal meningitis, also exhibit high levels of CSF neopterin. Combination antiretroviral therapy, with its potent effect on CNS HIV infection and CSF HIV RNA, mitigates both intrathecal immunoactivation and lowers CSF neopterin. However, despite suppression of plasma and CSF HIV RNA to below the detection limits of clinical assays (<50 copies HIV RNA/mL), CSF neopterin often remains mildly elevated, indicating persistent low-level intrathecal immune activation and raising the important questions of whether this elevation is driven by continued CNS infection and whether it causes continued indolent CNS injury.Although nonspecific, CSF neopterin can serve as a useful biomarker in the diagnosis of HIV dementia in the setting of confounding conditions, in monitoring the CNS inflammatory effects of antiretroviral treatment, and give valuable information to the cause of ongoing brain injury.

  12. HIV Serostatus Disclosure to Sexual Partners Among Sexually Active People Living with HIV in South Africa: Results from the 2012 National Population-Based Household Survey.

    Science.gov (United States)

    Simbayi, Leickness C; Zungu, Nompumelelo; Evans, Meredith; Mehlomakulu, Vuyelwa; Kupamupindi, Takura; Mafoko, Goitseone; Zuma, Khangelani

    2017-01-01

    This paper explores the prevalence and correlates of HIV seropositive status disclosure to sexual partners by people living with HIV (PLHIV) in South Africa. Secondary analysis of the 2012 South African National HIV Prevalence, Incidence and Behaviour Survey was conducted on data obtained from 934 sexually active PLHIV aged 15 years and older who responded to the question about HIV seropositive status disclosure. Overall, a large majority of respondents (77.1 %) reported disclosing their HIV-positive status to all their current sex partners. Multiple regression analysis, after adjustments for sex, marital status and locality type, revealed that those who were living together, going steady, and those who were single were all 60 % [adjusted odds ratio (AOR) = 0.4, 95 % CIs 0.20-0.78; AOR = 0.4, 95 % CIs 0.24-0.77; and AOR = 0.4, 95 % CIs 0.19-1.00, all ps < 0.05] less likely to disclose their HIV positive status to their partners compared to those who were married. Those who lived in rural formal areas were 70 % less likely to disclose their HIV status to their partners compared to those who stayed in urban formal areas (AOR = 0.3, 95 % CI 0.17-0.69, p < 0.001). Those who had correct HIV knowledge and rejection of myths were 2.0 times more likely to disclose their HIV status to their partners compared to those who did not have correct HIV knowledge and rejection of myths (AOR = 2.0, 95 % CI 1.04-3.68, p < 0.05). In conclusion, intervention programmes which help improve HIV seropositive status disclosure are needed by PLHIV who are not married, live in rural formal areas, and have incorrect HIV knowledge and rejection of myths.

  13. Emerging Trends of HIV Drug Resistance in Chinese HIV-Infected Patients Receiving First-Line Highly Active Antiretroviral Therapy: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Liu, Huixin; Ma, Ye; Su, Yingying; Smith, M. Kumi; Liu, Ying; Jin, Yantao; Gu, Hongqiu; Wu, Jing; Zhu, Lin; Wang, Ning

    2014-01-01

    Background. Highly active antiretroviral therapy (HAART) has led to a dramatic decrease in AIDS-related morbidity and mortality through sustained suppression of human immunodeficiency virus (HIV) replication and reconstitution of the immune response. Settings like China that experienced rapid HAART rollout and relatively limited drug selection face considerable challenges in controlling HIV drug resistance (DR). Methods. We conducted a systematic review and meta-analysis to describe trends in emergent HIV DR to first-line HAART among Chinese HIV-infected patients, as reflected in the point prevalence of HIV DR at key points and fixed intervals after treatment initiation, using data from cohort studies and cross-sectional studies respectively. Results. Pooled prevalence of HIV DR from longitudinal cohorts studies was 10.79% (95% confidence interval [CI], 5.85%–19.07%) after 12 months of HAART and 80.58% (95% CI, 76.6%–84.02%) after 72 months of HAART. The HIV DR prevalence from cross-sectional studies was measured in treatment intervals; during the 0–12-month HAART treatment interval, the pooled prevalence of HIV DR was 11.1% (95% CI, 7.49%–16.14%), which increased to 22.92% at 61–72 months (95% CI, 9.45%–45.86%). Stratified analyses showed that patients receiving a didanosine-based regimen had higher HIV DR prevalence than those not taking didanosine (15.82% vs 4.97%). Patients infected through former plasma donation and those receiving AIDS treatment at village clinics had higher HIV DR prevalence than those infected through sexual transmission or treated at a county-level hospital. Conclusions. Our findings indicate higher prevalence of HIV DR for patients with longer cumulative HAART exposure, highlighting important subgroups for future HIV DR surveillance and control. PMID:25053721

  14. HIV, human papillomavirus, and cervical neoplasia and cancer in the era of highly active antiretroviral therapy.

    Science.gov (United States)

    De Vuyst, Hugo; Lillo, Flavia; Broutet, Nathalie; Smith, Jennifer S

    2008-11-01

    The objective of this study was to review the literature on the epidemiological association between human papillomavirus (HPV), HIV, and cervical neoplasia, and the impact of highly active antiretroviral therapy (HAART) on this association. MEDLINE was searched using the terms 'human papillomavirus', 'HPV', 'HIV', 'cervix', 'neoplasm', and 'antiretroviral' to identify articles published before December 2006. HIV-infection was strongly associated with a higher prevalence, incidence, and persistence of HPV infection and correlated with prevalence, incidence, persistence, and progression of squamous intraepithelial lesions. The association between HIV and invasive cervical carcinoma has been more difficult to establish, but is now fully recognized. HAART seems to have little, if any, beneficial effect on the natural history of intraepithelial lesions in HIV-positive women. Despite this fact, HAART, does increase the life expectancy of HIV-positive women. Therefore, it remains important to closely monitor HPV-related disease in women with HIV who are receiving HAART, particularly in regions of the world where cervical screening is not available routinely.

  15. Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation.

    Science.gov (United States)

    Zhyvoloup, Alexander; Melamed, Anat; Anderson, Ian; Planas, Delphine; Lee, Chen-Hsuin; Kriston-Vizi, Janos; Ketteler, Robin; Merritt, Andy; Routy, Jean-Pierre; Ancuta, Petronela; Bangham, Charles R M; Fassati, Ariberto

    2017-07-01

    HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

  16. Digoxin reveals a functional connection between HIV-1 integration preference and T-cell activation.

    Directory of Open Access Journals (Sweden)

    Alexander Zhyvoloup

    2017-07-01

    Full Text Available HIV-1 integrates more frequently into transcribed genes, however the biological significance of HIV-1 integration targeting has remained elusive. Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D in the capsid protein. We confirmed that digoxin repressed viral gene expression by targeting the cellular Na+/K+ ATPase, but this did not explain its selectivity. Parallel RNAseq and integration mapping in infected cells demonstrated that digoxin inhibited expression of genes involved in T-cell activation and cell metabolism. Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism. Two main gene networks down-regulated by the drug were CD40L and CD38. Blocking CD40L by neutralizing antibodies selectively inhibited WT virus infection, phenocopying digoxin. Thus the selectivity of digoxin depends on a combination of integration targeting and repression of specific gene networks. The drug unmasked a functional connection between HIV-1 integration and T-cell activation. Our results suggest that HIV-1 evolved integration site selection to couple its early gene expression with the status of target CD4+ T-cells, which may affect latency and viral reactivation.

  17. Trans-activation function of a 3' truncated X gene-cell fusion product from integrated hepatitis B virus DNA in chronic hepatitis tissues

    International Nuclear Information System (INIS)

    Takada, Shinako; Koike, Katsuro

    1990-01-01

    To investigate the expression and transactivation function of the X gene in integrated hepatitis B virus (HBV) DNA from chronic hepatitis tissues, a series of transfectants containing cloned integrated HBV DNAs was made and analyzed for X mRNA expression and trans-activation activity by using a chloramphenicol acetyltransferase assay. Most of the integrated HBV DNAs expressed X mRNA and encoded a product with trans-activation activity in spite of the loss of the 3' end region of the X gene due to integration. From cDNA cloning and sequence analysis of X mRNA transcribed from native or integrated HBV DNA, the X protein was found to be translated from the X open reading frame without splicing. For integrated HBV DNA, transcription was extended to a cellular flanking DNA and an X gene-cell fusion transcript was terminated by using a cellular poly(A) signal. The amino acid sequence deduced from an X-cell fusion transcript indicated truncation of the carboxyl-terminal five amino acids, but the upstream region of seven amino acids conserved among hepadnaviruses was retained in the integrated HBV DNA, suggesting that this conserved region is essential for the transactivation function of the X protein. These findings support the following explanation for hepatocarcinogenesis by HBV DNA integration: the expression of a cellular oncogene(s) is transactivated at the time of chronic infection by the increasing amounts of the integrated HBV gene product(s), such as the X-cell fusion product

  18. Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy

    DEFF Research Database (Denmark)

    Ostrowski, Sisse R; Katzenstein, Terese L; Thim, Per T.

    2005-01-01

    Immunological and virological consequences of low-level viremia in human immunodeficiency virus (HIV) type 1-infected patients receiving highly active antiretroviral therapy (HAART) remain to be determined....

  19. Broad anti-HIV activity of the Oscillatoria agardhii agglutinin homologue lectin family.

    Science.gov (United States)

    Férir, Geoffrey; Huskens, Dana; Noppen, Sam; Koharudin, Leonardus M I; Gronenborn, Angela M; Schols, Dominique

    2014-10-01

    Oscillatoria agardhii agglutinin homologue (OAAH) proteins belong to a recently discovered lectin family. The founding member OAA and a designed hybrid OAAH (OPA) recognize similar but unique carbohydrate structures of Man-9, compared with other antiviral carbohydrate-binding agents (CBAs). These two newly described CBAs were evaluated for their inactivating properties on HIV replication and transmission and for their potential as microbicides. Various cellular assays were used to determine antiviral activity against wild-type and certain CBA-resistant HIV-1 strains: (i) free HIV virion infection in human T lymphoma cell lines and PBMCs; (ii) syncytium formation assay using persistently HIV-infected T cells and non-infected CD4+ T cells; (iii) DC-SIGN-mediated viral capture; and (iv) transmission to uninfected CD4+ T cells. OAA and OPA were also evaluated for their mitogenic properties and potential synergistic effects using other CBAs. OAA and OPA inhibit HIV replication, syncytium formation between HIV-1-infected and uninfected T cells, DC-SIGN-mediated HIV-1 capture and transmission to CD4+ target T cells, thereby rendering a variety of HIV-1 and HIV-2 clinical isolates non-infectious, independent of their coreceptor use. Both CBAs competitively inhibit the binding of the Manα(1-2)Man-specific 2G12 monoclonal antibody (mAb) as shown by flow cytometry and surface plasmon resonance analysis. The HIV-1 NL4.3(2G12res), NL4.3(MVNres) and IIIB(GRFTres) strains were equally inhibited as the wild-type HIV-1 strains by these CBAs. Combination studies indicate that OAA and OPA act synergistically with Hippeastrum hybrid agglutinin, 2G12 mAb and griffithsin (GRFT), with the exception of OPA/GRFT. OAA and OPA are unique CBAs with broad-spectrum anti-HIV activity; however, further optimization will be necessary for microbicidal application. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights

  20. Correlation of immune activation with HIV-1 RNA levels assayed by real-time RT-PCR in HIV-1 Subtype C infected patients in Northern India

    Science.gov (United States)

    Agarwal, Atima; Sankaran, Sumathi; Vajpayee, Madhu; Sreenivas, V; Seth, Pradeep; Dandekar, Satya

    2014-01-01

    Background Assays with specificity and cost effectiveness are needed for the measurement of HIV-1 burden to monitor disease progression or response to anti-retroviral therapy (ART) in HIV-1 subtype C infected patients. Objectives The objective of this study was to develop and validate an affordable; one step Real-Time RT-PCR assay with high specificity and sensitivity to measure plasma HIV-1 loads in HIV-1 subtype C infected patients. Results We developed an RT-PCR assay to detect and quantitate plasma HIV-1 levels in HIV-1 subtype C infected patients. An inverse correlation between plasma viral loads (PVL) and CD4+ T-cell numbers was detected at all CDC stages. Significant correlations were found between CD8+ T-cell activation and PVL, as well as with the clinical and immunological status of the patients. Conclusions The RT-PCR assay provides a sensitive method to measure PVL in HIV-1 subtype C infected patients. Viral loads correlated with immune activation and can be used to monitor HIV care in India. PMID:17962068

  1. Non-Cationic Proteins Are Associated with HIV Neutralizing Activity in Genital Secretions of Female Sex Workers.

    Science.gov (United States)

    Birse, Kenzie D M; Cole, Amy L; Hirbod, Taha; McKinnon, Lyle; Ball, Terry B; Westmacott, Garrett R; Kimani, Joshua; Plummer, Frank; Cole, Alexander M; Burgener, Adam; Broliden, Kristina

    2015-01-01

    Cationic proteins found in cervicovaginal secretions (CVS) are known to contribute to the early antiviral immune response against HIV-infection in vitro. We here aimed to define additional antiviral factors that are over-expressed in CVS from female sex workers at high risk of infection. CVS were collected from Kenyan HIV-seronegative (n = 34) and HIV-seropositive (n = 12) female sex workers, and were compared with those from HIV-seronegative low-risk women (n = 12). The highly exposed seronegative (HESN) sex workers were further divided into those with less (n = 22) or more (n = 12) than three years of documented sex work. Cationic protein-depleted CVS were assessed for HIV-neutralizing activity by a PBMC-based HIV-neutralizing assay, and then characterized by proteomics. HIV neutralizing activity was detected in all unprocessed CVS, however only CVS from the female sex worker groups maintained its HIV neutralizing activity after cationic protein-depletion. Differentially abundant proteins were identified in the cationic protein-depleted secretions including 26, 42, and 11 in the HESN>3 yr, HESNHIV-positive groups, respectively. Gene ontology placed these proteins into functional categories including proteolysis, oxidation-reduction, and epidermal development. The proteins identified in this study include proteins previously associated with the HESN phenotype in other cohorts as well as novel proteins not yet associated with anti-HIV activities. While cationic proteins appear to contribute to the majority of the intrinsic HIV neutralizing activity in the CVS of low-risk women, a broader range of non-cationic proteins were associated with HIV neutralizing activity in HESN and HIV-positive female sex workers. These results indicate that novel protein factors found in CVS of women with high-risk sexual practices may have inherent antiviral activity, or are involved in other aspects of anti-HIV host defense, and warrant further exploration into their mode of action.

  2. Anti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicides

    Directory of Open Access Journals (Sweden)

    Li Yun-Yao

    2002-11-01

    Full Text Available Abstract Background Cellulose acetate phthalate (CAP in soluble form blocks coreceptor binding sites on the virus envelope glycoprotein gp120 and elicits gp41 six-helix bundle formation, processes involved in virus inactivation. CAP is not soluble at pH Methods Enzyme linked immunosorbent assays (ELISA were used to (1 study HIV-1 IIIB and BaL binding to micronized CAP; (2 detect virus disintegration; and (3 measure gp41 six-helix bundle formation. Cells containing integrated HIV-1 LTR linked to the β-gal gene and expressing CD4 and coreceptors CXCR4 or CCR5 were used to measure virus infectivity. Results 1 HIV-1 IIIB and BaL, respectively, effectively bound to micronized CAP. 2 The interaction between HIV-1 and micronized CAP led to: (a gp41 six-helix bundle formation; (b virus disintegration and shedding of envelope glycoproteins; and (c rapid loss of infectivity. Polymers other than CAP, except Carbomer 974P, elicited gp41 six-helix bundle formation in HIV-1 IIIB but only poly(napthalene sulfonate, in addition to CAP, had this effect on HIV-1 BaL. These polymers differed with respect to their virucidal activities, the differences being more pronounced for HIV-1 BaL. Conclusions Micronized CAP is the only candidate topical microbicide with the capacity to remove rapidly by adsorption from physiological fluids HIV-1 of both the X4 and R5 biotypes and is likely to prevent virus contact with target cells. The interaction between micronized CAP and HIV-1 leads to rapid virus inactivation. Among other anionic polymers, cellulose sulfate, BufferGel and aryl sulfonates appear most effective in this respect.

  3. Virucidal activity of the dendrimer microbicide SPL7013 against HIV-1.

    Science.gov (United States)

    Telwatte, Sushama; Moore, Katie; Johnson, Adam; Tyssen, David; Sterjovski, Jasminka; Aldunate, Muriel; Gorry, Paul R; Ramsland, Paul A; Lewis, Gareth R; Paull, Jeremy R A; Sonza, Secondo; Tachedjian, Gilda

    2011-06-01

    Topical microbicides for use by women to prevent the transmission of human immunodeficiency virus (HIV) and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. SPL7013 is a dendrimer with broad-spectrum activity against HIV type I (HIV-1) and -2 (HIV-2), herpes simplex viruses type-1 (HSV-1) and -2 (HSV-2) and human papillomavirus. SPL7013 [3% (w/w)] has been formulated in a mucoadhesive carbopol gel (VivaGel®) for use as a topical microbicide. Previous studies showed that SPL7013 has similar potency against CXCR4-(X4) and CCR5-using (R5) strains of HIV-1 and that it blocks viral entry. However, the ability of SPL7013 to directly inactivate HIV-1 is unknown. We examined whether SPL7013 demonstrates virucidal activity against X4 (NL4.3, MBC200, CMU02 clade EA and 92UG046 clade D), R5 (Ba-L, NB25 and 92RW016 clade A) and dual-tropic (R5X4; MACS1-spln) HIV-1 using a modified HLA-DR viral capture method and by polyethylene glycol precipitation. Evaluation of virion integrity was determined by ultracentrifugation through a sucrose cushion and detection of viral proteins by Western blot analysis. SPL7013 demonstrated potent virucidal activity against X4 and R5X4 strains, although virucidal activity was less potent for the 92UG046 X4 clade D isolate. Where potent virucidal activity was observed, the 50% virucidal concentrations were similar to the 50% effective concentrations previously reported in drug susceptibility assays, indicating that the main mode of action of SPL7013 is by direct viral inactivation for these strains. In contrast, SPL7013 lacked potent virucidal activity against R5 HIV-1 strains. Evaluation of the virucidal mechanism showed that SPL7013-treated NL4.3, 92UG046 and MACS1-spln virions were intact with no significant decrease in gp120 surface protein with respect to p24 capsid content compared to the corresponding untreated virus. These studies demonstrate that SPL

  4. The dual action of poly(ADP-ribose polymerase -1 (PARP-1 inhibition in HIV-1 infection: HIV-1 LTR inhibition and diminution in Rho GTPase activity

    Directory of Open Access Journals (Sweden)

    Slava eRom

    2015-08-01

    Full Text Available The transcription of HIV-1 (HIV is regulated by complex mechanisms involving various cellular factors and virus-encoded transactivators. Poly(ADP-ribose polymerase 1 (PARP-1 inhibition has emerged recently as a potent anti-inflammatory tool, since PARP-1 is involved in the regulation of some genes through its interaction with various transcription factors. We propose a novel approach to diminish HIV replication via PARP-1 inhibition using human primary monocyte-derived macrophages (MDM as an in vitro model system. PARP-1 inhibitors were able to reduce HIV replication in MDM by 60-80% after 7 days infection. Long Terminal Repeat (LTR acts as a switch in virus replication and can be triggered by several agents such as: Tat, tumor necrosis factor α (TNFα, and phorbol 12-myristate 13-acetate (PMA. Overexpression of Tat in MDM transfected with an LTR reporter plasmid led to a 4.2-fold increase in LTR activation; PARP inhibition resulted in 70% reduction of LTR activity. LTR activity, which increased 3-fold after PMA or TNFα treatment, was reduced by PARP inhibition (by 85-95%. MDM treated with PARP inhibitors showed 90% reduction in NFκB activity (known to mediate PMA- and TNFα-induced HIV LTR activation. Cytoskeleton rearrangements are important in effective HIV-1 infection. PARP inactivation reduced actin cytoskeleton rearrangements by affecting Rho GTPase machinery. These findings suggest that HIV replication in MDM could be suppressed by PARP inhibition via NFκB suppression, diminution of LTR activation and its effects on the cytoskeleton. PARP appears to be essential for HIV replication and its inhibition may provide a potent approach to treatment of HIV infection.

  5. Facts about trans fats

    Science.gov (United States)

    Trans fat is a type of dietary fat . Of all the fats, trans fat is the worst for your health. Too much ... from solid margarine to soft margarine. Ask what type of fats foods are cooked in when you eat out ...

  6. Trans as Contested Intelligibility

    DEFF Research Database (Denmark)

    Raun, Tobias

    2014-01-01

    Denne artikel rejser en række epistemologiske og metodologiske spørgsmål vedrørende læsningen af trans som identitetskategori. Disse spørgsmål er stærkt underbelyste i en skandinavisk akademisk kontekst, om end der el- lers i stigende grad produceres analyser af trans identitetsnarrativer. Artikl...

  7. Different profiles of immune reconstitution in children and adults with HIV-infection after highly active antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Leal Manuel

    2006-07-01

    Full Text Available Abstract Background Recent advances in characterizing the immune recovery of HIV-1-infected people have highlighted the importance of the thymus for peripheral T-cell diversity and function. The aim of this study was to investigate differences in immune reconstitution profiles after highly active antiretroviral therapy (HAART between HIV-children and adults. Methods HIV patients were grouped according to their previous clinical and immunological status: 9 HIV-Reconstituting-adults (HIV-Rec-adults and 10 HIV-Reconstituting-children (HIV-Rec-children on HAART with viral load (VL ≤400 copies/ml and CD4+ ≥500 cells/μL at least during 6 months before the study and CD4+ ≤300 cells/μL anytime before. Fifteen healthy-adults and 20 healthy-children (control subjects were used to calculate Z-score values to unify value scales between children and adults to make them comparable. Results HIV-Rec-children had higher T-cell receptor excision circles (TREC and lower interleukin (IL-7 levels than HIV-Rec-adults (p + (CD4+CD45RA hi+CD27+, naïve CD8+ (CD8+CD45RA hi+CD27+, and memory CD8+ (CD8+CD45RO+ cells/μl than HIV-Rec-adults, but similar memory CD4+ (CD4+CD45RO+ counts. HIV-Rec-children had lower naïve CD8+ Z-score values than HIV-Rec-adults (p = 0.05. Conclusion Our data suggest that HIV-Rec-children had better thymic function than HIV-Rec-adults and this fact affects the peripheral T-cell subsets. Thus, T-cell recovery after HAART in HIV-Rec-adults could be the consequence of antigen-independent peripheral T-cell expansion while in HIV-Rec-children thymic output could play a predominant role in immune reconstitution.

  8. HIV LIFE CYCLE AND POTENTIAl TARGETS FOR DRUG ACTIVITY

    African Journals Online (AJOL)

    TABLE Ill. STAGES IN THE HIV UFE CYCLE THAT ARE TARGETS FOR CURRENTLY AVAIlABLE ANTIRETROVIRAlS. Fig. 7. Life cycle ofHIVand targets for ontiretrovirol theropy. (Reproduced with permission from: 5Miller, The Clinician's Guide to. Antiretroviral Resistance, 2007.) JULY 2002. Budding: immature virus.

  9. Immunoregulatory activities of human immunodeficiency virus (HIV) proteins: Effect of HIV recombinant and synthetic peptides on immunoglobulin synthesis and proliferative responses by normal lymphocytes

    International Nuclear Information System (INIS)

    Nair, M.P.N.; Pottathil, R.; Heimer, E.P.; Schwartz, S.A.

    1988-01-01

    Recombinant and synthetic peptides corresponding to envelope proteins of the human immunodeficiency virus (HIV) were examined for their effects on the activities of lymphocytes from normal donors in vitro. Although lymphocytes cultured with env-gag peptides produced significant amounts of IgG, addition of env-gag peptides to a pokeweed mitogen-induced B-cell activation system resulted in suppression of immunoglobulin synthesis by normal lymphocytes. Recombinant antigens, env-gag and env-80 dihydrofolate reductase (DHFR), produced a substantial proliferative response by peripheral blood mononuclear cells (PBMC) as determined by [ 3 H]thymidine incorporation. PBMC precultured with HIV synthetic peptide env 578-608 also manifested significant proliferative responses as compared to control cultures. CD3 + lymphocytes precultured with recombinant HIV antigens, env-gag and env-80 DHFR, and synthetic HIV peptide, env 487-511, showed moderate but significant proliferative responses. Both recombinant antigens and synthetic peptides also produced a dose-dependent stimulatory effect on proliferation by CD3 - lymphocytes. These studies demonstrate that recombinant and synthetic peptides of the HIV genome express immunoregulatory T- and B-cell epitopes. Identification of unique HIV epitopes with immunogenic and immunoregulatory activities is necessary for the development of an effective vaccine against HIV infection

  10. Inhibition of ecto-ATPase activities impairs HIV-1 infection of macrophages.

    Science.gov (United States)

    Schachter, Julieta; Delgado, Kelly Valcárcel; Barreto-de-Souza, Victor; Bou-Habib, Dumith Chequer; Persechini, Pedro Muanis; Meyer-Fernandes, José Roberto

    2015-05-01

    Nucleotides and nucleosides are secreted into extracellular media at different concentrations as a consequence of different physiologic and pathological conditions. Ecto-nucleotidases, enzymes present on the surface of most cells, hydrolyze these extracellular nucleotides and reduce the concentration of them, thus affecting the activation of different nucleotide and nucleoside receptors. Also, ecto-nucleotidases are present in a number of microorganisms and play important roles in host-pathogen interactions. Here, we characterized the ecto-ATPase activities present on the surface of HIV-1 particle and human macrophages as well. We found that the kinetic properties of HIV-1 and macrophage ecto-ATPases are similar, suggesting that the enzyme is the same. This ecto-ATPase activity was increased in macrophages infected in vitro with HIV-1. Using three different non-related ecto-ATPase inhibitors-POM-1, ARL67156 and BG0-we showed that the inhibition of these macrophage and viral ecto-ATPase activities impairs HIV-1 infection. In addition, we also found that elevated extracellular concentrations of ATP inhibit HIV-1 production by infected macrophages. Copyright © 2014 Elsevier GmbH. All rights reserved.

  11. Radical scavenging and antimicrobial activities of Croton zehntneri, Pterodon emarginatus and Schinopsis brasiliensis essential oils and their major constituents: estragole, trans-anethole, β-caryophyllene and myrcene.

    Science.gov (United States)

    Donati, Maddalena; Mondin, Andrea; Chen, Zheng; Miranda, Fabricio Mendes; do Nascimento, Baraquizio Braga; Schirato, Giulia; Pastore, Paolo; Froldi, Guglielmina

    2015-01-01

    The essential oils (EOs) from the Brazilian species Croton zehntneri, Pterodon emarginatus and Schinopsis brasiliensis were examined for their chemical constituents, and antioxidant and antimicrobial activities. The composition of EOs was determined by using gas chromatography coupled with mass spectrometry analysis, while the antioxidant activity was evaluated through the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) assays. Furthermore, the antimicrobial activity was investigated against Escherichia coli and Pseudomonas aeruginosa (both Gram-negative), Staphylococcus aureus (Gram-positive) and Candida parapsilosis (fungus). The main components of C. zehntneri, P. emarginatus and S. brasiliensis were identified as estragole, trans-anethole, β-caryophyllene and myrcene. Among the EOs, P. emarginatus showed the highest antioxidant activity, with an IC50 of 7.36 mg/mL and a Trolox equivalent antioxidant capacity of 3748 μmol/g determined by DPPH and ORAC assays, respectively. All EOs showed low activities against the bacterial strains tested, whereas the C. zehntneri oil and its main constituent estragole exhibited an appreciable antifungal activity against C. parapsilosis.

  12. Interferon-alpha administration enhances CD8+ T cell activation in HIV infection.

    Directory of Open Access Journals (Sweden)

    Maura Manion

    Full Text Available Type I interferons play important roles in innate immune defense. In HIV infection, type I interferons may delay disease progression by inhibiting viral replication while at the same time accelerating disease progression by contributing to chronic immune activation.To investigate the effects of type I interferons in HIV-infection, we obtained cryopreserved peripheral blood mononuclear cell samples from 10 subjects who participated in AIDS Clinical Trials Group Study 5192, a trial investigating the activity of systemic administration of IFNα for twelve weeks to patients with untreated HIV infection. Using flow cytometry, we examined changes in cell cycle status and expression of activation antigens by circulating T cells and their maturation subsets before, during and after IFNα treatment.The proportion of CD38+HLA-DR+CD8+ T cells increased from a mean of 11.7% at baseline to 24.1% after twelve weeks of interferon treatment (p = 0.006. These frequencies dropped to an average of 20.1% six weeks after the end of treatment. In contrast to CD8+ T cells, the frequencies of activated CD4+ T cells did not change with administration of type I interferon (mean percentage of CD38+DR+ cells = 2.62% at baseline and 2.17% after 12 weeks of interferon therapy. As plasma HIV levels fell with interferon therapy, this was correlated with a "paradoxical" increase in CD8+ T cell activation (p<0.001.Administration of type I interferon increased expression of the activation markers CD38 and HLA DR on CD8+ T cells but not on CD4+ T cells of HIV+ persons. These observations suggest that type I interferons may contribute to the high levels of CD8+ T cell activation that occur during HIV infection.

  13. Assessing the effect of TB-HIV collaborative activities on knowledge ...

    African Journals Online (AJOL)

    Assessing the effect of TB-HIV collaborative activities on knowledge and perception of TB patients ... Tanzania Journal of Health Research ... which requires to be corrected as soon as possible so as to enable patients to undertake active steps ...

  14. Homologous SV40 RNA trans-splicing: Special case or prime example of viral RNA trans-splicing?

    Directory of Open Access Journals (Sweden)

    Sushmita Poddar

    2014-06-01

    Full Text Available To date the Simian Virus 40 (SV40 is the only proven example of a virus that recruits the mechanism of RNA trans-splicing to diversify its sequences and gene products. Thereby, two identical viral transcripts are efficiently joined by homologous trans-splicing triggering the formation of a highly transforming 100 kDa super T antigen. Sequences of other viruses including HIV-1 and the human adenovirus type 5 were reported to be involved in heterologous trans-splicing towards cellular or viral sequences but the meaning of these events remains unclear. We computationally and experimentally investigated molecular features associated with viral RNA trans-splicing and identified a common pattern: Viral RNA trans-splicing occurs between strong cryptic or regular viral splice sites and strong regular or cryptic splice sites of the trans-splice partner sequences. The majority of these splice sites are supported by exonic splice enhancers. Splice sites that could compete with the trans-splicing sites for cis-splice reactions are weaker or inexistent. Finally, all but one of the trans-splice reactions seem to be facilitated by one or more complementary binding domains of 11 to 16 nucleotides in length which, however occur with a statistical probability close to one for the given length of the involved sequences. The chimeric RNAs generated via heterologous viral RNA trans-splicing either did not lead to fusion proteins or led to proteins of unknown function. Our data suggest that distinct viral RNAs are highly susceptible to trans-splicing and that heterologous viral trans-splicing, unlike homologous SV40 trans-splicing, represents a chance event.

  15. The impact of inflammation and immune activation on B cell differentiation during HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Nicolas eRuffin

    2012-01-01

    Full Text Available HIV-1 infection is characterized by continuous antigenic stimulation, chronic immune activation and impaired survival of T and B cells. A decline of resting memory B cells has previously been reported to occur in both children and adults infected with HIV-1; these cells are responsible for mounting and maintaining an adequate serological response to antigens previously encountered in life through natural infection or vaccination. Further understanding of the mechanisms leading to impaired B cell differentiation and germinal center reaction might be essential to design new HIV vaccines and therapies that could improve humoral immune responses in HIV-1 infected individuals. In the present article we summarize the literature and present our view on critical mechanisms of B cell development which are impaired during HIV-1 infection. We also discuss the impact of microbial translocation, a driving force for persistent inflammation during HIV-1 infection, on survival of terminally differentiated B cells and how the altered expression of cytokines/chemokines pivotal for communication between T and B cells in lymphoid tissues may impair formation of memory B cells.

  16. Erectile Dysfunction Among HIV Patients Undergoing Highly Active Antiretroviral Therapy: Dyslipidemia as a Main Risk Factor

    Science.gov (United States)

    Romero-Velez, Gustavo; Lisker-Cervantes, Andrés; Villeda-Sandoval, Christian I; Sotomayor de Zavaleta, Mariano; Olvera-Posada, Daniel; Sierra-Madero, Juan Gerardo; Arreguin-Camacho, Lucrecia O; Castillejos-Molina, Ricardo A

    2014-01-01

    Objective To assess the prevalence and risk factors of erectile dysfunction (ED) in HIV patients from the HIV clinic of a tertiary referral center in Mexico City. Design Prevalence was obtained from cross-sectional studies, and the International Index of Erectile Function (IIEF), a standardized method, was used to assess ED. Methods A cross-sectional study was performed in the HIV clinic. Participants completed the IIEF to allow ED assessment. Information on demographics, clinical and HIV-related variables was retrieved from their medical records. Results One hundred and nine patients were included, with a mean age of 39.9 ± 8.8 years. ED was present in 65.1% of the individuals. Patients had been diagnosed with HIV for a mean of 92.7 ± 70.3 months and had undergone a mean 56.4 ± 45.5 months of HAART. The only variable associated with ED in the univariate analysis was dyslipidemia, and this association was also found in the multivariate analysis (P = 0.01). Conclusions ED is highly prevalent in HIV patients. Dyslipidemia should be considered as a risk factor for ED in HIV patients. Romero-Velez G, Lisker-Cervantes A, Villeda-Sandoval CI, Sotomayor de Zavaleta M, Olvera-Posada D, Sierra-Madero JG, Arreguin-Camacho LO, and Castillejos-Molina RA. Erectile dysfunction among HIV patients undergoing highly active antiretroviral therapy: Dyslipidemia as a main risk factor. Sex Med 2014;2:24–30. PMID:25356298

  17. Depression and Anxiety are Common in Acute HIV Infection and Associate with Plasma Immune Activation.

    Science.gov (United States)

    Hellmuth, Joanna; Colby, Donn; Valcour, Victor; Suttichom, Duanghathai; Spudich, Serena; Ananworanich, Jintanat; Prueksakaew, Peeriya; Sailasuta, Napapon; Allen, Isabel; Jagodzinski, Linda L; Slike, Bonnie; Ochi, Derek; Paul, Robert

    2017-11-01

    This observational study of 123 Thai participants sought to determine the rate and severity of affective symptoms during acute HIV infection (AHI) and possible associations to disease mechanisms. At diagnosis, just prior to starting combination antiretroviral therapy (cART), AHI participants completed assessments of depression and anxiety symptoms that were repeated at 4, 12, and 24 weeks. Blood markers of HIV infection and immune activation were measured at study entry, with optional cerebrospinal fluid measures. A high frequency of participants reported symptoms that exceeded published thresholds supportive of depression (55.0%) and anxiety (65.8%) at diagnosis, with significant reductions after starting cART. Meeting a threshold for clinically relevant depressive symptoms at study entry was associated with higher baseline plasma HIV RNA (5.98 vs. 5.50, t = 2.46, p = 0.015), lower CD4 counts (328 vs. 436 cells/mm 3 , t = 3.46, p = 0.001), and higher plasma neopterin, a marker of macrophage activation (2694 vs. 1730 pg/mL, Mann-Whitney U = 152.5, p = 0.011). Controlling for plasma HIV RNA and CD4 count, higher baseline plasma neopterin correlated with worse initial depression and anxiety scores. Depression and anxiety symptoms are frequent in acute HIV infection, associate with plasma immune activation, and can improve concurrent with cART.

  18. Engagement in Care During Active Duty HIV Treatment

    Science.gov (United States)

    2017-06-01

    Technical Manual NMCPHC – TM 6100.99-9F, Sexual Health and Responsibility Program, Department of the Navy, Portsmouth, VA. 67 Navy and Marine Corps...Corps Public Health Center (2016b) Reproductive and Sexual Health: Human Immunodeficiency Virus (HIV) among sailors and marines. Fact Sheet, Navy...information is estimated to average 1 hour per response , including the time for reviewing instruction, searching existing data sources, gathering and

  19. Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells.

    Science.gov (United States)

    Vacharaksa, Anjalee; Asrani, Anil C; Gebhard, Kristin H; Fasching, Claudine E; Giacaman, Rodrigo A; Janoff, Edward N; Ross, Karen F; Herzberg, Mark C

    2008-07-17

    Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers. To determine the plausibility that oral keratinocytes are primary targets of HIV-1, we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner. To study the fate of HIV-1, immortalized oral keratinocytes (OKF6/TERT-2; TERT-2 cells) were characterized for the fate of HIV-specific RNA and DNA. At 6 h post inoculation with X4 or R5-tropic HIV-1, HIV-1gag RNA was detected maximally within TERT-2 cells. Reverse transcriptase activity in TERT-2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Deltaenv-EGFP. AZT inhibited EGFP expression in a dose-dependent manner, suggesting that viral replication can be supported if receptors are bypassed. Within 3 h post inoculation, integrated HIV-1 DNA was detected in TERT-2 cell nuclei and persisted after subculture. Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation, suggesting that HIV replication may abort and that infection is non-productive. Within 48 h post inoculation, however, virus harbored by CD4 negative TERT-2 cells trans infected co-cultured peripheral blood mononuclear cells (PBMCs) or MOLT4 cells (CD4+ CCR5+) by direct cell-to-cell transfer or by releasing low levels of infectious virions. Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner. Oral keratinocytes appear, therefore, to support stable non-replicative integration, while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h.

  20. Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells

    Directory of Open Access Journals (Sweden)

    Giacaman Rodrigo A

    2008-07-01

    Full Text Available Abstract Background Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers. To determine the plausibility that oral keratinocytes are primary targets of HIV-1, we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner. Results To study the fate of HIV-1, immortalized oral keratinocytes (OKF6/TERT-2; TERT-2 cells were characterized for the fate of HIV-specific RNA and DNA. At 6 h post inoculation with X4 or R5-tropic HIV-1, HIV-1gag RNA was detected maximally within TERT-2 cells. Reverse transcriptase activity in TERT-2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Δenv-EGFP. AZT inhibited EGFP expression in a dose-dependent manner, suggesting that viral replication can be supported if receptors are bypassed. Within 3 h post inoculation, integrated HIV-1 DNA was detected in TERT-2 cell nuclei and persisted after subculture. Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation, suggesting that HIV replication may abort and that infection is non-productive. Within 48 h post inoculation, however, virus harbored by CD4 negative TERT-2 cells trans infected co-cultured peripheral blood mononuclear cells (PBMCs or MOLT4 cells (CD4+ CCR5+ by direct cell-to-cell transfer or by releasing low levels of infectious virions. Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner. Conclusion Oral keratinocytes appear, therefore, to support stable non-replicative integration, while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h.

  1. Synthesis of high specific activity tritium labelled 1S,2S-(-)-trans-2-isothiocyanato-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)benzene acetamide, a specific irreversible ligand for kappa opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Costa, B.R. de; Thurkauf, A.; Rothman, R.R. (National Inst. of Mental Health, Bethesda, MD (USA)); Jacobson, A.E.; Rice, K.C. (National Inst. of Digestive Diabetes, and Kidney Diseases, Bethesda, MD (USA))

    1990-11-01

    Optically pure tritium labeled 1S,2S-(-)-trans-2-isothiocyanato-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl )benzeneacetamide, an affinity ligand specific for the kappa opioid receptor was synthesized from optically pure 1S,2S-(-)-trans-2-amino-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)benzeneacetamide via the sequence of dibromination (57%) followed by catalytic tritiation of the dibromide. The resulting tritium labelled aniline (14% yield, specific activity 31.2 Ci/mmol) was transformed to the title compound in 13.3% yield and 99+% radiochemical purity by treatment with thiophosgene. (author).

  2. eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients.

    Directory of Open Access Journals (Sweden)

    Meredith E Davis-Gardner

    2017-12-01

    Full Text Available Antibody-dependent cell-mediated cytotoxity (ADCC can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8. Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1 can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2 exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10-1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFα. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells.

  3. Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity.

    Science.gov (United States)

    Almeida, Jorge R; Sauce, Delphine; Price, David A; Papagno, Laura; Shin, So Youn; Moris, Arnaud; Larsen, Martin; Pancino, Gianfranco; Douek, Daniel C; Autran, Brigitte; Sáez-Cirión, Asier; Appay, Victor

    2009-06-18

    CD8(+) T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8(+) T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIV-suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8(+) T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8(+) T cells from infected donors. We report that attributes of CD8(+) T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8(+) T cells display polyfunctional profiles and potent HIV-suppressive activity. These data provide new insights into the mechanisms underlying CD8(+) T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T cells with high levels of antigen sensitivity to elicit potent antiviral efficacy.

  4. Persistent inflammation and endothelial activation in HIV-1 infected patients after 12 years of antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Frederikke F Rönsholt

    Full Text Available The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART.Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, β2-microglobulin, interleukin (IL 8, tumor necrosis factor α (TNFα, vascular cell adhesion molecule-1 (sVCAM-1, intercellular adhesion molecule-1 (sICAM-1, sE-Selectin, and sP-Selectin.HIV infected patients had higher levels of β2-microglobulin, IL-8, TNFα, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls.Discrete signs of systemic and vascular inflammation persist even after very long term cART.

  5. Cis By Trans

    OpenAIRE

    Rodovalho,Amara Moira

    2017-01-01

    Cis, trans: above all, metaphors. Cisjordan, region skirting the Jordan River. Cisplatin, Uruguay’s ancient name, region occupying one of the banks of the Prata River. Trans- Amazonian, that which crosses the Amazon; transatlantic, that which crosses the Atlantic. Cisalpine, transalpine. The geometric isomerism of Organic Chemistry, where “cis” are atoms that, when molecules are divided in half, remain on the same side, and “trans” those remaining on opposite sides. Ev...

  6. HIV Infection Is Associated With Poor Outcomes for Patients With Anal Cancer in the Highly Active Antiretroviral Therapy Era.

    Science.gov (United States)

    Grew, David; Bitterman, Danielle; Leichman, Cynthia G; Leichman, Lawrence; Sanfilippo, Nicholas; Moore, Harvey G; Du, Kevin

    2015-12-01

    HIV status may affect outcomes after definitive chemoradiotherapy for anal cancer. Here, we report a large series in the highly active antiretroviral therapy era comparing outcomes between HIV-positive and HIV-negative patients with anal cancer. This was a retrospective chart review. The study was conducted at an outpatient oncology clinic at large academic center. A total of 107 patients were reviewed, 39 HIV positive and 68 HIV negative. All of the patients underwent definitive chemoradiation for anal cancer. Data on patient characteristics, treatment, toxicity, and outcomes were collected. Overall survival, colostomy-free survival, local recurrence-free survival, and distant metastasis-free survival were analyzed. Median follow-up was 15 months. HIV-positive patients were younger (median, 52 vs 64 years; p HIV-positive patients had a significantly longer duration from biopsy to start of chemoradiation (mean number of days, 82 vs 54; p = 0.042). There were no differences in rates of acute toxicities including diarrhea, fatigue, or dermatitis. HIV-positive patients had significantly higher rates of hospitalization (33% vs 15%; p = 0.024). The 3-year overall survival rate was 42% in HIV-positive and 76% in HIV-negative patients (p = 0.037; HR, 2.335 (95% CI, 1.032-5.283)). Three-year colostomy-free survival was 67% in HIV-positive and 88% in HIV-negative patients (p = 0.036; HR, 3.231 (95% CI, 1.014-10.299)). Differences in overall survival rates were not significant on multivariate analysis. This study was limited by its retrospective design and small patient numbers. In this cohort, HIV-positive patients had significantly worse overall and colostomy-free survival rates than HIV-negative patients. However, differences in survival were not significant on multivariate analysis. Additional studies are necessary to establish the etiology of this difference.

  7. Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression.

    Science.gov (United States)

    Zaikos, Thomas D; Painter, Mark M; Sebastian Kettinger, Nadia T; Terry, Valeri H; Collins, Kathleen L

    2018-03-15

    Combinations of drugs that affect distinct mechanisms of HIV latency aim to induce robust latency reversal leading to cytopathicity and elimination of the persistent HIV reservoir. Thus far, attempts have focused on combinations of protein kinase C (PKC) agonists and pan-histone deacetylase inhibitors (HDIs) despite the knowledge that HIV gene expression is regulated by class 1 histone deacetylases. We hypothesized that class 1-selective HDIs would promote more robust HIV latency reversal in combination with a PKC agonist than pan-HDIs because they preserve the activity of proviral factors regulated by non-class 1 histone deacetylases. Here, we show that class 1-selective agents used alone or with the PKC agonist bryostatin-1 induced more HIV protein expression per infected cell. In addition, the combination of entinostat and bryostatin-1 induced viral outgrowth, whereas bryostatin-1 combinations with pan-HDIs did not. When class 1-selective HDIs were used in combination with pan-HDIs, the amount of viral protein expression and virus outgrowth resembled that of pan-HDIs alone, suggesting that pan-HDIs inhibit robust gene expression induced by class 1-selective HDIs. Consistent with this, pan-HDI-containing combinations reduced the activity of NF-κB and Hsp90, two cellular factors necessary for potent HIV protein expression, but did not significantly reduce overall cell viability. An assessment of viral clearance from in vitro cultures indicated that maximal protein expression induced by class 1-selective HDI treatment was crucial for reservoir clearance. These findings elucidate the limitations of current approaches and provide a path toward more effective strategies to eliminate the HIV reservoir. IMPORTANCE Despite effective antiretroviral therapy, HIV evades eradication in a latent form that is not affected by currently available drug regimens. Pharmacologic latency reversal that leads to death of cellular reservoirs has been proposed as a strategy for

  8. Controlling cellular P-TEFb activity by the HIV-1 transcriptional transactivator Tat.

    Directory of Open Access Journals (Sweden)

    Lisa Muniz

    Full Text Available The human immunodeficiency virus 1 (HIV-1 transcriptional transactivator (Tat is essential for synthesis of full-length transcripts from the integrated viral genome by RNA polymerase II (Pol II. Tat recruits the host positive transcription elongation factor b (P-TEFb to the HIV-1 promoter through binding to the transactivator RNA (TAR at the 5'-end of the nascent HIV transcript. P-TEFb is a general Pol II transcription factor; its cellular activity is controlled by the 7SK small nuclear RNA (snRNA and the HEXIM1 protein, which sequester P-TEFb into transcriptionally inactive 7SK/HEXIM/P-TEFb snRNP. Besides targeting P-TEFb to HIV transcription, Tat also increases the nuclear level of active P-TEFb through promoting its dissociation from the 7SK/HEXIM/P-TEFb RNP by an unclear mechanism. In this study, by using in vitro and in vivo RNA-protein binding assays, we demonstrate that HIV-1 Tat binds with high specificity and efficiency to an evolutionarily highly conserved stem-bulge-stem motif of the 5'-hairpin of human 7SK snRNA. The newly discovered Tat-binding motif of 7SK is structurally and functionally indistinguishable from the extensively characterized Tat-binding site of HIV TAR and importantly, it is imbedded in the HEXIM-binding elements of 7SK snRNA. We show that Tat efficiently replaces HEXIM1 on the 7SK snRNA in vivo and therefore, it promotes the disassembly of the 7SK/HEXIM/P-TEFb negative transcriptional regulatory snRNP to augment the nuclear level of active P-TEFb. This is the first demonstration that HIV-1 specifically targets an important cellular regulatory RNA, most probably to promote viral transcription and replication. Demonstration that the human 7SK snRNA carries a TAR RNA-like Tat-binding element that is essential for the normal transcriptional regulatory function of 7SK questions the viability of HIV therapeutic approaches based on small drugs blocking the Tat-binding site of HIV TAR.

  9. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).

    Science.gov (United States)

    Yamamoto, Nobuto; Ushijima, Naofumi; Koga, Yoshihiko

    2009-01-01

    Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-N-acetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore, macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage activating factor (termed GcMAF), which produces no side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a large amount of Fc-receptors as well as an enormous variation of receptors that recognize IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and constantly release HIV virions, the activated macrophages rapidly intercept the released HIV virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18 weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection, which was also confirmed by no infectious center formation by provirus inducing agent-treated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were maintained for 7 years.

  10. Electrochemistry of deferiprone as an orally active iron chelator and HIV-1 replication inhibitor and its determination

    OpenAIRE

    Yadegari, H.; Jabbari, A.; Heli, H.; Moosavi-Movahedi, A. A.; Majdi, S.

    2008-01-01

    The electrochemical behavior of the anti-thalassemia and anti-HIV replication drug, deferiprone, was investigated by cyclic voltammetry (CV) at a platinum electrode. In an acetate buffer solution, pH = 4.0, two irreversible anodic peaks for deferiprone, with E(0)1 = 875 mV and E(0)2 = 1235 mV (vs. Ag/AgCl) appeared at a potential sweep rate of 50 mV s-1. Cyclic voltammetric study indicated that the oxidation process is irreversible and diffusion-controlled. The diffusion and the electron tran...

  11. Development of a Fish Cell Biosensor System for Genotoxicity Detection Based on DNA Damage-Induced Trans-Activation of p21 Gene Expression

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    Huarong Guo

    2012-09-01

    Full Text Available p21CIP1/WAF1 is a p53-target gene in response to cellular DNA damage. Here we report the development of a fish cell biosensor system for high throughput genotoxicity detection of new drugs, by stably integrating two reporter plasmids of pGL3-p21-luc (human p21 promoter linked to firefly luciferase and pRL-CMV-luc (CMV promoter linked to Renilla luciferase into marine flatfish flounder gill (FG cells, referred to as p21FGLuc. Initial validation of this genotoxicity biosensor system showed that p21FGLuc cells had a wild-type p53 signaling pathway and responded positively to the challenge of both directly acting genotoxic agents (bleomycin and mitomycin C and indirectly acting genotoxic agents (cyclophosphamide with metabolic activation, but negatively to cyclophosphamide without metabolic activation and the non-genotoxic agents ethanol and D-mannitol, thus confirming a high specificity and sensitivity, fast and stable response to genotoxic agents for this easily maintained fish cell biosensor system. This system was especially useful in the genotoxicity detection of Di(2-ethylhexyl phthalate (DEHP, a rodent carcinogen, but negatively reported in most non-mammalian in vitro mutation assays, by providing a strong indication of genotoxicity for DEHP. A limitation for this biosensor system was that it might give false positive results in response to sodium butyrate and any other agents, which can trans-activate the p21 gene in a p53-independent manner.

  12. Implementation and outcomes of an active defaulter tracing system for HIV, prevention of mother to child transmission of HIV (PMTCT), and TB patients in Kibera, Nairobi, Kenya.

    Science.gov (United States)

    Thomson, Kerry A; Cheti, Erastus O; Reid, Tony

    2011-06-01

    Retention of patients in long term care and adherence to treatment regimens are a constant challenge for HIV, prevention of mother to child transmission of HIV (PMTCT), and TB programmes in sub-Saharan Africa. This study describes the implementation and outcomes of an active defaulter tracing system used to reduce loss to follow-up (LTFU) among HIV, PMTCT, TB, and HIV/TB co-infected patients receiving treatment at three Médecins Sans Frontières clinics in the informal settlement of Kibera, Nairobi, Kenya. Patients are routinely contacted by a social worker via telephone, in-person visit, or both very soon after they miss an appointment. Patient outcomes identified through 1066 tracing activities conducted between 1 April 2008 and 31 March 2009 included: 59.4% returned to the clinic, 9.0% unable to return to clinic, 6.3% died, 4.7% refused to return to clinic, 4.5% went to a different clinic, and 0.8% were hospitalized. Fifteen percent of patients identified for tracing could not be contacted. LTFU among all HIV patients decreased from 21.2% in 2006 to 11.5% in 2009. An active defaulter tracing system is feasible in a resource poor setting, solicits feedback from patients, retains a mobile population of patients in care, and reduces LTFU among HIV, PMTCT, and TB patients. Copyright © 2011 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

  13. HIV-1-negative female sex workers sustain high cervical IFNɛ, low immune activation, and low expression of HIV-1-required host genes.

    Science.gov (United States)

    Abdulhaqq, S A; Zorrilla, C; Kang, G; Yin, X; Tamayo, V; Seaton, K E; Joseph, J; Garced, S; Tomaras, G D; Linn, K A; Foulkes, A S; Azzoni, L; VerMilyea, M; Coutifaris, C; Kossenkov, A V; Showe, L; Kraiselburd, E N; Li, Q; Montaner, L J

    2016-07-01

    Sex workers practicing in high HIV endemic areas have been extensively targeted to test anti-HIV prophylactic strategies. We hypothesize that in women with high levels of genital exposure to semen changes in cervico-vaginal mucosal and/or systemic immune activation will contribute to a decreased susceptibility to HIV-1 infection. To address this question, we assessed sexual activity and immune activation status (in peripheral blood), as well as cellular infiltrates and gene expression in ectocervical mucosa biopsies in female sex workers (FSWs; n=50), as compared with control women (CG; n=32). FSWs had low-to-absent HIV-1-specific immune responses with significantly lower CD38 expression on circulating CD4(+) or CD8(+) T-cells (both: PHIV-1 integration and replication. A correlative relationship between semen exposure and elevated type-1 IFN expression in FSWs was also established. Overall, our data suggest that long-term condomless sex work can result in multiple changes within the cervico-vaginal compartment that would contribute to sustaining a lower susceptibility for HIV-1 infection in the absence of HIV-specific responses.

  14. Rapid turnover of 2-LTR HIV-1 DNA during early stage of highly active antiretroviral therapy.

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    Weijun Zhu

    Full Text Available BACKGROUND: Despite prolonged treatment with highly active antiretroviral therapy (HAART, the infectious HIV-1 continues to replicate and resides latently in the resting memory CD4+ T lymphocytes, which blocks the eradication of HIV-1. The viral persistence of HIV-1 is mainly caused by its proviral DNA being either linear nonintegrated, circular nonintegrated, or integrated. Previous reports have largely focused on the dynamics of HIV-1 DNA from the samples collected with relatively long time intervals during the process of disease and HAART treatment, which may have missed the intricate changes during the intervals in early treatment. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the dynamics of HIV-1 DNA in patients during the early phase of HARRT treatment. Using optimized real time PCR, we observed significant changes in 2-LTR during the first 12-week of treatment, while total and integrated HIV-1 DNA remained stable. The doubling time and half-life of 2-LTR were not correlated with the baseline and the rate of changes in plasma viral load and various CD4+ T-cell populations. Longitudinal analyses on 2-LTR sequences and plasma lipopolysaccharide (LPS levels did not reveal any significant changes in the same treatment period. CONCLUSIONS/SIGNIFICANCE: Our study revealed the rapid changes in 2-LTR concentration in a relatively large number of patients during the early HAART treatment. The rapid changes indicate the rapid infusion and clearance of cells bearing 2-LTR in the peripheral blood. Those changes are not expected to be caused by the blocking of viral integration, as our study did not include the integrase inhibitor raltegravir. Our study helps better understand the dynamics of HIV-DNA and its potential role as a biomarker for the diseases and for the treatment efficacy of HAART.

  15. Quality of life of people living with HIV/AIDS and on highly active ...

    African Journals Online (AJOL)

    Quality of life of people living with HIV/AIDS and on highly active ... the Short Form-36 Health Survey (SF-36) was used to measure quality of life among patients on ... instrument for use in Ethiopia to assess the quality of life of people living with ...

  16. Estimation of Anti-HIV Activity of HEPT Analogues Using MLR, ANN, and SVM Techniques

    Directory of Open Access Journals (Sweden)

    Basheerulla Shaik

    2013-01-01

    value than those of MLR and SVM techniques. Rm2= metrics and ridge regression analysis indicated that the proposed four-variable model MATS5e, RDF080u, T(O⋯O, and MATS5m as correlating descriptors is the best for estimating the anti-HIV activity (log 1/C present set of compounds.

  17. Prevalence of oral candidiasis in HIV/AIDS children in highly active antiretroviral therapy era. A literature analysis.

    Science.gov (United States)

    Gaitán-Cepeda, Luis Alberto; Sánchez-Vargas, Octavio; Castillo, Nydia

    2015-08-01

    SummaryHighly active antiretroviral therapy has decreased the morbidity and mortality related to HIV infection, including oral opportunistic infections. This paper offers an analysis of the scientific literature on the epidemiological aspects of oral candidiasis in HIV-positive children in the combination antiretroviral therapy era. An electronic databases search was made covering the highly active antiretroviral therapy era (1998 onwards). The terms used were oral lesions, oral candidiasis and their combination with highly active antiretroviral therapy and HIV/AIDS children. The following data were collected from each paper: year and country in which the investigation was conducted, antiretroviral treatment, oral candidiasis prevalence and diagnostic parameters (clinical or microbiological). Prevalence of oral candidiasis varied from 2.9% in American HIV-positive children undergoing highly active antiretroviral therapy to 88% in Chilean HIV-positive children without antiretroviral therapy. With respect to geographical location and antiretroviral treatment, higher oral candidiasis prevalence in HIV-positive children on combination antiretroviral therapy/antiretroviral therapy was reported in African children (79.1%) followed by 45.9% reported in Hindu children. In HIV-positive Chilean children on no antiretroviral therapy, high oral candidiasis prevalence was reported (88%) followed by Nigerian children (80%). Oral candidiasis is still frequent in HIV-positive children in the highly active antiretroviral therapy era irrespective of geographical location, race and use of antiretroviral therapy. © The Author(s) 2014.

  18. Serum neutralizing activities from a Beijing homosexual male cohort infected with different subtypes of HIV-1 in China.

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    Mingshun Zhang

    Full Text Available Protective antibodies play a critical role in an effective HIV vaccine; however, eliciting antibodies to block infection by viruses from diverse genetic subtypes remains a major challenge. As the world's most populous country, China has been under the threat of at least three major subtypes of circulating HIV-1 viruses. Understanding the cross reactivity and specificities of serum antibody responses that mediate broad neutralization of the virus in HIV-1 infected Chinese patients will provide valuable information for the design of vaccines to prevent HIV-1 transmission in China. Sera from a cohort of homosexual men, who have been managed by a major HIV clinical center in Beijing, China, were analyzed for cross-sectional neutralizing activities against pseudotyped viruses expressing Env antigens of the major subtype viruses (AE, BC and B subtypes circulating in China. Neutralizing activities in infected patients' blood were most capable of neutralizing viruses in the homologous subtype; however, a subset of blood samples was able to achieve broad neutralizing activities across different subtypes. Such cross neutralizing activity took 1-2 years to develop and CD4 binding site antibodies were critical components in these blood samples. Our study confirmed the presence of broadly neutralizing sera in China's HIV-1 patient population. Understanding the specificity and breadth of these neutralizing activities can guide efforts for the development of HIV vaccines against major HIV-1 viruses in China.

  19. Physical Activity Status and Position of Governmental Employees in Changing Stage Based on the Trans-Theoretical Model in Hamadan, Iran.

    Science.gov (United States)

    Abdi, Jalal; Eftekhar, Hassan; Mahmoodi, Mahmood; Shojayzadeh, Davood; Sadeghi, Roya

    2015-02-24

    Physical inactivity is the fourth leading risk factor for death worldwide. Given the key role of employees as valuable human resources and increasing sedentary life style among them, the aim of this study was to evaluate physical activity status and position of governmental employees in changing stage based on the Trans-Theoretical Model (TTM) in Hamadan, Iran, in 2014.This descriptive-analytical study was performed on 1200 government employees selected using proportional stratified random sampling. Data collection was performed using a three-section questionnaire containing demographic characteristics, SQUASH (Short questionnaire to assess health-enhancing physical activity) questionnaire and Marcus et al's five-part algoritm. Data were analyzed by multiple linear and logistic regression, Chi-square, T-test and ANOVA using SPSS-20. The mean age of the participants was 38.12±8.04 years. About a half of the employees were in the preparatory stage of TTM.49.2% and 50.8% of the sample were classified as active and inactive, respectively .Associations between physical activity status and exercise stage of change were found. The associations between exercise stage of change and age, sex, work experience, education and marital status were significant (pphysical activity (PA) status and accounted for 31.2% of variance in PA (adjusted R2=0.312, R2 change=0.01). The results of this study showed that TTM was useful to evaluate and predict physical activity behavior among the Iranian governmental employees and can be utilized by health planners to inform appropriate intervention strategies, specifically in work place.

  20. Peer outreach work as economic activity: implications for HIV prevention interventions among female sex workers.

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    Annie George

    Full Text Available Female sex workers (FSWs who work as peer outreach workers in HIV prevention programs are drawn from poor socio-economic groups and consider outreach work, among other things, as an economic activity. Yet, while successful HIV prevention outcomes by such programs are attributed in part to the work of peers who have dense relations with FSW communities, there is scant discussion of the economic implications for FSWs of their work as peers. Using observational data obtained from an HIV prevention intervention for FSWs in south India, we examined the economic benefits and costs to peers of doing outreach work and their implications for sex workers' economic security. We found that peers considered their payment incommensurate with their workload, experienced long delays receiving compensation, and at times had to advance money from their pockets to do their assigned peer outreach work. For the intervention these conditions resulted in peer attrition and difficulties in recruitment of new peer workers. We discuss the implications of these findings for uptake of services, and the possibility of reaching desired HIV outcomes. Inadequate and irregular compensation to peers and inadequate budgetary outlays to perform their community-based outreach work could weaken peers' relationships with FSW community members, undermine the effectiveness of peer-mediated HIV prevention programs and invalidate arguments for the use of peers.

  1. Predictors of psychological well-being in a diverse sample of HIV-positive patients receiving highly active antiretroviral therapy.

    Science.gov (United States)

    Safren, Steven A; Radomsky, Adam S; Otto, Michael W; Salomon, Elizabeth

    2002-01-01

    The purpose of the present study was to identify variables relevant to psychological well-being in HIV patients receiving highly active antiretroviral therapy (HAART). Multiple stressors accompany living with HIV while managing a HAART regimen. However, a variety of cognitive and behavioral variables can protect against or augment the deleterious effects of stress in this population. The authors hypothesized that satisfaction with social support, coping styles, and maladaptive attributions about HIV would explain more variance in psychological well-being than stressful life events per se. Participants were individuals with HIV receiving antiretroviral therapy-either starting a new HAART regimen or having difficulties adhering to their current regimen. Satisfaction with social support, coping styles, and punishment beliefs about HIV were uniquely associated with depression, quality of life, and self-esteem over and above the effects of stressful life events. These results provide support for continued psychosocial interventions that target these variables among patients with HIV.

  2. CD4+ and CD8+ T cell activation are associated with HIV DNA in resting CD4+ T cells.

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    Leslie R Cockerham

    Full Text Available The association between the host immune environment and the size of the HIV reservoir during effective antiretroviral therapy is not clear. Progress has also been limited by the lack of a well-accepted assay for quantifying HIV during therapy. We examined the association between multiple measurements of HIV and T cell activation (as defined by markers including CD38, HLA-DR, CCR5 and PD-1 in 30 antiretroviral-treated HIV-infected adults. We found a consistent association between the frequency of CD4+ and CD8+ T cells expressing HLA-DR and the frequency of resting CD4+ T cells containing HIV DNA. This study highlights the need to further examine this relationship and to better characterize the biology of markers commonly used in HIV studies. These results may also have implications for reactivation strategies.

  3. Whole-genome analysis of genetic recombination of hepatitis delta virus: molecular domain in delta antigen determining trans-activating efficiency.

    Science.gov (United States)

    Chao, Mei; Lin, Chia-Chi; Lin, Feng-Ming; Li, Hsin-Pai; Iang, Shan-Bei

    2015-12-01

    Hepatitis delta virus (HDV) is the only animal RNA virus that has an unbranched rod-like genome with ribozyme activity and is replicated by host RNA polymerase. HDV RNA recombination was previously demonstrated in patients and in cultured cells by analysis of a region corresponding to the C terminus of the delta antigen (HDAg), the only viral-encoded protein. Here, a whole-genome recombination map of HDV was constructed using an experimental system in which two HDV-1 sequences were co-transfected into cultured cells and the recombinants were analysed by sequencing of cloned reverse transcription-PCR products. Fifty homologous recombinants with 60 crossovers mapping to 22 junctions were identified from 200 analysed clones. Small HDAg chimeras harbouring a junction newly detected in the recombination map were then constructed. The results further indicated that the genome-replication level of HDV was sensitive to the sixth amino acid within the N-terminal 22 aa of HDAg. Therefore, the recombination map established in this study provided a tool for not only understanding HDV RNA recombination, but also elucidating the related mechanisms, such as molecular elements responsible for the trans-activation levels of the small HDAg.

  4. Hepatitis C virus NS5A protein is a substrate for the peptidyl-prolyl cis/trans isomerase activity of cyclophilins A and B.

    Science.gov (United States)

    Hanoulle, Xavier; Badillo, Aurélie; Wieruszeski, Jean-Michel; Verdegem, Dries; Landrieu, Isabelle; Bartenschlager, Ralf; Penin, François; Lippens, Guy

    2009-05-15

    We report here a biochemical and structural characterization of domain 2 of the nonstructural 5A protein (NS5A) from the JFH1 Hepatitis C virus strain and its interactions with cyclophilins A and B (CypA and CypB). Gel filtration chromatography, circular dichroism spectroscopy, and finally NMR spectroscopy all indicate the natively unfolded nature of this NS5A-D2 domain. Because mutations in this domain have been linked to cyclosporin A resistance, we used NMR spectroscopy to investigate potential interactions between NS5A-D2 and cellular CypA and CypB. We observed a direct molecular interaction between NS5A-D2 and both cyclophilins. The interaction surface on the cyclophilins corresponds to their active site, whereas on NS5A-D2, it proved to be distributed over the many proline residues of the domain. NMR heteronuclear exchange spectroscopy yielded direct evidence that many proline residues in NS5A-D2 form a valid substrate for the enzymatic peptidyl-prolyl cis/trans isomerase (PPIase) activity of CypA and CypB.

  5. O6-alkylguanine-DNA alkyltransferase activity correlates with the therapeutic response of human rhabdomyosarcoma xenografts to 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea

    International Nuclear Information System (INIS)

    Brent, T.P.; Houghton, P.J.; Houghton, J.A.

    1985-01-01

    Immune-deprived female CBA/CaJ mice bearing xenografts of six different human rhabdomyosarcoma lines were treated with 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU). Tumor responses were compared with levels of O 6 -methylguanine-DNA methyltransferase activity because of evidence indicating that repair of DNA interstrand cross-link precursors, mediated by the transferase, may be an important determinant of MeCCNU cytotoxicity. Levels of methyltransferase in tumor extracts were measured by determining the loss of O 6 -methylguanine from 3 H-labeled methylated DNA. Five of the six tumor lines examined showed either no response to MeCCNU or regrowth after an incomplete response. In each instance, the extent of tumor regression correlated with the level of O 6 -methylguanine-DNA methyltransferase activity in tumor extracts. These results suggest that O 6 -methylguanine-DNA methyltransferase levels in human tumor cells may be a clinically useful predictor of sensitivity to the chloroethylnitrosoureas

  6. Antimicrobial, antioxidant and sensory features of eugenol, carvacrol and trans-anethole in active packaging for organic ready-to-eat iceberg lettuce.

    Science.gov (United States)

    Wieczyńska, Justyna; Cavoski, Ivana

    2018-09-01

    In this study, bio-based emitting sachets containing eugenol (EUG), carvacrol (CAR) and trans-anethole (ANT) were inserted into cellulose (CE) and polypropylene (PP) pillow packages of organic ready-to-eat (RTE) iceberg lettuce to investigate their functional features. EUG, CAR and ANT sachets in CE; and CAR in PP packages showed antimicrobial activities against coliforms (Δlog CFU g -1 of -1.38, -0.91, -0.93 and -0.93, respectively). EUG and ANT sachets in both packages reduced discoloration (ΔE of 9.5, 1.8, 9.4 and 5.6, respectively). ANT in both, and EUG only in PP packages induced biosynthesis of caffeoyl derivatives (C a T A , D i C a T A , D i C a Q A ), total phenolics and antioxidant activity (FRAP). Also, ANT and EUG in both packages improved overall freshness and odor. Principal component analysis separated ANT and EUG from CAR in both packages. The Pearson correlation confirmed that overall quality improvements were more pronounced by ANT inside the packages in comparison to EUG and CAR. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Trans fat consumption and aggression.

    Directory of Open Access Journals (Sweden)

    Beatrice A Golomb

    Full Text Available Dietary trans fatty acids (dTFA are primarily synthetic compounds that have been introduced only recently; little is known about their behavioral effects. dTFA inhibit production of omega-3 fatty acids, which experimentally have been shown to reduce aggression. Potential behavioral effects of dTFA merit investigation. We sought to determine whether dTFA are associated with aggression/irritability. METHODOLGY/PRINICPAL FINDINGS: We capitalized on baseline dietary and behavioral assessments in an existing clinical trial to analyze the relationship of dTFA to aggression. Of 1,018 broadly sampled baseline subjects, the 945 adult men and women who brought a completed dietary survey to their baseline visit are the target of this analysis. Subjects (seen 1999-2004 were not on lipid medications, and were without LDL-cholesterol extremes, diabetes, HIV, cancer or heart disease. Outcomes assessed adverse behaviors with impact on others: Overt Aggression Scale Modified-aggression subscale (primary behavioral endpoint; Life History of Aggression; Conflict Tactics Scale; and self-rated impatience and irritability. The association of dTFA to aggression was analyzed via regression and ordinal logit, unadjusted and adjusted for potential confounders (sex, age, education, alcohol, and smoking. Additional analyses stratified on sex, age, and ethnicity, and examined the prospective association. Greater dTFA were strongly significantly associated with greater aggression, with dTFA more consistently predictive than other assessed aggression predictors. The relationship was upheld with adjustment for confounders, was preserved across sex, age, and ethnicity strata, and held cross-sectionally and prospectively.This study provides the first evidence linking dTFA with behavioral irritability and aggression. While confounding is always a concern in observational studies, factors including strength and consistency of association, biological gradient, temporality, and

  8. Intimacy versus isolation: a qualitative study of sexual practices among sexually active HIV-infected patients in HIV care in Brazil, Thailand, and Zambia.

    Directory of Open Access Journals (Sweden)

    Elizabeth F Closson

    Full Text Available The success of global treatment as prevention (TasP efforts for individuals living with HIV/AIDS (PLWHA is dependent on successful implementation, and therefore the appropriate contribution of social and behavioral science to these efforts. Understanding the psychosocial context of condomless sex among PLWHA could shed light on effective points of intervention. HPTN 063 was an observational mixed-methods study of sexually active, in-care PLWHA in Thailand, Zambia, and Brazil as a foundation for integrating secondary HIV prevention into HIV treatment. From 2010-2012, 80 qualitative interviews were conducted with PLWHA receiving HIV care and reported recent sexual risk. Thirty men who have sex with women (MSW and 30 women who have sex with men (WSM participated in equal numbers across the sites. Thailand and Brazil also enrolled 20 biologically-born men who have sex with men (MSM. Part of the interview focused on the impact of HIV on sexual practices and relationships. Interviews were recorded, transcribed, translated into English and examined using qualitative descriptive analysis. The mean age was 25 (SD = 3.2. There were numerous similarities in experiences and attitudes between MSM, MSW and WSM across the three settings. Participants had a high degree of HIV transmission risk awareness and practiced some protective sexual behaviors such as reduced sexual activity, increased use of condoms, and external ejaculation. Themes related to risk behavior can be categorized according to struggles for intimacy and fears of isolation, including: fear of infecting a sex partner, guilt about sex, sexual communication difficulty, HIV-stigma, and worry about sexual partnerships. Emphasizing sexual health, intimacy and protective practices as components of nonjudgmental sex-positive secondary HIV prevention interventions is recommended. For in-care PLWHA, this approach has the potential to support TasP. The overlap of themes across groups and countries

  9. The mismatch repair and meiotic recombination endonuclease Mlh1-Mlh3 is activated by polymer formation and can cleave DNA substrates in trans.

    Science.gov (United States)

    Manhart, Carol M; Ni, Xiaodan; White, Martin A; Ortega, Joaquin; Surtees, Jennifer A; Alani, Eric

    2017-04-01

    Crossing over between homologs is initiated in meiotic prophase by the formation of DNA double-strand breaks that occur throughout the genome. In the major interference-responsive crossover pathway in baker's yeast, these breaks are resected to form 3' single-strand tails that participate in a homology search, ultimately forming double Holliday junctions (dHJs) that primarily include both homologs. These dHJs are resolved by endonuclease activity to form exclusively crossovers, which are critical for proper homolog segregation in Meiosis I. Recent genetic, biochemical, and molecular studies in yeast are consistent with the hypothesis of Mlh1-Mlh3 DNA mismatch repair complex acting as the major endonuclease activity that resolves dHJs into crossovers. However, the mechanism by which the Mlh1-Mlh3 endonuclease is activated is unknown. Here, we provide evidence that Mlh1-Mlh3 does not behave like a structure-specific endonuclease but forms polymers required to generate nicks in DNA. This conclusion is supported by DNA binding studies performed with different-sized substrates that contain or lack polymerization barriers and endonuclease assays performed with varying ratios of endonuclease-deficient and endonuclease-proficient Mlh1-Mlh3. In addition, Mlh1-Mlh3 can generate religatable double-strand breaks and form an active nucleoprotein complex that can nick DNA substrates in trans. Together these observations argue that Mlh1-Mlh3 may not act like a canonical, RuvC-like Holliday junction resolvase and support a novel model in which Mlh1-Mlh3 is loaded onto DNA to form an activated polymer that cleaves DNA.

  10. Association between diarrhea and quality of life in HIV-infected patients receiving highly active antiretroviral therapy

    NARCIS (Netherlands)

    Tramarin, A; Parise, N; Campostrini, S; Yin, DD; Postma, MJ; Lyu, R; Grisetti, R; Capetti, A; Cattelan, AM; Di Toro, MT; Mastroianni, A; Pignattari, E; Mondardini, [No Value; Calleri, G; Raise, E; Starace, F

    Diarrhea is a common symptom that many HIV patients experience either as a consequence of HIV infection or of highly active antiretroviral therapy (HAART). A multicenter, prospective observational study was conducted in 11 AIDS clinics in Italy to determine the effect of diarrhea on health-related

  11. (IgA, IgG and IgM) levels and complement fixation activity in HIV

    African Journals Online (AJOL)

    The study was designed to evaluate the immunoglobulin A, G and M levels and complement fixation activity in HIV infected participants, who were not administered antiretroviral therapy (ART). Eighty (80) HIV infected participants, aged between 15 – 55 years (38 ±10 years), were recruited for the study. Forty five (45) of the ...

  12. The Croton megalobotrys Müll Arg. traditional medicine in HIV/AIDS management: Documentation of patient use, in vitro activation of latent HIV-1 provirus, and isolation of active phorbol esters.

    Science.gov (United States)

    Tietjen, Ian; Ngwenya, Barbara N; Fotso, Ghislain; Williams, David E; Simonambango, Sundana; Ngadjui, Bonaventure T; Andersen, Raymond J; Brockman, Mark A; Brumme, Zabrina L; Andrae-Marobela, Kerstin

    2018-01-30

    Current HIV therapies do not act on latent cellular HIV reservoirs; hence they are not curative. While experimental latency reversal agents (LRAs) can promote HIV expression in these cells, thereby exposing them to immune recognition, existing LRAs exhibit limited clinical efficacy and high toxicity. We previously described a traditional 3-step medicinal plant regimen used for HIV/AIDS management in Northern Botswana that inhibits HIV replication in vitro. Here we describe use of one component of the regimen that additionally contains novel phorbol esters possessing HIV latency-reversal properties. We sought to document experiences of traditional medicine users, assess the ability of traditional medicine components to reverse HIV latency in vitro, and identify pure compounds that conferred these activities. Experiences of two HIV-positive traditional medicine users (patients) were documented using qualitative interview techniques. Latency reversal activity was assessed using a cell-based model (J-Lat, clone 9.2). Crude plant extracts were fractionated by open column chromatography and reverse-phase HPLC. Compound structures were elucidated using NMR spectroscopy and mass spectrometry. Patients using the 3-step regimen reported improved health over several years despite no reported use of standard HIV therapies. Crude extracts from Croton megalobotrys Müll Arg. ("Mukungulu"), the third component of the 3-step regimen, induced HIV expression in J-lat cells to levels comparable to the known LRA prostratin. Co-incubation with known LRAs and pharmacological inhibitors indicated that the active agent(s) in C. megalobotrys were likely to be protein kinase C (PKC) activator(s). Consistent with these results, two novel phorbol esters (Namushen 1 and 2) were isolated as abundant components of C. megalobotrys and were sufficient to confer HIV latency reversal in vitro. We have identified novel LRAs of the phorbol ester class from a medicinal plant used in HIV/AIDS management

  13. Residual limb fluid volume change and volume accommodation: Relationships to activity and self-report outcomes in people with trans-tibial amputation.

    Science.gov (United States)

    Sanders, Joan E; Youngblood, Robert T; Hafner, Brian J; Ciol, Marcia A; Allyn, Katheryn J; Gardner, David; Cagle, John C; Redd, Christian B; Dietrich, Colin R

    2018-02-01

    Fluctuations in limb volume degrade prosthesis fit and require users to accommodate changes using management strategies, such as donning and doffing prosthetic socks. To examine how activities and self-report outcomes relate to daily changes in residual limb fluid volume and volume accommodation. Standardized, two-part laboratory protocol with an interim observational period. Participants were classified as "accommodators" or "non-accommodators," based on self-report prosthetic sock use. Participants' residual limb fluid volume change was measured using a custom bioimpedance analyzer and a standardized in-laboratory activity protocol. Self-report health outcomes were assessed with the Socket Comfort Score and Prosthesis Evaluation Questionnaire. Activity was monitored while participants left the laboratory for at least 3 h. They then returned to repeat the bioimpedance test protocol. Twenty-nine people were enrolled. Morning-to-afternoon percent limb fluid volume change per hour was not strongly correlated to percent time weight-bearing or to self-report outcomes. As a group, non-accommodators ( n = 15) spent more time with their prosthesis doffed and reported better outcomes than accommodators. Factors other than time weight-bearing may contribute to morning-to-afternoon limb fluid volume changes and reported satisfaction with the prosthesis among trans-tibial prosthesis users. Temporary doffing may be a more effective and satisfying accommodation method than sock addition. Clinical relevance Practitioners should be mindful that daily limb fluid volume change and prosthesis satisfaction are not dictated exclusively by activity. Temporarily doffing the prosthesis may slow daily limb fluid volume loss and should be investigated as an alternative strategy to sock addition.

  14. 7,8-secolignans from Schisandra neglecta and their anti-HIV-1 activities

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Xuemei; Mu, Huaixue; Hu, Qiufen, E-mail: huqiufena@yahoo.com.cn [Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan University of Nationalities (China); Wang, Ruirui; Yang, Liumeng; Zheng, Yongtang [Kunming Institute of Zoology, Chinese Academy of Sciences (China); Sun, Handong; Xiao, Weilie, E-mail: xwl@mail.kib.ac.cn [State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming (China)

    2012-10-15

    Four new 7,8-secolignans (neglectahenols A-D), together with two known 7,8-secolignans, were isolated from leaves and stems of Schisandra neglecta. The structures were elucidated by spectroscopic methods, including extensive one and two dimension NMR (nuclear magnetic resonance) techniques. 7,8-Secolignans and neglectahenols A-D were also tested for their anti-HIV-1 (human immunodeficiency virus type 1) activities, and all of them showed modest activities. (author)

  15. Movement, Knowledge, Emotion : gay activism and HIV/AIDS in Australia

    OpenAIRE

    x

    2011-01-01

    This book is about community activism around HIV/AIDS in Australia. It looks at the role that the gay community played in the social, medical and political response to the virus. Drawing conclusions about the cultural impact of social movements, the author argues that AIDS activism contributed to improving social attitudes towards gay men and lesbians in Australia, while also challenging some entrenched cultural patterns of the Australian medical system, allowing greater scope for non-medical...

  16. CRISPR/Cas9 and active genetics-based trans-species replacement of the endogenous Drosophila kni-L2 CRM reveals unexpected complexity.

    Science.gov (United States)

    Xu, Xiang-Ru Shannon; Gantz, Valentino Matteo; Siomava, Natalia; Bier, Ethan

    2017-12-23

    The knirps ( kni ) locus encodes transcription factors required for induction of the L2 wing vein in Drosophila . Here, we employ diverse CRISPR/Cas9 genome editing tools to generate a series of targeted lesions within the endogenous cis-regulatory module (CRM) required for kni expression in the L2 vein primordium. Phenotypic analysis of these ' in locus ' mutations based on both expression of Kni protein and adult wing phenotypes, reveals novel unexpected features of L2-CRM function including evidence for a chromosome pairing-dependent process that promotes transcription. We also demonstrate that self-propagating active genetic elements (CopyCat elements) can efficiently delete and replace the L2-CRM with orthologous sequences from other divergent fly species. Wing vein phenotypes resulting from these trans-species enhancer replacements parallel features of the respective donor fly species. This highly sensitive phenotypic readout of enhancer function in a native genomic context reveals novel features of CRM function undetected by traditional reporter gene analysis. © 2017, Xu et al.

  17. Synthesis and Anti-HIV-1 Activity of New MKC-442 Analogues with an Alkynyl-Substituted 6-Benzyl Group

    DEFF Research Database (Denmark)

    Aly, Youssef L.; Pedersen, Erik Bjerreg.; La Colla, Paolo

    2007-01-01

    Synthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse...... transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding...

  18. A Service Delivery Model for Addressing Activity and Social Participation Needs of People Living with HIV

    Directory of Open Access Journals (Sweden)

    Gayle Restall

    2017-05-01

    Full Text Available Background: Occupational therapy can contribute to the health and well-being of people with human immunodeficiency virus (HIV who are experiencing health consequences of living long term with this disease. However, there are no comprehensive rehabilitation service delivery models to guide this emerging area of practice. The purpose of this study was to obtain critical feedback about a service delivery model to address the activity and social participation needs of people living with HIV. Method: We developed a service delivery model from a synthesis of the literature. Using a qualitative research design, we conducted individual and focus group interviews with 35 informants from diverse backgrounds and involvement in HIV-related research, service provision, and policymaking to provide critical feedback about the model. The interviews were audio-recorded, transcribed verbatim, and analyzed using inductive qualitative methods. Results: The informants identified the strengths and limitations of the model and supports and barriers to its implementation. They highlighted the importance of principle-based services, increasing resources for service navigation, building capacity of rehabilitation services to address the needs of people with HIV, and increasing research and program evaluation targeted to achieving activity and social participation outcomes. Conclusions: The model provides a framework for occupational therapists to design and evaluate services for this population.

  19. Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention.

    Science.gov (United States)

    Dezzutti, Charlene S; Yandura, Sarah; Wang, Lin; Moncla, Bernard; Teeple, Elizabeth A; Devlin, Brid; Nuttall, Jeremy; Brown, Elizabeth R; Rohan, Lisa C

    2015-11-01

    Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission. 0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety. The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 μg/cm(2)/min(1/2)), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 μg/cm(2)/min(1/2)). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe. The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.

  20. Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents.

    Science.gov (United States)

    Penthala, Narsimha Reddy; Zong, Hongliang; Ketkar, Amit; Madadi, Nikhil Reddy; Janganati, Venumadav; Eoff, Robert L; Guzman, Monica L; Crooks, Peter A

    2015-03-06

    A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stabilized by van der Waals' interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  1. Systemic activation of the immune system in HIV infection: The role of the immune complexes (hypothesis).

    Science.gov (United States)

    Korolevskaya, Larisa B; Shmagel, Konstantin V; Shmagel, Nadezhda G; Saidakova, Evgeniya V

    2016-03-01

    Currently, immune activation is proven to be the basis for the HIV infection pathogenesis and a strong predictor of the disease progression. Among the causes of systemic immune activation the virus and its products, related infectious agents, pro-inflammatory cytokines, and regulatory CD4+ T cells' decrease are considered. Recently microbial translocation (bacterial products yield into the bloodstream as a result of the gastrointestinal tract mucosal barrier integrity damage) became the most popular hypothesis. Previously, we have found an association between immune complexes present in the bloodstream of HIV infected patients and the T cell activation. On this basis, we propose a significantly modified hypothesis of immune activation in HIV infection. It is based on the immune complexes' participation in the immunocompetent cells' activation. Immune complexes are continuously formed in the chronic phase of the infection. Together with TLR-ligands (viral antigens, bacterial products coming from the damaged gut) present in the bloodstream they interact with macrophages. As a result macrophages are transformed into the type II activated forms. These macrophages block IL-12 production and start synthesizing IL-10. High level of this cytokine slows down the development of the full-scale Th1-response. The anti-viral reactions are shifted towards the serogenesis. Newly synthesized antibodies' binding to viral antigens leads to continuous formation of the immune complexes capable of interacting with antigen-presenting cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Engagement in activities revealing the body and psychosocial adjustment in adults with a trans-tibial prosthesis.

    Science.gov (United States)

    Donovan-Hall, M K; Yardley, L; Watts, R J

    2002-04-01

    The purpose of this study was to examine the effects of the appearance of a prosthesis on social behaviour, social discomfort and psychological well-being in eleven amputees taking delivery of a prosthesis with a silicone cover. Two new scales were developed: the 'Engagement in everyday activities involving revealing the body' (EEARB); and the 'Discomfort-Engagement in everyday activities involving revealing the body' (Discomfort-EEARB) scales. The psychometric properties of these scales were determined using a sample of 101 able-bodied adults. The Hospital Anxiety and Depression Scale and the Rosenberg Self-Esteem Scale were also used to measure psychological well-being in the amputee sample. The EEARB and Discomfort-EEARB proved to have good reliability and validity. Comparison of amputees' scores prior to receiving the silicone cosmesis with those of the able-bodied adults revealed significant behavioural limitations and social discomfort, associated with low self-esteem, anxiety and depression. There was a significant increase in amputees' scores three months afier taking delivery of their prosthesis, indicating that amputees reported engaging in more activities which involved revealing their body, and that they would feel more comfortable in situations which involved revealing the body. As the amputee sample available was small and self-selected, it is not possible to generalise these findings to the amputee population as a whole. However, since there is little previous research investigating the effects of the appearance of the prosthesis, these findings demonstrate the need for further research in this area.

  3. Cervical Shedding of HIV-1 RNA Among Women With Low Levels of Viremia While Receiving Highly Active Antiretroviral Therapy

    Science.gov (United States)

    Neely, Michael N.; Benning, Lorie; Xu, Jiaao; Strickler, Howard D.; Greenblatt, Ruth M.; Minkoff, Howard; Young, Mary; Bremer, James; Levine, Alexandra M.; Kovacs, Andrea

    2011-01-01

    Background Among women with low o r undetectable quantities of HIV-1 RNA in plasma, factors associated with genital HIV-1 RNA shedding, including choice of treatment regimen, are poorly characterized. Methods We measured HIV-1 RNA in cervical swab specimens obtained from participants in the Women’s Interagency HIV Study who had concurrent plasma viral RNA levels <500 copies/mL, and we assessed factors associated with genital HIV shedding. The study was powered to determine the relative effects of antiretroviral protease inhibitors (PIs) versus nonnucleoside reverse transcriptase inhibitors (NNRTIs) on viral RNA shedding. Results Overall, 44 (15%) of 290 women had detectable HIV-1 RNA in cervical specimens. In the final multivariate model, shedding was independently associated with NNRTI (vs. PI) use (odds ratio [OR], 95% confidence interval [CI]: 2.24, 1.13 to 4.45) and illicit drug use (OR, 95% CI: 2.41, 0.96 to 5.69). Conclusions This is the largest study to define risks for genital HIV-1 RNA shedding in women with low/undetectable plasma virus. Shedding in this population was common, and NNRTI-based highly active antiretroviral therapy (HAART) (vs. PI-based HAART) was associated with genital HIV shedding. Further study is required to determine the impact of these findings on transmission of HIV from mother to child or to sexual partners. PMID:17106279

  4. Mechanisms by Which Interleukin-12 Corrects Defective NK Cell Anticryptococcal Activity in HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    Stephen K. Kyei

    2016-08-01

    Full Text Available Cryptococcus neoformans is a pathogenic yeast and a leading cause of life-threatening meningitis in AIDS patients. Natural killer (NK cells are important immune effector cells that directly recognize and kill C. neoformans via a perforin-dependent cytotoxic mechanism. We previously showed that NK cells from HIV-infected patients have aberrant anticryptococcal killing and that interleukin-12 (IL-12 restores the activity at least partially through restoration of NKp30. However, the mechanisms causing this defect or how IL-12 restores the function was unknown. By examining the sequential steps in NK cell killing of Cryptococcus, we found that NK cells from HIV-infected patients had defective binding of NK cells to C. neoformans. Moreover, those NK cells that bound to C. neoformans failed to polarize perforin-containing granules to the microbial synapse compared to healthy controls, suggesting that binding was insufficient to restore a defect in perforin polarization. We also identified lower expression of intracellular perforin and defective perforin release from NK cells of HIV-infected patients in response to C. neoformans. Importantly, treatment of NK cells from HIV-infected patients with IL-12 reversed the multiple defects in binding, granule polarization, perforin content, and perforin release and restored anticryptococcal activity. Thus, there are multiple defects in the cytolytic machinery of NK cells from HIV-infected patients, which cumulatively result in defective NK cell anticryptococcal activity, and each of these defects can be reversed with IL-12.

  5. Trans-nationalisation Processes in the Ukrainian Economy

    OpenAIRE

    Bolharova Natalya K.; Panevnyk Tetyana M.

    2013-01-01

    The article considers main processes of trans-nationalisation of Ukrainian economy, identifies specific features of trans-national production and explains some theoretical aspects of these issues. It provides main stages of theoretical comprehension of activity of trans-national corporations (TNC), specific features of the theory of competitive advantages of TNC and specifies the basic ones of them. The article conducts analysis of flows of direct foreign investments into the Ukrainian econom...

  6. An Intracellular Peptidyl-Prolyl cis/trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease.

    Science.gov (United States)

    Wiemels, Richard E; Cech, Stephanie M; Meyer, Nikki M; Burke, Caleb A; Weiss, Andy; Parks, Anastacia R; Shaw, Lindsey N; Carroll, Ronan K

    2017-01-01

    Staphylococcus aureus is an important human pathogen that relies on a large repertoire of secreted and cell wall-associated proteins for pathogenesis. Consequently, the ability of the organism to cause disease is absolutely dependent on its ability to synthesize and successfully secrete these proteins. In this study, we investigate the role of peptidyl-prolyl cis/trans isomerases (PPIases) on the activity of the S. aureus secreted virulence factor nuclease (Nuc). We identify a staphylococcal cyclophilin-type PPIase (PpiB) that is required for optimal activity of Nuc. Disruption of ppiB results in decreased nuclease activity in culture supernatants; however, the levels of Nuc protein are not altered, suggesting that the decrease in activity results from misfolding of Nuc in the absence of PpiB. We go on to demonstrate that PpiB exhibits PPIase activity in vitro, is localized to the bacterial cytosol, and directly interacts with Nuc in vitro to accelerate the rate of Nuc refolding. Finally, we demonstrate an additional role for PpiB in S. aureus hemolysis and demonstrate that the S. aureus parvulin-type PPIase PrsA also plays a role in the activity of secreted virulence factors. The deletion of prsA leads to a decrease in secreted protease and phospholipase activity, similar to that observed in other Gram-positive pathogens. Together, these results demonstrate, for the first time to our knowledge, that PPIases play an important role in the secretion of virulence factors in S. aureus IMPORTANCE: Staphylococcus aureus is a highly dangerous bacterial pathogen capable of causing a variety of infections throughout the human body. The ability of S. aureus to cause disease is largely due to an extensive repertoire of secreted and cell wall-associated proteins, including adhesins, toxins, exoenzymes, and superantigens. These virulence factors, once produced, are typically transported across the cell membrane by the secretory (Sec) system in a denatured state. Consequently

  7. Montessori-Based Activities as a Trans-Generational Interface for Persons with Dementia and Preschool Children.

    Science.gov (United States)

    Camp, Cameron J; Lee, Michelle M

    2011-12-12

    Montessori-based activities for persons with dementia have been used to successfully provide opportunities for programming between older adults and preschool children in shared site. intergenerational care programs. Such intergenerational programming allows older adults with dementia to fulfill roles of teacher or mentor to younger children or as collaborative workmates for persons with more advanced dementia while providing children with positive one-on-one interactions with older adults. We review several studies using this approach, describe characteristics of the programs, participants and results obtained and provide recommendations for those interested in extending this line of work.

  8. Montessori-Based Activities as a Trans-Generational Interface for Persons with Dementia and Preschool Children*

    Science.gov (United States)

    Camp, Cameron J.; Lee, Michelle M.

    2012-01-01

    Montessori-based activities for persons with dementia have been used to successfully provide opportunities for programming between older adults and preschool children in shared site. intergenerational care programs. Such intergenerational programming allows older adults with dementia to fulfill roles of teacher or mentor to younger children or as collaborative workmates for persons with more advanced dementia while providing children with positive one-on-one interactions with older adults. We review several studies using this approach, describe characteristics of the programs, participants and results obtained and provide recommendations for those interested in extending this line of work. PMID:22423215

  9. A high throughput Cre–lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry

    Energy Technology Data Exchange (ETDEWEB)

    Esposito, Anthony M. [Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute, New York, NY (United States); Cheung, Pamela [Integrated Screening Core, Icahn School of Medicine at Mount Sinai, New York, NY (United States); Swartz, Talia H.; Li, Hongru [Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute, New York, NY (United States); Tsibane, Tshidi [Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY (United States); Durham, Natasha D. [Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute, New York, NY (United States); Basler, Christopher F. [Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY (United States); Felsenfeld, Dan P. [Integrated Screening Core, Icahn School of Medicine at Mount Sinai, New York, NY (United States); Chen, Benjamin K., E-mail: benjamin.chen@mssm.edu [Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Immunology Institute, New York, NY (United States)

    2016-03-15

    Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors that block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes. - Highlights: • Cre recombinase viral fusion assay screens cell-free or cell–cell entry inhibitors. • This Gag-iCre based assay is specific for the entry step of HIV replication. • Screened a library of known pharmacologic compounds for HIV fusion antagonists. • Many top hits were previously noted as HIV inhibitors, but here are classified as entry antagonists. Many top hits were previously noted as HIV inhibitors, but not as entry antagonists. • The assay is compatible with pseudotyping with HIV and heterologous viruses.

  10. A high throughput Cre–lox activated viral membrane fusion assay identifies pharmacological inhibitors of HIV entry

    International Nuclear Information System (INIS)

    Esposito, Anthony M.; Cheung, Pamela; Swartz, Talia H.; Li, Hongru; Tsibane, Tshidi; Durham, Natasha D.; Basler, Christopher F.; Felsenfeld, Dan P.; Chen, Benjamin K.

    2016-01-01

    Enveloped virus entry occurs when viral and cellular membranes fuse releasing particle contents into the target cell. Human immunodeficiency virus (HIV) entry occurs by cell-free virus or virus transferred between infected and uninfected cells through structures called virological synapses. We developed a high-throughput cell-based assay to identify small molecule inhibitors of cell-free or virological synapse-mediated entry. An HIV clone carrying Cre recombinase as a Gag-internal gene fusion releases active Cre into cells upon viral entry activating a recombinatorial gene switch changing dsRed to GFP-expression. A screen of a 1998 known-biological profile small molecule library identified pharmacological HIV entry inhibitors that block both cell-free and cell-to-cell infection. Many top hits were noted as HIV inhibitors in prior studies, but not previously recognized as entry antagonists. Modest therapeutic indices for simvastatin and nigericin were observed in confirmatory HIV infection assays. This robust assay is adaptable to study HIV and heterologous viral pseudotypes. - Highlights: • Cre recombinase viral fusion assay screens cell-free or cell–cell entry inhibitors. • This Gag-iCre based assay is specific for the entry step of HIV replication. • Screened a library of known pharmacologic compounds for HIV fusion antagonists. • Many top hits were previously noted as HIV inhibitors, but here are classified as entry antagonists. Many top hits were previously noted as HIV inhibitors, but not as entry antagonists. • The assay is compatible with pseudotyping with HIV and heterologous viruses.

  11. Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial.

    Directory of Open Access Journals (Sweden)

    Christian Prebensen

    Full Text Available Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.

  12. Trans-Spatial Utopias

    Science.gov (United States)

    Kramsch, Claire

    2018-01-01

    The "trans-" perspectives offered in this special issue are heady stuff. Post-structuralism (philosophy) meets the digital age (electronics), meets globalization (economics), and meets translingual practice (linguistics) to create a perfectly utopian or placeless space for future exploration. I want to first add my voice to the…

  13. Low Trans Hydrogenation

    Science.gov (United States)

    Although hydrogenation has been the technology of choice for fat formulation for many years recent concerns over the health and nutrition of trans fatty acids have had a profound effect on the edible oil industry. Since Jan. 1, 2006, TFA has been required on nutrition labels along with saturated an...

  14. Analysis of the Phenotype of Mycobacterium tuberculosis-Specific CD4+ T Cells to Discriminate Latent from Active Tuberculosis in HIV-Uninfected and HIV-Infected Individuals

    Directory of Open Access Journals (Sweden)

    Catherine Riou

    2017-08-01

    Full Text Available Several immune-based assays have been suggested to differentiate latent from active tuberculosis (TB. However, their relative performance as well as their efficacy in HIV-infected persons, a highly at-risk population, remains unclear. In a study of 81 individuals, divided into four groups based on their HIV-1 status and TB disease activity, we compared the differentiation (CD27 and KLRG1, activation (HLA-DR, homing potential (CCR4, CCR6, CXCR3, and CD161 and functional profiles (IFNγ, IL-2, and TNFα of Mycobacterium tuberculosis (Mtb-specific CD4+ T cells using flow cytometry. Active TB disease induced major changes within the Mtb-responding CD4+ T cell population, promoting memory maturation, elevated activation and increased inflammatory potential when compared to individuals with latent TB infection. Moreover, the functional profile of Mtb-specific CD4+ T cells appeared to be inherently related to their degree of differentiation. While these specific cell features were all capable of discriminating latent from active TB, irrespective of HIV status, HLA-DR expression showed the best performance for TB diagnosis [area-under-the-curve (AUC = 0.92, 95% CI: 0.82–1.01, specificity: 82%, sensitivity: 84% for HIV− and AUC = 0.99, 95% CI: 0.98–1.01, specificity: 94%, sensitivity: 93% for HIV+]. In conclusion, these data support the idea that analysis of T cell phenotype can be diagnostically useful in TB.

  15. Molecular cloning and anti-HIV-1 activities of APOBEC3s from northern pig-tailed macaques (Macaca leonina

    Directory of Open Access Journals (Sweden)

    Xiao-Liang ZHANG

    2016-07-01

    Full Text Available Northern pig-tailed macaques (NPMs, Macaca leonina are susceptible to HIV-1 infection largely due to the loss of HIV-1-restricting factor TRIM5α. However, great impediments still exist in the persistent replication of HIV-1 in vivo, suggesting some viral restriction factors are reserved in this host. The APOBEC3 proteins have demonstrated a capacity to restrict HIV-1 replication, but their inhibitory effects in NPMs remain elusive. In this study, we cloned the NPM A3A-A3H genes, and determined by BLAST searching that their coding sequences (CDSs showed 99% identity to the corresponding counterparts from rhesus and southern pig-tailed macaques. We further analyzed the anti-HIV-1 activities of the A3A-A3H genes, and found that A3G and A3F had the greatest anti-HIV-1 activity compared with that of other members. The results of this study indicate that A3G and A3F might play critical roles in limiting HIV-1 replication in NPMs in vivo. Furthermore, this research provides valuable information for the optimization of monkey models of HIV-1 infection.

  16. Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women.

    Directory of Open Access Journals (Sweden)

    Genevieve E Martin

    Full Text Available Aging is associated with immune dysfunction and the related development of conditions with an inflammatory pathogenesis. Some of these immune changes are also observed in HIV infection, but the interaction between immune changes with aging and HIV infection are unknown. Whilst sex differences in innate immunity are recognized, little research into innate immune aging has been performed on women.This cross-sectional study of HIV positive and negative women used whole blood flow cytometric analysis to characterize monocyte and CD8(+ T cell subsets. Plasma markers of innate immune activation were measured using standard ELISA-based assays.HIV positive women exhibited elevated plasma levels of the innate immune activation markers CXCL10 (p<0.001, soluble CD163 (sCD163, p = 0.001, sCD14 (p = 0.022, neopterin (p = 0.029 and an increased proportion of CD16(+ monocytes (p = 0.009 compared to uninfected controls. Levels of the innate immune aging biomarkers sCD163 and the proportion of CD16(+ monocytes were equivalent to those observed in HIV negative women aged 14.5 and 10.6 years older, respectively. CXCL10 increased with age at an accelerated rate in HIV positive women (p = 0.002 suggesting a synergistic effect between HIV and aging on innate immune activation. Multivariable modeling indicated that age-related increases in innate immune biomarkers CXCL10 and sCD163 are independent of senescent changes in CD8(+ T lymphocytes.Quantifying the impact of HIV on immune aging reveals that HIV infection in women confers the equivalent of a 10-14 year increase in the levels of innate immune aging markers. These changes may contribute to the increased risk of inflammatory age-related diseases in HIV positive women.

  17. Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women.

    Science.gov (United States)

    Martin, Genevieve E; Gouillou, Maelenn; Hearps, Anna C; Angelovich, Thomas A; Cheng, Allen C; Lynch, Fiona; Cheng, Wan-Jung; Paukovics, Geza; Palmer, Clovis S; Novak, Richard M; Jaworowski, Anthony; Landay, Alan L; Crowe, Suzanne M

    2013-01-01

    Aging is associated with immune dysfunction and the related development of conditions with an inflammatory pathogenesis. Some of these immune changes are also observed in HIV infection, but the interaction between immune changes with aging and HIV infection are unknown. Whilst sex differences in innate immunity are recognized, little research into innate immune aging has been performed on women. This cross-sectional study of HIV positive and negative women used whole blood flow cytometric analysis to characterize monocyte and CD8(+) T cell subsets. Plasma markers of innate immune activation were measured using standard ELISA-based assays. HIV positive women exhibited elevated plasma levels of the innate immune activation markers CXCL10 (p<0.001), soluble CD163 (sCD163, p = 0.001), sCD14 (p = 0.022), neopterin (p = 0.029) and an increased proportion of CD16(+) monocytes (p = 0.009) compared to uninfected controls. Levels of the innate immune aging biomarkers sCD163 and the proportion of CD16(+) monocytes were equivalent to those observed in HIV negative women aged 14.5 and 10.6 years older, respectively. CXCL10 increased with age at an accelerated rate in HIV positive women (p = 0.002) suggesting a synergistic effect between HIV and aging on innate immune activation. Multivariable modeling indicated that age-related increases in innate immune biomarkers CXCL10 and sCD163 are independent of senescent changes in CD8(+) T lymphocytes. Quantifying the impact of HIV on immune aging reveals that HIV infection in women confers the equivalent of a 10-14 year increase in the levels of innate immune aging markers. These changes may contribute to the increased risk of inflammatory age-related diseases in HIV positive women.

  18. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection

    DEFF Research Database (Denmark)

    Rodger, Alison J; Fox, Zoe; Lundgren, Jens

    2009-01-01

    BACKGROUND: Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)-positive patients were examined. METHODS: Inflammatory (high-sensi...

  19. Cis-trans photoisomerization of abscisic acid

    International Nuclear Information System (INIS)

    Brabham, D.E.; Biggs, R.H.

    1981-01-01

    An important regulator of numerous physiological processes in higher plants is abscisic acid (ABA), which is photoisomerized from the more biologically active cis isomer to the nearly inactive trans isomer by natural sunlight. It is possible that this photoisomerization is a UV control mechanism in functions regulated by ABA. The quantum yields of both the cis to trans and trans to cis photoisomerizations were measured under various conditions of pH and oxygen concentration at room temperature. The yield for photoisomerization of cis-ABA ranged from 0.25 at pH 3.0 to 0.11 at pH 7.0. Oxygen partially quenched the process. The quantum yield varied only slightly with wavelength. The quantum yield of photolysis of cis-ABA was reported for pH 3.0 as 0.06. This yield also varied slightly with wavelength and was relatively insensitive to oxygen. This relatively high yield explains the loss of potency of ABA during UV irradiation. Phosphorescence of cis- and trans-ABA was observed in methanol at 77 K. Onset of the emission was at 350 nm. The emission spectra were the same for both isomers. From these results a mechanism of UV action on plants based on the photoisomerization of the inactive trans-ABA to the biologically active cis isomer is proposed. (author)

  20. Differential in vitro inhibitory activity against HIV-1 of alpha-(1-3- and alpha-(1-6-D-mannose specific plant lectins : Implication for microbicide development

    Directory of Open Access Journals (Sweden)

    Balzarini Jan

    2007-06-01

    Full Text Available Abstract Background Plant lectins such as Galanthus nivalis agglutinin (GNA and Hippeastrum hybrid agglutinin (HHA are natural proteins able to link mannose residues, and therefore inhibit HIV-target cell interactions. Plant lectins are candidate for microbicide development. Objective To evaluate the activity against HIV of the mannose-specific plant lectins HHA and GNA at the cellular membrane level of epithelial cells and monocyte-derived dendritic cells (MDDC, two potential target cells of HIV at the genital mucosal level. Methods The inhibitory effects of HHA and GNA were evaluated on HIV adsorption to genital epithelial HEC-1A cell line, on HIV transcytosis throughout a monolayer of polarized epithelial HEC-1A cells, on HIV adsorption to MDDC and on transfer of HIV from MDDC to autologous T lymphocytes. Results HHA faintly inhibited attachment to HEC-1A cells of the R5-tropic HIV-1Ba-L strain, in a dose-dependent manner, whereas GNA moderately inhibited HIV adsorption in the same context, but only at high drug doses. Only HHA, but not GNA, inhibited HIV-1JR-CSF transcytosis in a dose-dependent manner. By confocal microscopy, HHA, but not GNA, was adsorbed at the epithelial cell surface, suggesting that HHA interacts specifically with receptors mediating HIV-1 transcytosis. Both plant lectins partially inhibited HIV attachment to MDDC. HHA inhibited more efficiently the transfer of HIV from MDDC to T cell, than GNA. Both HHA and GNA lacked toxicity below 200 μg/ml irrespective the cellular system used and do not disturb the monolayer integrity of epithelial cells. Conclusion These observations demonstrate higher inhibitory activities of the lectin plant HHA by comparison to GNA, on HIV adsorption to HEC-1A cell line, HIV transcytosis through HEC-1A cell line monolayer, HIV adsorption to MDDC and HIV transfer from MDDC to T cells, highlighting the potential interest of HHA as effective microbicide against HIV.

  1. High risk exposure to HIV among sexually active individuals who tested negative on rapid HIV Tests in the Tshwane District of South Africa-The importance of behavioural prevention measures.

    Directory of Open Access Journals (Sweden)

    Simnikiwe H Mayaphi

    Full Text Available To assess the prevalence of HIV risk behaviour among sexually active HIV sero-negative individuals in the Tshwane district of South Africa (SA.Demographic and HIV risk behaviour data were collected on a questionnaire from participants of a cross-sectional study that screened for early HIV infection using pooled nucleic acid amplification testing (NAAT. The study enrolled individuals who tested negative on rapid HIV tests performed at five HIV counseling and testing (HCT clinics, which included four antenatal clinics and one general HCT clinic.The study enrolled 9547 predominantly black participants (96.6% with a median age of 27 years (interquartile range [IQR]: 23-31. There were 1661 non-pregnant and 7886 pregnant participants largely enrolled from the general and antenatal HCT clinics, respectively. NAAT detected HIV infection in 61 participants (0.6%; 95% confidence interval [CI]: 0.4-0.8 in the whole study. A high proportion of study participants, 62.8% and 63.0%, were unaware of their partner's HIV status; and also had high prevalence, 88.5% and 99.5%, of recent unprotected sex in the general and pregnant population, respectively. Consistent use of condoms was associated with protection against HIV infection in the general population. Trends of higher odds for HIV infection were observed with most demographic and HIV risk factors at univariate analysis, however, multivariate analysis did not show statistical significance for almost all these factors. A significantly lower risk of HIV infection was observed in circumcised men (p <0.001.These data show that a large segment of sexually active people in the Tshwane district of SA have high risk exposure to HIV. The detection of newly diagnosed HIV infections in all study clinics reflects a wide distribution of individuals who are capable of sustaining HIV transmission in the setting where HIV risk behaviour is highly prevalent. A questionnaire that captures HIV risk behaviour would be useful

  2. Anti-HIV-1 integrase activity of medicinal plants used as self medication by AIDS patients

    Directory of Open Access Journals (Sweden)

    Sopa Kummee

    2006-07-01

    Full Text Available The extracts of selected medicinal plants used as self medication by AIDS patients were investigated for their inhibitory activities against HIV-1 integrase (HIV-1 IN using the multiplate integration assay (MIA. Of these, the water extract of Eclipta prostrata (whole plant exhibited the most potent inhibitory activity with an IC50 value of 4.8 μg/ml, followed by the methanol extract of Eclipta prostrata (whole plant, IC50 = 21.1 μg/ ml, the water extract of Barleria lupulina (stem, IC50 = 26.4 μg/ml, the chloroform extract of Barleria lupulina (stem, IC50 = 33.0 μg/ml, the methanol extract of Barleria lupulina (stem, IC50 = 38.2 μg/ml and the chloroform extract of Piper betle (leaf, IC50 = 39.3 μg/ml, respectively.

  3. ONSET OF SEXUAL ACTIVITY AMONG ADOLESCENTS IN HIV/AIDS-AFFECTED HOUSEHOLDS IN SUB-SAHARAN AFRICA.

    Science.gov (United States)

    Magadi, Monica A; Uchudi, Joseph

    2015-03-01

    This paper examines the effect of orphanhood and HIV status of adults in a household on onset of sexual activity among adolescent girls and boys aged 15-17 years in sub-Saharan Africa. Multilevel logistic regression models were applied to pooled Demographic and Health Surveys data from nineteen countries of sub-Saharan Africa where HIV test data were collected during 2003-2008 from nationally representative samples of men and women of reproductive age. The results highlight increased vulnerability among adolescent boys and girls living in households where an adult is infected with HIV, and adolescent boys who are paternal orphans. On average, adolescent boys and girls living in households where at least one adult is HIV-positive have about 25% higher odds of having initiated sexual activity compared with their counterparts of similar characteristics in households where no adult is HIV-positive. Furthermore, adolescent boys who are paternal orphans have about 25% higher odds of having initiated sexual activity than their non-orphan counterparts of similar individual characteristics. Further analysis reveals that household circumstances relating to living arrangements and poverty are important pathways through which household HIV/AIDS status is linked to adolescent sexual debut. The findings underscore the importance of international efforts in the sub-Saharan Africa region to address the plight of other children in HIV/AIDS-affected households, beyond orphans.

  4. Breast cancer and HIV in the era of highly active antiretroviral therapy: two case reports and review of the literature.

    Science.gov (United States)

    Latif, Naeem; Rana, Fauzia; Guthrie, Troy

    2011-01-01

    The incidence of human immunodeficiency virus (HIV) infection is rising in US women; however its impact on breast cancer incidence, stage at presentation, response and treatment toxicity remains unknown. To address the impact of HIV infection and use of highly active antiretroviral therapy (HAART) on the natural history of breast cancer we present two cases of breast cancer in HIV-infected women and also review the literature. A literature search was done on Medline using the key words HIV/AIDS, breast cancer, and HAART therapy, restricted to English language. There were mostly case reports and one large series of 20 cases reported by Hurley et al. Data concerning the impact of HIV infection and HAART therapy regarding pathogenesis, stage at presentation, tumor type, response, and toxicity associated with treatment were reviewed. The literature review shows that the breast cancer incidence is either same or less in HIV-infected patients compared to the general population. However, the patients with HIV infection present with more advanced stage and aggressive disease, and they also have poor chemotherapy tolerance. The impact of HAART on breast cancer incidence in HIV-infected patients is still unclear. © 2010 Wiley Periodicals, Inc.

  5. HIV prevention and transmission myths among heterosexually active adults in low-income areas of South Florida.

    Science.gov (United States)

    Beck, Dano W; Lalota, Marlene; Metsch, Lisa R; Cardenas, Gabriel A; Forrest, David W; Lieb, Spencer; Liberti, Thomas M

    2012-04-01

    Misconceptions about HIV transmission and prevention may inhibit individuals' accurate assessment of their level of risk. We used venue-based sampling to conduct a cross-sectional study of heterosexually active adults (N = 1,221) within areas exhibiting high poverty and HIV/AIDS rates in Miami-Dade and Broward counties in 2007. Two logistic regression analyses identified correlates of holding inaccurate beliefs about HIV transmission and prevention. Belief in incorrect HIV prevention methods (27.2%) and modes of transmission (38.5%) was common. Having at least one incorrect prevention belief was associated with being Hispanic compared to white (non-Hispanic), being depressed, and not knowing one's HIV status. Having at least one incorrect transmission belief was associated with being younger, heavy alcohol use, being depressed, not having seen a physician in the past 12 months, and not knowing one's HIV status. Among low-income heterosexuals, HIV prevention and transmission myths are widespread. Debunking them could have HIV prevention value.

  6. Identification of novel 2-benzoxazolinone derivatives with specific inhibitory activity against the HIV-1 nucleocapsid protein.

    Science.gov (United States)

    Gamba, Elia; Mori, Mattia; Kovalenko, Lesia; Giannini, Alessia; Sosic, Alice; Saladini, Francesco; Fabris, Dan; Mély, Yves; Gatto, Barbara; Botta, Maurizio

    2018-02-10

    In this report, we present a new benzoxazole derivative endowed with inhibitory activity against the HIV-1 nucleocapsid protein (NC). NC is a 55-residue basic protein with nucleic acid chaperone properties, which has emerged as a novel and potential pharmacological target against HIV-1. In the pursuit of novel NC-inhibitor chemotypes, we performed virtual screening and in vitro biological evaluation of a large library of chemical entities. We found that compounds sharing a benzoxazolinone moiety displayed putative inhibitory properties, which we further investigated by considering a series of chemical analogues. This approach provided valuable information on the structure-activity relationships of these compounds and, in the process, demonstrated that their anti-NC activity could be finely tuned by the addition of specific substituents to the initial benzoxazolinone scaffold. This study represents the starting point for the possible development of a new class of antiretroviral agents targeting the HIV-1 NC protein. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Proline substitutions in a Mip-like peptidyl-prolyl cis-trans isomerase severely affect its structure, stability, shape and activity

    Directory of Open Access Journals (Sweden)

    Soumitra Polley

    2015-01-01

    Full Text Available FKBP22, an Escherichia coli-specific peptidyl-prolyl cis-trans isomerase, shows substantial homology with the Mip-like virulence factors. Mip-like proteins are homodimeric and possess a V-shaped conformation. Their N-terminal domains form dimers, whereas their C-terminal domains bind protein/peptide substrates and distinct inhibitors such as rapamycin and FK506. Interestingly, the two domains of the Mip-like proteins are separated by a lengthy, protease-susceptible α-helix. To delineate the structural requirement of this domain-connecting region in Mip-like proteins, we have investigated a recombinant FKBP22 (rFKBP22 and its three point mutants I65P, V72P and A82P using different probes. Each mutant harbors a Pro substitution mutation at a distinct location in the hinge region. We report that the three mutants are not only different from each other but also different from rFKBP22 in structure and activity. Unlike rFKBP22, the three mutants were unfolded by a non-two state mechanism in the presence of urea. In addition, the stabilities of the mutants, particularly I65P and V72P, differed considerably from that of rFKBP22. Conversely, the rapamycin binding affinity of no mutant was different from that of rFKBP22. Of the mutants, I65P showed the highest levels of structural/functional loss and dissociated partly in solution. Our computational study indicated a severe collapse of the V-shape in I65P due to the anomalous movement of its C-terminal domains. The α-helical nature of the domain-connecting region is, therefore, critical for the Mip-like proteins.

  8. A single source precursor route to group 13 homo- and heterometallic oxides as highly active supports for gold-catalyzed aerobic epoxidation of trans-stilbene

    KAUST Repository

    Mishra, Shashank K.; Mendez, Violaine; Jeanneau, Erwann; Caps, Valerie; Daniè le, Sté phane

    2012-01-01

    A new Mitsubishi-type of star-shaped homoleptic derivative of indium(III), In4(mdea)6 (2, mdeaH2 = N-methyldiethanolamine) , was synthesized by the chloro-aminoalkoxo exchange reaction of a heteroleptic complex In6Cl6(mdea)6 (1) and used as a facile single source molecular precursor for the sol-gel preparation of high surface area indium oxide. Successful deposition of gold nanoparticles (1 wt.-%) of average size 3.3 nm on the above metal oxide by using HAuCl4· 3H2O afforded a highly efficient Au/In2O3 catalyst for the aerobic epoxidation of trans-stilbene at low temperature. The above single source precursor approach was further extended to obtain other group 13 homo- and heterometallic oxides, namely, α-Ga2O 3, β-Ga2O3 and Al4Ga 2O9, as highly active supports for gold catalysts. The obtained Au/M2O3 (M = Ga, In) and Au/Al4Ga 2O9 catalysts were thoroughly characterized by using several physicochemical techniques such as XRD, high resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray (EDX) spectroscopy, and X-ray photoelectron spectroscopy (XPS). A comparative study of the above catalysts for the model aerobic oxidation of stilbene in methylcyclohexane was undertaken. Highly efficient catalysts for aerobic oxidation reactions were obtained by depositing gold nanoparticles on group 13 mono- or mixed metal oxides prepared from the hydrolysis of well-characterized homo- and heterometallic N-methyldiethanolaminate derivatives. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. A single source precursor route to group 13 homo- and heterometallic oxides as highly active supports for gold-catalyzed aerobic epoxidation of trans-stilbene

    KAUST Repository

    Mishra, Shashank K.

    2012-12-14

    A new Mitsubishi-type of star-shaped homoleptic derivative of indium(III), In4(mdea)6 (2, mdeaH2 = N-methyldiethanolamine) , was synthesized by the chloro-aminoalkoxo exchange reaction of a heteroleptic complex In6Cl6(mdea)6 (1) and used as a facile single source molecular precursor for the sol-gel preparation of high surface area indium oxide. Successful deposition of gold nanoparticles (1 wt.-%) of average size 3.3 nm on the above metal oxide by using HAuCl4· 3H2O afforded a highly efficient Au/In2O3 catalyst for the aerobic epoxidation of trans-stilbene at low temperature. The above single source precursor approach was further extended to obtain other group 13 homo- and heterometallic oxides, namely, α-Ga2O 3, β-Ga2O3 and Al4Ga 2O9, as highly active supports for gold catalysts. The obtained Au/M2O3 (M = Ga, In) and Au/Al4Ga 2O9 catalysts were thoroughly characterized by using several physicochemical techniques such as XRD, high resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray (EDX) spectroscopy, and X-ray photoelectron spectroscopy (XPS). A comparative study of the above catalysts for the model aerobic oxidation of stilbene in methylcyclohexane was undertaken. Highly efficient catalysts for aerobic oxidation reactions were obtained by depositing gold nanoparticles on group 13 mono- or mixed metal oxides prepared from the hydrolysis of well-characterized homo- and heterometallic N-methyldiethanolaminate derivatives. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection.

    Science.gov (United States)

    Suh, Joome; Sinclair, Elizabeth; Peterson, Julia; Lee, Evelyn; Kyriakides, Tassos C; Li, Fang-Yong; Hagberg, Lars; Fuchs, Dietmar; Price, Richard W; Gisslen, Magnus; Spudich, Serena

    2014-12-03

    Central nervous system (CNS) inflammation is a mediator of brain injury in HIV infection. To study the natural course of CNS inflammation in the early phase of infection, we analyzed longitudinal levels of soluble and cellular markers of inflammation in cerebrospinal fluid (CSF) and blood, beginning with primary HIV-1 infection (PHI). Antiretroviral-naïve subjects identified as having PHI (less than one year since HIV transmission) participated in phlebotomy and lumbar puncture at baseline and at variable intervals thereafter. Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and percentages of activated cluster of differentiation (CD)4+ and CD8+ T-cells (co-expressing CD38 and human leukocyte antigen-D-related (HLA-DR)) in blood and CSF. A total of 81 subjects were enrolled at an average of 100 days after HIV transmission and had an average follow-up period of 321 days, with the number of visits ranging from one to 13. At baseline, the majority of subjects had CSF neopterin concentrations above the upper limit of normal. The baseline concentration was associated with the longitudinal trajectory of CSF neopterin. In subjects with baseline levels of less than 21 nmol/L, a cutoff value obtained from a mixed-effects model, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P <0.001), whereas it decreased by 6.7% in subjects with baseline levels of more than 21 nmol/L (n = 11; P = 0.001). In a subset with available flow cytometry data (n = 42), the percentages of activated CD4+ and CD8+ T-cells in CSF increased by 0.8 (P <0.001) and 0.73 (P = 0.02) per 10 weeks, respectively. Neopterin levels and the percentages of activated CD4+ and CD8+ T-cells in CSF progressively increase in most subjects without treatment during early HIV-1 infection, suggesting an accrual of intrathecal inflammation, a major contributor to neuropathology in HIV infection.

  11. HIV-1 Env and Nef Cooperatively Contribute to Plasmacytoid Dendritic Cell Activation via CD4-Dependent Mechanisms.

    Science.gov (United States)

    Reszka-Blanco, Natalia J; Sivaraman, Vijay; Zhang, Liguo; Su, Lishan

    2015-08-01

    Plasmacytoid dendritic cells (pDCs) are the major source of type I IFN (IFN-I) in response to human immunodeficiency virus type 1 (HIV-1) infection. pDCs are rapidly activated during HIV-1 infection and are implicated in reducing the early viral load, as well as contributing to HIV-1-induced pathogenesis. However, most cell-free HIV-1 isolates are inefficient in activating human pDCs, and the mechanisms of HIV-1 recognition by pDCs and pDC activation are not clearly defined. In this study, we report that two genetically similar HIV-1 variants (R3A and R3B) isolated from a rapid progressor differentially activated pDCs to produce alpha interferon (IFN-α). The highly pathogenic R3A efficiently activated pDCs to induce robust IFN-α production, while the less pathogenic R3B did not. The viral determinant for efficient pDC activation was mapped to the V1V2 region of R3A Env, which also correlated with enhanced CD4 binding activity. Furthermore, we showed that the Nef protein was also required for the activation of pDCs by R3A. Analysis of a panel of R3A Nef functional mutants demonstrated that Nef domains involved in CD4 downregulation were necessary for R3A to activate pDCs. Our data indicate that R3A-induced pDC activation depends on (i) the high affinity of R3A Env for binding the CD4 receptor and (ii) Nef activity, which is involved in CD4 downregulation. Our findings provide new insights into the mechanism by which HIV-1 induces IFN-α in pDCs, which contributes to pathogenesis. Plasmacytoid dendritic cells (pDCs) are the major type I interferon (IFN-I)-producing cells, and IFN-I actually contributes to pathogenesis during chronic viral infections. How HIV-1 activates pDCs and the roles of pDCs/IFN-I in HIV-1 pathogenesis remain unclear. We report here that the highly pathogenic HIV R3A efficiently activated pDCs to induce IFN-α production, while most HIV-1 isolates are inefficient in activating pDCs. We have discovered that R3A-induced pDC activation depends on

  12. The HIV-1 Nef protein and phagocyte NADPH oxidase activation

    DEFF Research Database (Denmark)

    Vilhardt, Frederik; Plastre, Olivier; Sawada, Makoto

    2002-01-01

    of Rac by Clostridium difficile toxin B abolished the Nef effect. (ii) The fraction of activated Rac1 was increased in Nef-transduced cells, and (iii) the dominant positive Rac1(V12) mutant mimicked the effect of Nef. These results are to our knowledge the first analysis of the effect of Rac activation...

  13. 9G4 autoreactivity is increased in HIV-infected patients and correlates with HIV broadly neutralizing serum activity.

    Directory of Open Access Journals (Sweden)

    James J Kobie

    Full Text Available The induction of a broadly neutralizing antibody (BNAb response against HIV-1 would be a desirable feature of a protective vaccine. Vaccine strategies thus far have failed to elicit broadly neutralizing antibody responses; however a minority of HIV-infected patients do develop circulating BNAbs, from which several potent broadly neutralizing monoclonal antibodies (mAbs have been isolated. The findings that several BNmAbs exhibit autoreactivity and that autoreactive serum antibodies are observed in some HIV patients have advanced the possibility that enforcement of self-tolerance may contribute to the rarity of BNAbs. To examine the possible breakdown of tolerance in HIV patients, we utilized the 9G4 anti-idiotype antibody system, enabling resolution of both autoreactive VH4-34 gene-expressing B cells and serum antibodies. Compared with healthy controls, HIV patients had significantly elevated 9G4+ serum IgG antibody concentrations and frequencies of 9G4+ B cells, a finding characteristic of systemic lupus erythematosus (SLE patients, both of which positively correlated with HIV viral load. Compared to the global 9G4-IgD--memory B cell population, the 9G4+IgD--memory fraction in HIV patients was dominated by isotype switched IgG+ B cells, but had a more prominent bias toward "IgM only" memory. HIV envelope reactivity was observed both in the 9G4+ serum antibody and 9G4+ B cell population. 9G4+ IgG serum antibody levels positively correlated (r = 0.403, p = 0.0019 with the serum HIV BNAbs. Interestingly, other serum autoantibodies commonly found in SLE (anti-dsDNA, ANA, anti-CL did not correlate with serum HIV BNAbs. 9G4-associated autoreactivity is preferentially expanded in chronic HIV infection as compared to other SLE autoreactivities. Therefore, the 9G4 system provides an effective tool to examine autoreactivity in HIV patients. Our results suggest that the development of HIV BNAbs is not merely a consequence of a general breakdown in

  14. A trans world journey

    DEFF Research Database (Denmark)

    Stender, Steen; Dyerberg, Jørn; Bysted, Anette

    2006-01-01

    to a maximum of 2% of fat content from 2004. We assessed the potential exposure of consumers to IP-TFA by analysing popular foods in Denmark, and in 25 other countries. Fifty-five servings of French fries and chicken nuggets, 87 packages of microwave popcorn, and 393 samples of biscuits....../cakes/wafers with "partially hydrogenated vegetable fat" listed high on the food label were bought between November 2004, and February 2006. The content of IP-TFA was analysed by standardized methodology. We defined a "high trans menu" as a large size serving of French fries and nuggets, 100 g of microwave popcorn, and 100 g......A high intake of industrially produced trans fatty acids (IP-TFA) is associated with increased risk of coronary heart disease (CHD), and a daily intake as low as possible is required to minimize health risks. To achieve this at the individual level in Denmark, legislation limited IP-TFA in foods...

  15. Innate immunity in the vagina (Part II): Anti-HIV activity and antiviral content of human vaginal secretions.

    Science.gov (United States)

    Patel, Mickey V; Ghosh, Mimi; Fahey, John V; Ochsenbauer, Christina; Rossoll, Richard M; Wira, Charles R

    2014-07-01

    Whether the concentrations of antiviral proteins, and anti-HIV activity, within human vaginal secretions change across the menstrual cycle is unknown. Using a menstrual cup, vaginal secretions from pre-menopausal women were recovered at the proliferative (d6-8), mid-cycle (d13-15), and secretory (d21-23) stages of the menstrual cycle. Antiviral protein concentration was determined by ELISA, and anti-HIV activity assessed using the TZM-bl reporter cell line. CCL20, RANTES, elafin, HBD2, SDF-1α, and IL-8 levels were detectable in the secretions. Vaginal secretions had anti-HIV activity against specific clade B strains of HIV, with significant inhibition of IIIB and increased infectivity of transmitted/founder CH077.t. No significant differences in either antiviral protein concentration or anti-HIV activity with respect to menstrual cycle stage were measured, but marked differences were observed in both parameters over the course of the cycle between different women and in consecutive cycles from the same woman. The vagina contains a complement of antiviral proteins. The variation in anti-HIV activity demonstrates that immune protection in the vagina is not constant. Intra- and interindividual variations suggest that factors in addition to sex hormones influence antiviral protection. Lastly, the menstrual cup is a new model for recovering undiluted vaginal secretions from women throughout their reproductive life. © 2014 John Wiley & Sons Ltd.

  16. Immunity in the Vagina (Part II): Anti-HIV Activity and Antiviral Content of Human Vaginal Secretions

    Science.gov (United States)

    Patel, Mickey V.; Ghosh, Mimi; Fahey, John V.; Ochsenbauer, Christina; Rossoll, Richard M.; Wira, Charles R.

    2015-01-01

    Problem Whether the concentrations of antiviral proteins, and anti-HIV activity, within human vaginal secretions changes across the menstrual cycle is unknown. Method of Study Using a menstrual cup, vaginal secretions from premenopausal women were recovered at the proliferative (d6–8), mid-cycle (d13–15) and secretory (d21–23) stages of the menstrual cycle. Antiviral protein concentration was determined by ELISA, and anti-HIV activity assessed using the TZM-bl reporter cell line. Results CCL20, RANTES, elafin, HBD2, SDF-1α and IL-8 levels were detectable in the secretions. Vaginal secretions had anti-HIV activity against specific clade B strains of HIV, with significant inhibition of IIIB and increased infectivity of transmitted/founder CH077.t. No significant differences in either antiviral protein concentration or anti-HIV activity with respect to menstrual cycle stage were measured, but marked differences were observed in both parameters over the course of the cycle between different women, and in consecutive cycles from the same woman. Conclusion The vagina contains a complement of antiviral proteins. The variation in anti-HIV activity demonstrates that immune protection in the vagina is not constant. Intra- and inter-individual variations suggest that factors in addition to sex hormones influence antiviral protection. Lastly, the menstrual cup is a new model for recovering undiluted vaginal secretions from women throughout their reproductive life. PMID:24806967

  17. Experiences about HIV-AIDS preventive-control activities. Discourses from non-governmental organizations professionals and users.

    Science.gov (United States)

    Berenguera, Anna; Pujol-Ribera, Enriqueta; Violan, Concepció; Romaguera, Amparo; Mansilla, Rosa; Giménez, Albert; Almeda, Jesús

    2011-01-01

    The main aim of this study was to identify the experiences of professionals in nongovernmental organizations (NGO) in Catalonia (Spain) working in HIV/AIDS prevention and control activities and potential areas of improvement of these activities and their evaluation. A further aim was to characterize the experiences, knowledge and practices of users of these organizations with regard to HIV infection and its prevention. A phenomenological qualitative study was conducted with the participation of both professionals and users of Catalan nongovernmental organizations (NGO) working in HIV/AIDS. Theoretical sampling (professional) and opportunistic sampling (users) were performed. To collect information, the following techniques were used: four focus groups and one triangular group (professionals), 22 semi-structured interviews, and two observations (users). A thematic interpretive content analysis was conducted by three analysts. The professionals of nongovernmental organizations working in HIV/AIDS adopted a holistic approach in their activities, maintained confidentiality, had cultural and professional competence and followed the principles of equality and empathy. The users of these organizations had knowledge of HIV/AIDS and understood the risk of infection. However, a gap was found between knowledge, attitudes and behavior. NGO offer distinct activities adapted to users' needs. Professionals emphasize the need for support and improvement of planning and implementation of current assessment. The preventive activities of these HIV/AIDS organizations are based on a participatory health education model adjusted to people's needs and focused on empowerment. Copyright © 2010 SESPAS. Published by Elsevier Espana. All rights reserved.

  18. Role of immune activation in CD4+ T-cell depletion in HIV-1 infected Indian patients.

    Science.gov (United States)

    Vajpayee, M; Kaushik, S; Sreenivas, V; Mojumdar, K; Mendiratta, S; Chauhan, N K

    2009-01-01

    The correlation of immune activation with CD4(+) depletion and HIV-1 disease progression has been evidenced by several studies involving mainly clade B virus. However, this needs to be investigated in developing countries such as India predominately infected with clade C virus. In a cross-sectional study of 68 antiretroviral treatment naïve, HIV-1 infected Indian patients, we studied the association between CD4(+) T cells, plasma HIV-1 RNA levels, and immune activation markers using unadjusted and adjusted correlative analyses. Significant negative correlations of higher magnitude were observed between the CD4(+) T cell percentages and plasma HIV-1 RNA levels in the study population when adjusted for the effects of immune activation markers. However, the negative association of CD4(+) T cells with immune activation markers remained unaffected when controlled for the effects of plasma HIV-1 RNA levels. Our results support the important role of immune activation in CD4(+) T cell depletion and disease progression during untreated HIV-1 infection.

  19. Immune reconstitution inflammatory syndrome after initiating highly active antiretroviral therapy in HIV-infected children

    International Nuclear Information System (INIS)

    Kilborn, Tracy; Zampoli, Marco

    2009-01-01

    The outcome of HIV infection has improved since the widespread availability of highly active antiretroviral therapy (HAART). Some patients, however, develop a clinical and radiological deterioration following initiation of HAART due to either the unmasking of occult subclinical infection or an enhanced inflammatory response to a treated infection. This phenomenon is believed to result from the restored ability to mount an immune response and is termed immune reconstitution inflammatory syndrome (IRIS) or immune reconstitution disease. IRIS is widely reported in the literature in adult patients, most commonly associated with mycobacterial infections. There is, however, a paucity of data documenting the radiological findings of IRIS in children. Radiologists need to be aware of this entity. As a diagnosis of exclusion it is essential that the radiological findings be assessed in the context of the clinical presentation. This article reviews the common clinical and radiological manifestations of IRIS in HIV-infected children. (orig.)

  20. Synthesis of single- and double-chain fluorocarbon and hydrocarbon galactosyl amphiphiles and their anti-HIV-1 activity.

    Science.gov (United States)

    Faroux-Corlay, B; Clary, L; Gadras, C; Hammache, D; Greiner, J; Santaella, C; Aubertin, A M; Vierling, P; Fantini, J

    2000-07-24

    Galactosylceramide (GalCer) is an alternative receptor allowing HIV-1 entry into CD4(-)/GalCer(+) cells. This glycosphingolipid recognizes the V3 loop of HIV gp120, which plays a key role in the fusion of the HIV envelope and cellular membrane. To inhibit HIV uptake and infection, we designed and synthesized analogs of GalCer. These amphiphiles and bolaamphiphiles consist of single and double hydrocarbon and/or fluorocarbon chain beta-linked to galactose and galactosamine. They derive from serine (GalSer), cysteine (GalCys), and ethanolamine (GalAE). The anti-HIV activity and cytotoxicity of these galactolipids were evaluated in vitro on CEM-SS (a CD4(+) cell line), HT-29, a CD4(-) cell line expressing high levels of GalCer receptor, and/or HT29 genetically modified to express CD4. GalSer and GalAE derivatives, tested in aqueous medium or as part of liposome preparation, showed moderate anti-HIV-1 activities (IC50 in the 20-220 microM range), whereas none of the GalCys derivatives was found to be active. Moreover, only some of these anti-HIV active analogs inhibited the binding of [3H]suramin (a polysulfonyl compound which displays a high affinity for the V3 loop) to SPC3, a synthetic peptide which contains the conserved GPGRAF region of the V3 loop. Our results most likely indicate that the neutralization of the virion through masking of this conserved V3 loop region is not the only mechanism involved in the HIV-1 antiviral activity of our GalCer analogs.

  1. Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of Alpha Interferon

    Science.gov (United States)

    Akiyama, Hisashi; Ramirez, Nora-Guadalupe Pina; Gibson, Gregory; Kline, Christopher; Watkins, Simon; Ambrose, Zandrea

    2017-01-01

    ABSTRACT A hallmark of human immunodeficiency virus type 1 (HIV-1) infection in vivo is chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in many cell types, HIV-1 can replicate in vivo via mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein, CD169, as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4+ T cells in trans. Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells in cis and CD4+ T cells in trans and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activation in vivo, was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27gag and CD169, suggesting productive infection of CD169+ myeloid cells in vivo. While cell-free HIV-1 infection of IFN-α-treated CD4+ T cells was robustly decreased, initiation of infection in trans via coculture with CD169+ IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 in cis and in trans to attenuate a type I IFN-induced antiviral state. IMPORTANCE HIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN

  2. Feasibility of Measuring Immune Resp, Activation in Foreskin/Mucosa in HIV-, Uncircumcised High-HIV-risk MSM, Lima Peru

    Science.gov (United States)

    2015-12-10

    HIV Infections; Acquired Immunodeficiency Syndrome; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases

  3. Further screening of Venda medicinal plants for activity against HIV ...

    African Journals Online (AJOL)

    Owner

    2006-03-15

    Mar 15, 2006 ... by an NIH image apparatus. This means none of the fractions inhibited IN activity at the concentrations tested. (Data not shown). 1H and 14C nuclear magnetic resonance data, MS, UV and infrared spectroscopic data revealed that substance X and Y were the known phytosterols friedelin and β-sistosterol, ...

  4. Increased intrahepatic apoptosis but reduced immune activation in HIV-HBV co-infected patients with advanced immunosuppression.

    Science.gov (United States)

    Iser, David M; Avihingsanon, Anchalee; Wisedopas, Naruemon; Thompson, Alexander J; Boyd, Alison; Matthews, Gail V; Locarnini, Stephen A; Slavin, John; Desmond, Paul V; Lewin, Sharon R

    2011-01-14

    to determine if intrahepatic immune activation is increased in HIV-hepatitis B virus (HBV) co-infected patients compared to HBV mono-infected patients and whether this reduced following HBV-active antiretroviral therapy (ART) in HIV-HBV co-infected patients. : Case-control observational study. we examined liver biopsies for markers of T-cell and monocyte infiltration and activation, natural killer cells, hepatic stellate cell (HSC) activation (staining for alpha smooth muscle actin) and apoptosis [using terminal dUTP nick-end labelling (TUNEL)] in treatment-naive Asian HIV-HBV co-infected (n = 16) and HBV mono-infected patients matched for age and HBV e-antigen status (n = 16). Liver biopsies from a subset of co-infected patients (n = 15) were also compared prior to and following 48 weeks of HBV-active ART. HIV-HBV co-infected patients had a median CD4 T-cell count of 25 cells/microl and lower alanine aminotransferase levels than HBV mono-infected patients (P = 0.03). In HIV-HBV co-infected patients, hepatocyte apoptosis was increased (P = 0.04) but there were fewer intrahepatic CD4 and CD8 T cells (P < 0.001), lower activation of intrahepatic T cells, Kupffer cells and HSC (P = 0.002, 0.008 and < 0.001, respectively). Following ART, there was a significant decrease in intrahepatic HBsAg staining (P = 0.04) and Kupffer cell activation (P = 0.003). we found no evidence of increased intrahepatic mononuclear and HSC activation in this cohort of HIV-HBV co-infected individuals with advanced immune suppression. An increase in intra-hepatic apoptosis in HIV-HBV co-infected individuals may potentially contribute to accelerated fibrosis in this setting. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

  5. Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4

    International Nuclear Information System (INIS)

    Short, Duncan M.; Lyon, Robert; Watson, David G.; Barski, Oleg A.; McGarvie, Gail; Ellis, Elizabeth M.

    2006-01-01

    The reductive metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, was studied in mouse liver. Using an HPLC-based stopped assay, the primary reduced metabolite was identified as 6-hydroxy-trans, trans-2,4-hexadienal (OH/CHO) and the secondary metabolite as 1,6-dihydroxy-trans, trans-2,4-hexadiene (OH/OH). The main enzymes responsible for the highest levels of reductase activity towards trans, trans-muconaldehyde were purified from mouse liver soluble fraction first by Q-sepharose chromatography followed by either blue or red dye affinity chromatography. In mouse liver, trans, trans-muconaldehyde is predominantly reduced by an NADH-dependent enzyme, which was identified as alcohol dehydrogenase (Adh1). Kinetic constants obtained for trans, trans-muconaldehyde with the native Adh1 enzyme showed a V max of 2141 ± 500 nmol/min/mg and a K m of 11 ± 4 μM. This enzyme was inhibited by pyrazole with a K I of 3.1 ± 0.57 μM. Other fractions were found to contain muconaldehyde reductase activity independent of Adh1, and one enzyme was identified as the NADPH-dependent aldehyde reductase AKR1A4. This showed a V max of 115 nmol/min/mg and a K m of 15 ± 2 μM and was not inhibited by pyrazole

  6. Health systems in the Republic of Congo: challenges and opportunities for implementing tuberculosis and HIV collaborative service, research, and training activities.

    Science.gov (United States)

    Linguissi, Laure Stella Ghoma; Gwom, Luc Christian; Nkenfou, Celine Nguefeu; Bates, Matthew; Petersen, Eskild; Zumla, Alimuddin; Ntoumi, Francine

    2017-03-01

    The Republic of Congo is on the World Health Organization (WHO) list of 'high burden' countries for tuberculosis (TB) and HIV. TB is the leading cause of death among HIV-infected patients in the Republic of Congo. In this viewpoint, the available data on TB and HIV in the Republic of Congo are reviewed, and the gaps and bottlenecks that the National TB Control Program (NTCP) faces are discussed. Furthermore, priority requirements for developing and implementing TB and HIV collaborative service activities are identified. HIV and TB control programs operate as distinct entities with separate case management plans. The implementation of collaborative TB/HIV activities to evaluate and monitor the management of TB/HIV co-infected individuals remains inefficient in most regions, and these activities are sometimes non-existent. This reveals major challenges that require definition in order to improve the delivery of healthcare. The NTCP lacks adequate resources for optimal implementation of control measures of TB and HIV compliance and outcomes. The importance of aligning and integrating TB and HIV treatment services (including follow-up) and adherence support services through coordinated and collaborative efforts between individual TB and HIV programs is discussed. Aligning and integrating TB and HIV treatment services through coordinated and collaborative efforts between individual TB and HIV programs is required. However, the WHO recommendations are generic, and health services in the Republic of Congo need to tailor their TB and HIV programs according to the availability of resources and operational feasibility. This will also open opportunities for synergizing collaborative TB/HIV research and training activities, which should be prioritized by the donors supporting the TB/HIV programs. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  7. Health systems in the Republic of Congo: challenges and opportunities for implementing tuberculosis and HIV collaborative service, research, and training activities

    Directory of Open Access Journals (Sweden)

    Laure Stella Ghoma Linguissi

    2017-03-01

    Full Text Available The Republic of Congo is on the World Health Organization (WHO list of ‘high burden’ countries for tuberculosis (TB and HIV. TB is the leading cause of death among HIV-infected patients in the Republic of Congo. In this viewpoint, the available data on TB and HIV in the Republic of Congo are reviewed, and the gaps and bottlenecks that the National TB Control Program (NTCP faces are discussed. Furthermore, priority requirements for developing and implementing TB and HIV collaborative service activities are identified. HIV and TB control programs operate as distinct entities with separate case management plans. The implementation of collaborative TB/HIV activities to evaluate and monitor the management of TB/HIV co-infected individuals remains inefficient in most regions, and these activities are sometimes non-existent. This reveals major challenges that require definition in order to improve the delivery of healthcare. The NTCP lacks adequate resources for optimal implementation of control measures of TB and HIV compliance and outcomes. The importance of aligning and integrating TB and HIV treatment services (including follow-up and adherence support services through coordinated and collaborative efforts between individual TB and HIV programs is discussed. Aligning and integrating TB and HIV treatment services through coordinated and collaborative efforts between individual TB and HIV programs is required. However, the WHO recommendations are generic, and health services in the Republic of Congo need to tailor their TB and HIV programs according to the availability of resources and operational feasibility. This will also open opportunities for synergizing collaborative TB/HIV research and training activities, which should be prioritized by the donors supporting the TB/HIV programs.

  8. Impact of Active Drug Use on Antiretroviral Therapy Adherence and Viral Suppression in HIV-infected Drug Users

    OpenAIRE

    Arnsten, Julia H; Demas, Penelope A; Grant, Richard W; Gourevitch, Marc N; Farzadegan, Homayoon; Howard, Andrea A; Schoenbaum, Ellie E

    2002-01-01

    Despite a burgeoning literature on adherence to HIV therapies, few studies have examined the impact of ongoing drug use on adherence and viral suppression, and none of these have utilized electronic monitors to quantify adherence among drug users. We used 262 electronic monitors to measure adherence with all antiretrovirals in 85 HIV-infected current and former drug users, and found that active cocaine use, female gender, not receiving Social Security benefits, not being married, screening po...

  9. Programming of neurotoxic cofactor CXCL-10 in HIV-1-associated dementia: abrogation of CXCL-10-induced neuro-glial toxicity in vitro by PKC activator

    Directory of Open Access Journals (Sweden)

    Mehla Rajeev

    2012-10-01

    Full Text Available Abstract Background More than 50% of patients undergoing lifelong suppressive antiviral treatment for HIV-1 infection develop minor HIV-1-associated neurocognitive disorders. Neurological complications during HIV-1 infection are the result of direct neuronal damage by proinflammatory products released from HIV-1-infected or -uninfected activated lymphocytes, monocytes, macrophages, microglia and astrocytes. The specific pro-inflammatory products and their roles in neurotoxicity are far from clear. We investigated proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF of HIV-demented (HIV-D and HIV-nondemented (HIV-ND patients and studied their affect on neuroglial toxicity. Methods and results Bioplex array showed elevated levels of signatory chemokines or cytokines (IL-6, IFN-γ, CXCL10, MCP-1 and PDGF in the CSF of HIV-D patients (n = 7 but not in that of HIV-ND patients (n = 7. Among the signatory cytokines and chemokines, CXCL10 was distinctly upregulated in-vitro in HIV-1 (NLENG1-activated human fetal astrocytes, HIV-1 (Ba-L-infected macrophages, and HIV-1 (NLENG1-infected lymphocytes. Virus-infected macrophages also had increased levels of TNF-α. Consistently, human fetal astrocytes treated with HIV-1 and TNF-α induced the signatory molecules. CXCL10 in combination with HIV-1 synergistically enhanced neuronal toxicity and showed chemotactic activity (~ 40 fold for activated peripheral blood mononuclear cells (PBMC, suggesting the intersection of signaling events imparted by HIV-1 and CXCL10 after binding to their respective surface receptors, CXCR4 and CXCR3, on neurons. Blocking CXCR3 and its downstream MAP kinase (MAPK signaling pathway suppressed combined CXCL10 and HIV-1-induced neurotoxicity. Bryostatin, a PKC modulator and suppressor of CXCR4, conferred neuroprotection against combined insult with HIV-1 and CXCL10. Bryostatin also suppressed HIV-1 and CXCL10-induced PBMC chemotaxis. Although, therapeutic targeting

  10. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals

    International Nuclear Information System (INIS)

    Tong-Starksen, S.E.; Luciw, P.A.; Peterlin, B.M.

    1987-01-01

    Human immunodeficiency virus (HIV), the causative agent of AIDS, infects and kills lymphoid cells bearing the CD4 antigen. In an infected cell, a number of cellular as well as HIV-encoded gene products determine the levels of viral gene expression and HIV replication. Efficient HIV replication occurs in activated T cells. Utilizing transient expression assays, the authors show that gene expression directed by the HIV long terminal repeat (LTR) increases in response to T-cell activation signals. The effects of T-cell activation and of the HIV-encoded trans-activator (TAT) are multiplicative. Analysis of mutations and deletions in the HIV LTR reveals that the region responding to T-cell activation signals is located at positions -105 to -80. These sequences are composed of two direct repeats, which are homologous to the core transcriptional enhancer elements in the simian virus 40 genome. The studies reveal that these elements function as the HIV enhancer. By acting directly on the HIV LTR, T-cell activation may play an important role in HIV gene expression and in the activation of latent HIV

  11. A Conserved GPG-Motif in the HIV-1 Nef Core Is Required for Principal Nef-Activities.

    Directory of Open Access Journals (Sweden)

    Marta Martínez-Bonet

    Full Text Available To find out new determinants required for Nef activity we performed a functional alanine scanning analysis along a discrete but highly conserved region at the core of HIV-1 Nef. We identified the GPG-motif, located at the 121-137 region of HIV-1 NL4.3 Nef, as a novel protein signature strictly required for the p56Lck dependent Nef-induced CD4-downregulation in T-cells. Since the Nef-GPG motif was dispensable for CD4-downregulation in HeLa-CD4 cells, Nef/AP-1 interaction and Nef-dependent effects on Tf-R trafficking, the observed effects on CD4 downregulation cannot be attributed to structure constraints or to alterations on general protein trafficking. Besides, we found that the GPG-motif was also required for Nef-dependent inhibition of ring actin re-organization upon TCR triggering and MHCI downregulation, suggesting that the GPG-motif could actively cooperate with the Nef PxxP motif for these HIV-1 Nef-related effects. Finally, we observed that the Nef-GPG motif was required for optimal infectivity of those viruses produced in T-cells. According to these findings, we propose the conserved GPG-motif in HIV-1 Nef as functional region required for HIV-1 infectivity and therefore with a potential interest for the interference of Nef activity during HIV-1 infection.

  12. Synthesis and evaluation of antiviral activities of novel sonochemical silver nanorods against HIV and HSV viruses

    Directory of Open Access Journals (Sweden)

    Mazyar Etemadzade

    2016-11-01

    Full Text Available Objective: To evaluate the effect of novel sonochemical silver nanorods on HIV and herpes simplex virus type 1 (HSV-1 viruses in human cervical cancer HeLa cells. Methods: The formation of silver nanorods conjugated with sodium 2-mercaptoethane sulfonate (Ag-MES was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy and thermal gravimetric analysis. The antiviral activity of this Ag-MES was examined against HIV and HSV-1 virus replication. Results: The characterizations of Ag-MES and physiochemical structure were determined by scanning electron microscopy, Fourier transform infrared spectroscopy and thermal gravimetric analysis. Approximately entire viral replication was inhibited by Ag-MES at 10 µmol/mL concentration. About 90% of HSV virions failed to replicate in the present of this concentration of nanorods. However, HIV showed more sensitivity to Ag-MES than HSV-1. Conclusions: According to the obtained data, the synthesized sonochemical silver nanorod in this study is a promising candidate for further drug discovery investigation.

  13. Anti-HIV-1 activities of the extracts from the medicinal plant Linum grandiflorum Desf

    DEFF Research Database (Denmark)

    Mohammed, Magdy M. D.; Christensen, Lars Porskjær; Ibrahim, Nabaweya A.

    2009-01-01

    As part of our screening of anti-AIDS agents from natural sources e.g. Ixora undulata, Paulownia tomentosa, Fortunella margarita, Aegle marmelos and Erythrina abyssinica, the different organic and aqueous extracts of Linum grandiflorum leaves and seeds were evaluated in vitro by the microculture...... tetrazolium (MTT) assay. The activity of the tested extracts against multiplication of HIV-1 wild type IIIB, N119, A17, and EFVR in acutely infected cells was based on inhibition of virus-induced cytopathicity in MT-4 cells. Results revealed that both the MeOH and the CHCl3 extracts of L. grandiflorum have...... significant inhibitory effects against HIV-1 induced infection with MT-4 cells. The MeOH extract of the leaves is more potent than other extracts against MT-4 cell cultures infected with the wild type HIV-1, strain IIIB with an ED50 of 46 ± 6 µM, while the CHCl3 extract of the seeds is more potent than other...

  14. Vitamin E concentrations in adults with HIV/AIDS on highly active antiretroviral therapy.

    Science.gov (United States)

    Itinoseki Kaio, Daniella J Itinoseki; Rondó, Patricia Helen C; Luzia, Liania Alves; Souza, José Maria P; Firmino, Aline Vale; Santos, Sigrid Sousa

    2014-09-15

    HIV/AIDS patients are probably more predisposed to vitamin E deficiency, considering that they are more exposed to oxidative stress. Additionally, there are an extensive number of drugs in the highly active antiretroviral therapy (HAART) regimens that may interfere with vitamin E concentrations. The objective of this study was to compare serum concentrations of alpha-tocopherol in 182 HIV/AIDS patients receiving different HAART regimens. The patients were divided into three groups according to regimen: nucleoside analog reverse-transcriptase inhibitors (NRTIs) + non-nucleoside analog reverse-transcriptase inhibitors (NNRTIs); NRTIs + protease inhibitors + ritonavir; NRTIs + other classes. Alpha-tocopherol was assessed by high-performance liquid chromatography. Multiple linear regression analysis was used to evaluate the effects of HAART regimen, time of use, and compliance with the regimen on alpha-tocopherol concentrations. Alpha-tocopherol concentrations were on average 4.12 μmol/L lower for the NRTIs + other classes regimen when compared to the NRTIs + NNRTIs regimen (p = 0.037). A positive association (p < 0.001) was observed between alpha-tocopherol and cholesterol concentrations, a finding due, in part, to the relationship between liposoluble vitamins and lipid profile. This study demonstrated differences in alpha-tocopherol concentrations between patients using different HAART regimens, especially regimens involving the use of new drugs. Long-term prospective cohort studies are needed to monitor vitamin E status in HIV/AIDS patients since the beginning of treatment.

  15. Sex issues in HIV-1-infected persons during highly active antiretroviral therapy: a systematic review.

    Science.gov (United States)

    Nicastri, Emanuele; Leone, Sebastiano; Angeletti, Claudio; Palmisano, Lucia; Sarmati, Loredana; Chiesi, Antonio; Geraci, Andrea; Vella, Stefano; Narciso, Pasquale; Corpolongo, Angela; Andreoni, Massimo

    2007-10-01

    Since the introduction of highly active antiretroviral therapy (HAART), morbidity and mortality rates have sharply decreased among HIV-infected patients. Studies of possible differences between men and women in the course of HIV infection give conflicting results. The objective of this study was to assess sex differences during HAART. A literature search by using the MEDLINE database between March 2002 and February 2007 was performed to identify all published studies on the sex-specific differences on the impact of HAART. All articles with measures of effect (preferably adjusted odds ratio, relative risk or hazard ratio with 95% CI) of sex on viroimmunological and clinical parameters during HAART were included. Five different topics of interest in our research were selected: time of initiation of HAART, adherence, viroimmunological response, clinical response and adverse reactions during HAART. US data report an initiation of HAART at an earlier disease stage in men compared with women. After initiation of HAART, most authors do not report any viroimmunological difference, although a few clinical studies showed a significantly better virological response in women compared with men. Nevertheless, women were more likely to be less adherent to antiretrovirals and to have non-structured treatment interruptions than men. This is likely to be related to the higher number of adverse reactions they experience during HAART. Finally, discordant opinions with regard to clinical benefits during HAART exist, but recent clinical and observational trials suggest a better clinical outcome for women. We found little evidence of sex differences during antiretroviral treatment. Nevertheless, most of these studies were underpowered to detect sex differences and had limited follow-up at 6 or 12 months. Design of new gender-sensitive clinical trials with both prolonged follow-up and sample size representative of the current HIV prevalence among women are strongly needed to detect the

  16. Improvement of trans-sialylation versus hydrolysis activity of an engineered sialidase from Trypanosoma rangeli by use of co-solvents

    DEFF Research Database (Denmark)

    Zeuner, Birgitte; Riisager, Anders; Mikkelsen, Jørn Dalgaard

    2014-01-01

    hexafluorophosphate), were examined as co-solvents for the improvement of the synthesis versus hydrolysis ratio in the trans-sialylation of lactose, catalysed by an engineered sialidase from Trypanosoma rangeli. The use of 25 % (v/v) t-butanol as co-solvent significantly increased 3'-sialyllactose production by 40...... % from 1.04 ± 0.09 to 1.47 ± 0.01 mM. The synthesis versus hydrolysis ratio increased correspondingly by 1.2-times. 1-2.5 % (v/v) EAN or [C2OHMIm][PF6] improved the synthesis versus hydrolysis ratio up to 2.5-times but simultaneously decreased the 3'-sialyllactose yield, probably due to enzyme...... inactivation caused by the ionic liquid. [MMIm][MeSO4] had a detrimental effect on the trans-sialylation yield and on the ratio between synthesis and hydrolysis....

  17. Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm

    DEFF Research Database (Denmark)

    Helledie, T; Antonius, M; Sorensen, R V

    2000-01-01

    Peroxisome proliferator-activated receptors (PPARs) are activated by a variety of fatty acids, eicosanoids, and hypolipidemic and insulin-sensitizing drugs. Many of these compounds bind avidly to members of a family of small lipid-binding proteins, the fatty acid-binding proteins (FABPs). Fatty...

  18. Expression of the helix-loop-helix protein inhibitor of DNA binding-1 (ID-1) is activated by all-trans retinoic acid in normal human keratinocytes

    International Nuclear Information System (INIS)

    Villano, C.M.; White, L.A.

    2006-01-01

    The ID (inhibitor of differentiation or DNA binding) helix-loop-helix proteins are important mediators of cellular differentiation and proliferation in a variety of cell types through regulation of gene expression. Overexpression of the ID proteins in normal human keratinocytes results in extension of culture lifespan, indicating that these proteins are important for epidermal differentiation. Our hypothesis is that the ID proteins are targets of the retinoic acid signaling pathway in keratinocytes. Retinoids, vitamin A analogues, are powerful regulators of cell growth and differentiation and are widely used in the prevention and treatment of a variety of cancers in humans. Furthermore, retinoic acid is necessary for the maintenance of epithelial differentiation and demonstrates an inhibitory action on skin carcinogenesis. We examined the effect of all-trans retinoic acid on expression of ID-1, -2, -3, and -4 in normal human keratinocytes and found that exposure of these cells to all-trans retinoic acid causes an increase in both ID-1 and ID-3 gene expression. Furthermore, our data show that this increase is mediated by increased transcription involving several cis-acting elements in the distal portion of the promoter, including a CREB-binding site, an Egr1 element, and an YY1 site. These data demonstrate that the ID proteins are direct targets of the retinoic acid signaling pathway. Given the importance of the ID proteins to epidermal differentiation, these results suggest that IDs may be mediating some of the effects of all-trans retinoic acid in normal human keratinocytes

  19. Networking activities and perceptions of HIV risk among male migrant market vendors in China.

    Science.gov (United States)

    Wang, Wenqing; Muessig, Kathryn E; Li, Mingqiang; Zhang, Ying-Xia; Zhang, Yingxia

    2014-02-01

    HIV research among internal migrants in China has not fully explored the contexts and perceptions of "risk". In 2011, urban markets in Liuzhou, China were mapped, and sixty male vendors, age 22-56, were selected for in-depth interviews on migration, social and family life, and perceptions and practices of sexual risk behavior. Participants were evenly divided among higher income shop and small stall vendors. All men were sexually active. Only the shop vendors reported non-marital sexual partners, including concurrent partners (n = 15), commercial partners (n = 10), and other sexual relationships (n = 11). Shop vendors engaged in networking activities that facilitated commercial and non-commercial high-risk sex. Perceptions of HIV risk from commercial sex led some men to doubt the protective ability of condoms and rely on local (unproven) self-protection techniques. Networking activities played a role in high-risk sex and shaping migrants' risk perceptions and health practices. The networks created through these processes could also be used to facilitate health promotion activities.

  20. Oral Candida colonization and its relation with predisposing factors in HIV-infected children and their uninfected siblings in Brazil: the era of highly active antiretroviral therapy.

    Science.gov (United States)

    Cerqueira, Daniella Ferraz; Portela, Maristela Barbosa; Pomarico, Luciana; de Araújo Soares, Rosangela Maria; de Souza, Ivete Pomarico Ribeiro; Castro, Glória Fernanda

    2010-02-01

    To evaluate predisposing factors such as orofacial manifestations, immunosuppression status and antiretroviral therapy in relation to oral colonization by Candida spp. in Brazilian HIV-infected children and their uninfected siblings in the era of highly active antiretroviral therapy (HAART). Whole stimulated saliva was collected from 65 HIV-infected children (HIV+) and 40 uninfected siblings (HIV-), followed by assessment of orofacial manifestation, caries indexes and the number of cavitated dentinal carious teeth (CDT). The salivary samples were cultured and the colonies were counted. After which they were identified by sugar assimilation and fermentation (API 20C). Data was analyzed using chi-square, Mann-Whitney, Spearman tests and logistic regression. Regarding positive growth, HIV+ presented 80% (52/65) and HIV- 57.5% (23/40) (P = 0.013). Absence of antiretroviral therapy and HAART increased the probability of Candida isolation (P oral candidiasis (OC) had no influence on Candida isolation. Mixed Candida spp. cultures were observed in HIV+ (40%) and HIV- (52%): C. albicans was more frequently found in both groups, with a higher prevalence in HIV+ (P = 0.05); other non-albicans species were isolated in HIV+ and HIV-. Low prevalence of orofacial manifestations was observed in HIV+ (10.7% of OC). There was an association between means of CDT and Candida growth (P children had a significantly higher prevalence of oral Candida spp. compared to their uninfected siblings. Absence of HAART and presence of dentinal carious teeth increased significantly Candida spp. colonization in these children.

  1. Incidence, clinical presentation, and outcome of HIV-1-associated cryptococcal meningitis during the highly active antiretroviral therapy era

    DEFF Research Database (Denmark)

    Touma, Madeleine; Rasmussen, Line D.; Martin-Iguacel, Raquel

    2017-01-01

    Background: Human immunodeficiency virus (HIV) infection with advanced immunosup-pression predisposes to cryptococcal meningitis (CM). We describe the incidence, clinical presentation, and outcome of CM in HIV-infected individuals during the highly active antiretroviral therapy (HAART) era. Methods......: A nationwide, population-based cohort of HIV-infected individuals was used to estimate incidence and mortality of CM including risk factors. A description of neurological symptoms of CM at presentation and follow-up in the study period 1995–2014 was included in this study. Results: Among 6,351 HIV...... was associated with increased risk of CM [IRR, 2.05 (95% CI, 1.00–4.20)]. The main signs and symptoms at presentation were headache, cognitive deficits, fever, neck stiffness, nausea, and vomiting. All individuals diagnosed with CM had a CD4 + cell count

  2. Incidence, clinical presentation, and outcome of HIV-1-associated cryptococcal meningitis during the highly active antiretroviral therapy era

    DEFF Research Database (Denmark)

    Touma, Madeleine; Rasmussen, Line D.; Martin-Iguacel, Raquel

    2017-01-01

    : A nationwide, population-based cohort of HIV-infected individuals was used to estimate incidence and mortality of CM including risk factors. A description of neurological symptoms of CM at presentation and follow-up in the study period 1995-2014 was included in this study. RESULTS: Among 6,351 HIV......BACKGROUND: Human immunodeficiency virus (HIV) infection with advanced immunosuppression predisposes to cryptococcal meningitis (CM). We describe the incidence, clinical presentation, and outcome of CM in HIV-infected individuals during the highly active antiretroviral therapy (HAART) era. METHODS...... was associated with increased risk of CM [IRR, 2.05 (95% CI, 1.00-4.20)]. The main signs and symptoms at presentation were headache, cognitive deficits, fever, neck stiffness, nausea, and vomiting. All individuals diagnosed with CM had a CD4(+) cell count

  3. Long-term effectiveness of highly active antiretroviral therapy (HAART) in perinatally HIV-infected children in Denmark

    DEFF Research Database (Denmark)

    Bracher, Linda; Valerius, Niels Henrik; Rosenfeldt, Vibeke

    2007-01-01

    children treated with HAART. Initial HAART included 2 nucleoside reverse-transcriptase inhibitors in combination with either a protease inhibitor (n =38) or a non-nucleoside reverse-transcriptase inhibitor (n =12). 19 (39%) patients were previously treated with mono- or dual therapy. Baseline......The long-term impact of highly active antiretroviral therapy (HAART) on HIV-1 infected children is not well known. The Danish Paediatric HIV Cohort Study includes all patients ... characteristics were median CD4 percentage 14% and HIV-RNA viral load 4.9 log(10). Within the first 12 weeks of therapy approximately 60% achieved HIV-RNA viral load children changed the components of HAART. The proportion of children with CD4...

  4. Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis, Biological Activities and Mechanism of Action

    Science.gov (United States)

    Di Santo, Roberto; Costi, Roberta; Roux, Alessandra; Artico, Marino; Lavecchia, Antonio; Marinelli, Luciana; Novellino, Ettore; Palmisano, Lucia; Andreotti, Mauro; Amici, Roberta; Galluzzo, Clementina Maria; Nencioni, Lucia; Palamara, Anna Teresa; Pommier, Yves; Marchand, Christophe

    2008-01-01

    The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the β-diketo acids (DKAs) represent a major lead for anti-HIV-1drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3′-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-crosslinking experiments. PMID:16539381

  5. [Active tuberculosis in a cohort of HIV-infected inmates in a prison in Mexico City: clinical and epidemiological characteristics].

    Science.gov (United States)

    Hernández-León, Christian; Badial-Hernández, Florentino; Ponce-de-León, Alfredo; Sierra-Madero, Juan G; Martínez-Gamboa, Areli; Crabtree-Ramírez, Brenda; Bautista-Arredondo, Sergio; González-Aguirre, Adrián; Guerrero-Almeida, María de Lourdes; del Valle, J Miriam Bobadilla; González-Rodríguez, Andrea; Sifuentes-Osornio, José

    2012-01-01

    To determine the clinical and epidemiological characteristics of prison inmates with active tuberculosis in HIV-positive prison populations. We conducted a cohort study in HIV-infected subjects in a prison in Mexico City, with the aim of determining clinical and epidemiological characteristics of cases with active TB. We detected 172 HIV infected inmates and TB in 28 of them (16.3%) - 21 (12.2) with pulmonary TB--with an incidence rate of 7.7/100 persons/year for active TB and 4.7/100 persons/year for pulmonary TB. No drug resistance was found. Two clusters (4 and 2 subjects) were observed after RFLP-typing of 18 isolates, with a transmission rate of 11% by molecular and clinical analysis. The prevalence of active TB was found to be a thousand times greater than in the general population. Evidence of transmission inside the prison was also found.

  6. Facilitators and barriers to active recall for HIV and STI testing of MSM at high risk of HIV infection in genito-urinary medicine clinics

    OpenAIRE

    Desai, M.

    2015-01-01

    Reminders have been successfully used in healthcare to improve reattendance rates but evidence for their effectiveness in sexual health remains unknown. A programme of studies explored the effectiveness of, and drivers and barriers to active recall reminders in increasing reattendance/re-testing rates for HIV/STIs among men who have sex with men (MSM), underpinned by the Theory of Planned Behaviour. The systematic literature review suggested efficacy of reminders in increasing reattendance/re...

  7. FACTS ABOUT TRANS FATTY ACIDS

    Directory of Open Access Journals (Sweden)

    Sedighe Asgary

    2010-12-01

    be involved in the pathogenesis of atherosclerosis, acute coronary syndromes, sudden death, insulin resistance, dyslipidemia, and heart failure. Fatty acids may also directly or indirectly modulate metabolic and inflammatory responses of the endoplasmic reticulum 31 (Figure 2. Evidence from both observational and experimental studies indicates that TFA are pro-inflammatory. Inflammation is an independent risk factor for cardiovascular diseases (CVD. Epidemiologic studies have suggested that TFA may have an adverse effect on inflammatory markers. In the Nurses’ Health Study, TFA intake, assessed by semi-quantitative food - frequency questionnaires, was  positively associated with tumor necrosis factor receptor (TNFR levels in healthy women (P for trend < 0.001, and was also associated with levels of C-reactive protein (CRP and IL-6 in women with higher BMI (P < 0.05 [32-35]. Limited evidence suggests that pro-inflammatory effects may be stronger for trans isomers of linoleic acid (trans-C18:2 and oleic acid (trans-C18:1, rather than of palmitoleic acid (trans-C16:1, but further study of potential isomer-specific effects is needed. TFA also appear to induce endothelial dysfunction. The mechanisms underlying this effect is not well-established, but may involve TFA incorporation into endothelial cell, monocyte/macrophage, or adipocyte cell membranes (affecting membrane signaling pathway relating to inflammation or ligand-dependent effects on peroxisome proliferator-activated receptor (PPAR or retinoid X receptor (RXR pathways.36,37 Activation of inflammatory responses and endothelial dysfunction may represent important mediating pathways between TFA consumption and risk of coronary heart disease, sudden death, and diabetes.16      The possibility that TFAs decrease the threshold for cardiac arrhythmias has been supported by the results from a more recent case control study of the risk of sudden cardiac death. When levels of TFAs in red blood cells as a marker for

  8. An assay to monitor HIV-1 protease activity for the identification of novel inhibitors in T-cells.

    Directory of Open Access Journals (Sweden)

    Brett J Hilton

    Full Text Available The emergence of resistant HIV strains, together with the severe side-effects of existing drugs and lack of development of effective anti-HIV vaccines highlight the need for novel antivirals, as well as innovative methods to facilitate their discovery. Here, we have developed an assay in T-cells to monitor the proteolytic activity of the HIV-1 protease (PR. The assay is based on the inducible expression of HIV-1 PR fused within the Gal4 DNA-binding and transactivation domains. The fusion protein binds to the Gal4 responsive element and activates the downstream reporter, enhanced green fluorescent protein (eGFP gene only in the presence of an effective PR Inhibitor (PI. Thus, in this assay, eGFP acts as a biosensor of PR activity, making it ideal for flow cytometry based screening. Furthermore, the assay was developed using retroviral technology in T-cells, thus providing an ideal environment for the screening of potential novel PIs in a cell-type that represents the natural milieu of HIV infection. Clones with the highest sensitivity, and robust, reliable and reproducible reporter activity, were selected. The assay is easily adaptable to other PR variants, a multiplex platform, as well as to high-throughput plate reader based assays and will greatly facilitate the search for novel peptide and chemical compound based PIs in T-cells.

  9. Reevaluation of immune activation in the era of cART and an aging HIV-infected population.

    Science.gov (United States)

    de Armas, Lesley R; Pallikkuth, Suresh; George, Varghese; Rinaldi, Stefano; Pahwa, Rajendra; Arheart, Kristopher L; Pahwa, Savita

    2017-10-19

    Biological aging is associated with immune activation (IA) and declining immunity due to systemic inflammation. It is widely accepted that HIV infection causes persistent IA and premature immune senescence despite effective antiretroviral therapy and virologic suppression; however, the effects of combined HIV infection and aging are not well defined. Here, we assessed the relationship between markers of IA and inflammation during biological aging in HIV-infected and -uninfected populations. Antibody response to seasonal influenza vaccination was implemented as a measure of immune competence and relationships between IA, inflammation, and antibody responses were explored using statistical modeling appropriate for integrating high-dimensional data sets. Our results show that markers of IA, such as coexpression of HLA antigen D related (HLA-DR) and CD38 on CD4+ T cells, exhibit strong associations with HIV infection but not with biological age. Certain variables that showed a strong relationship with aging, such as declining naive and CD38+ CD4 and CD8+ T cells, did so regardless of HIV infection. Interestingly, the variable of biological age was not identified in a predictive model as significantly impacting vaccine responses in either group, while distinct IA and inflammatory variables were closely associated with vaccine response in HIV-infected and -uninfected populations. These findings shed light on the most relevant and persistent immune defects during virological suppression with antiretroviral therapy.

  10. HIV/AIDS case management tasks and activities: the results of a functional analysis study.

    Science.gov (United States)

    Grube, B; Chernesky, R H

    2001-01-01

    Functional analysis, a variation of the time study technique, was used to examine how HIV/AIDS case managers in the tri-county region of New York State spend their time-the actual tasks and activities they choose to perform relative to the total universe of activities and tasks subsumed in the general category of case management. The picture developed was of a system operating primarily in a crisis mode, spending relatively brief amounts of time completing a range of activities and providing an extensive scope of services for or on behalf of clients. The bulk of the work was client centered, not administrative, and involved providing disease management and essential services (e.g., family and mental health). The implications of these findings are discussed, with particular attention paid to the potential influence of client profiles and worker demographics.

  11. Triterpenoids from Ocimum labiatum Activates Latent HIV-1 Expression In Vitro: Potential for Use in Adjuvant Therapy

    Directory of Open Access Journals (Sweden)

    Petrina Kapewangolo

    2017-10-01

    Full Text Available Latent HIV reservoirs in infected individuals prevent current treatment from eradicating infection. Treatment strategies against latency involve adjuvants for viral reactivation which exposes viral particles to antiretroviral drugs. In this study, the effect of novel triterpenoids isolated from Ocimum labiatum on HIV-1 expression was measured through HIV-1 p24 antigen capture in the U1 latency model of HIV-1 infection and in peripheral blood mononuclear cells (PBMCs of infected patients on combination antiretroviral therapy (cART. The mechanism of viral reactivation was determined through the compound’s effect on cytokine production, histone deacetylase (HDAC inhibition, and protein kinase C (PKC activation. Cytotoxicity of the triterpenoids was determined using a tetrazolium dye and flow cytometry. The isolated triterpene isomers, 3-hydroxy-4,6a,6b,11,12,14b-hexamethyl-1,2,3,4,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydropicene-4,8a-dicarboxylic acid (HHODC, significantly (p < 0.05 induced HIV-1 expression in a dose-dependent manner in U1 cells at non-cytotoxic concentrations. HHODC also induced viral expression in PBMCs of HIV-1 infected patients on cART. In addition, the compound up-regulated the production of interleukin (IL-2, IL-6, tumour necrosis factor (TNF-α, and interferon (IFN-γ but had no effect on HDAC and PKC activity, suggesting cytokine upregulation as being involved in latency activation. The observed in vitro reactivation of HIV-1 introduces the adjuvant potential of HHODC for the first time here.

  12. Cognitive and psychosocial development of HIV pediatric patients receiving highly active anti-retroviral therapy: a case-control study

    Directory of Open Access Journals (Sweden)

    Theodoridou Maria

    2010-12-01

    Full Text Available Abstract Background The psychosocial development of pediatric HIV patients has not been extensively evaluated. The study objectives were to evaluate whether emotional and social functions are differentially associated with HIV-related complications. Methods A matched case-control study design was conducted. The case group (n = 20 consisted of vertically infected children with HIV (aged 3-18 years receiving HAART in Greece. Each case was matched with two randomly selected healthy controls from a school-based population. CNS imaging and clinical findings were used to identify patients with HIV-related neuroimaging abnormalities. The Wechsler Intelligence Scale III and Griffiths Mental Abilities Scales were applied to assess cognitive abilities. The age specific Strengths and Difficulties Questionnaire was used to evaluate emotional adjustment and social skills. The Fisher's exact test, student's t-test, and Wilcoxon rank sum test were used to compare categorical, continuous, and ordinal scores, respectively, of the above scales between groups. Results HIV patients without neuroimaging abnormalities did not differ from patients with neuroimaging abnormalities with respect to either age at HAART initiation (p = 0.306 or months of HAART treatment (p = 0.964. While HIV patients without neuroimaging abnormalities had similar cognitive development with their healthy peers, patients with neuroimaging abnormalities had lower mean General (p = 0.027 and Practical (p = 0.042 Intelligence Quotient scores. HIV patients without neuroimaging abnormalities had an increased likelihood of both Abnormal Emotional Symptoms (p = 0.047 and Hyperactivity scores (p = 0.0009. In contrast, HIV patients with neuroimaging abnormalities had an increased likelihood of presenting with Abnormal Peer Problems (p = 0.033. Conclusions HIV patients without neuroimaging abnormalities are more likely to experience maladjustment with respect to their emotional and activity spheres

  13. Structural insights into the anti-HIV activity of the Oscillatoria agardhii agglutinin homolog lectin family.

    Science.gov (United States)

    Koharudin, Leonardus M I; Kollipara, Sireesha; Aiken, Christopher; Gronenborn, Angela M

    2012-09-28

    Oscillatoria agardhii agglutinin homolog (OAAH) proteins belong to a recently discovered lectin family. All members contain a sequence repeat of ~66 amino acids, with the number of repeats varying among different family members. Apart from data for the founding member OAA, neither three-dimensional structures, information about carbohydrate binding specificities, nor antiviral activity data have been available up to now for any other members of the OAAH family. To elucidate the structural basis for the antiviral mechanism of OAAHs, we determined the crystal structures of Pseudomonas fluorescens and Myxococcus xanthus lectins. Both proteins exhibit the same fold, resembling the founding family member, OAA, with minor differences in loop conformations. Carbohydrate binding studies by NMR and x-ray structures of glycan-lectin complexes reveal that the number of sugar binding sites corresponds to the number of sequence repeats in each protein. As for OAA, tight and specific binding to α3,α6-mannopentaose was observed. All the OAAH proteins described here exhibit potent anti-HIV activity at comparable levels. Altogether, our results provide structural details of the protein-carbohydrate interaction for this novel lectin family and insights into the molecular basis of their HIV inactivation properties.

  14. The role of Vif oligomerization and RNA chaperone activity in HIV-1 replication.

    Science.gov (United States)

    Batisse, Julien; Guerrero, Santiago; Bernacchi, Serena; Sleiman, Dona; Gabus, Caroline; Darlix, Jean-Luc; Marquet, Roland; Tisné, Carine; Paillart, Jean-Christophe

    2012-11-01

    The viral infectivity factor (Vif) is essential for the productive infection and dissemination of HIV-1 in non-permissive cells that involve most natural HIV-1 target cells. Vif counteracts the packaging of two cellular cytidine deaminases named APOBEC3G (A3G) and A3F by diverse mechanisms including the recruitment of an E3 ubiquitin ligase complex and the proteasomal degradation of A3G/A3F, the inhibition of A3G mRNA translation or by a direct competition mechanism. In addition, Vif appears to be an active partner of the late steps of viral replication by participating in virus assembly and Gag processing, thus regulating the final stage of virion formation notably genomic RNA dimerization and by inhibiting the initiation of reverse transcription. Vif is a small pleiotropic protein with multiple domains, and recent studies highlighted the importance of Vif conformation and flexibility in counteracting A3G and in binding RNA. In this review, we will focus on the oligomerization and RNA chaperone properties of Vif and show that the intrinsic disordered nature of some Vif domains could play an important role in virus assembly and replication. Experimental evidence demonstrating the RNA chaperone activity of Vif will be presented. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.

    Science.gov (United States)

    Rotili, Dante; Tarantino, Domenico; Artico, Marino; Nawrozkij, Maxim B; Gonzalez-Ortega, Emmanuel; Clotet, Bonaventura; Samuele, Alberta; Esté, José A; Maga, Giovanni; Mai, Antonello

    2011-04-28

    Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.

  16. Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids

    DEFF Research Database (Denmark)

    Pedersen, Erik Bjerregaard; Nielsen, Jakob Toudahl; Nielsen, Claus

    2011-01-01

    Two G-quadruplex forming sequences, 50-TGGGAG and the 17-mer sequence T30177, which exhibit anti-HIV-1 activity on cell lines, were modified using either locked nucleic acids (LNA) or via insertions of (R)-1-O-(pyren-1-ylmethyl)glycerol (intercalating nucleic acid, INA) or (R)-1-O-[4-(1......-pyrenylethynyl)phenylmethyl]glycerol (twisted intercalating nucleic acid, TINA). Incorporation of LNA or INA/TINA monomers provide as much as 8-fold improvement of anti-HIV-1 activity. We demonstrate for the first time a detailed analysis of the effect the incorporation of INA/TINA monomers in quadruplex forming...

  17. Immune activation in HIV-infected aging women on antiretrovirals--implications for age-associated comorbidities: a cross-sectional pilot study.

    Directory of Open Access Journals (Sweden)

    Maria L Alcaide

    Full Text Available Persistent immune activation and microbial translocation associated with HIV infection likely place HIV-infected aging women at high risk of developing chronic age-related diseases. We investigated immune activation and microbial translocation in HIV-infected aging women in the post-menopausal ages.Twenty-seven post-menopausal women with HIV infection receiving antiretroviral treatment with documented viral suppression and 15 HIV-negative age-matched controls were enrolled. Levels of immune activation markers (T cell immune phenotype, sCD25, sCD14, sCD163, microbial translocation (LPS and biomarkers of cardiovascular disease and impaired cognitive function (sVCAM-1, sICAM-1 and CXCL10 were evaluated.T cell activation and exhaustion, monocyte/macrophage activation, and microbial translocation were significantly higher in HIV-infected women when compared to uninfected controls. Microbial translocation correlated with T cell and monocyte/macrophage activation. Biomarkers of cardiovascular disease and impaired cognition were elevated in women with HIV infection and correlated with immune activation.HIV-infected antiretroviral-treated aging women who achieved viral suppression are in a generalized status of immune activation and therefore are at an increased risk of age-associated end-organ diseases compared to uninfected age-matched controls.

  18. Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain

    Directory of Open Access Journals (Sweden)

    Cowburn David

    2011-05-01

    Full Text Available Abstract Background The C-terminal domain (CTD of HIV-1 capsid (CA, like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs. Results Due to the pivotal role of the dimer interface, we reasoned that peptides from the α-helical region of the dimer interface might be effective as decoys to prevent CTD dimer formation. However, these small peptides do not have any structure in solution and they do not penetrate cells. Therefore, we used the hydrocarbon stapling technique to stabilize the α-helical structure and confirmed by confocal microscopy that this modification also made these peptides cell-penetrating. We also confirmed by using isothermal titration calorimetry (ITC, sedimentation equilibrium and NMR that these peptides indeed disrupt dimer formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease. Conclusions These preliminary data serve as the foundation for designing small, stable, α-helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind

  19. Collaborative activities and treatment outcomes in patients with HIV-associated tuberculosis in Viet Nam.

    Science.gov (United States)

    Huyen, T T T; Nhung, N V; Shewade, H D; Hoa, N B; Harries, A D

    2016-03-21

    The National Tuberculosis (TB) Programme in Viet Nam and Ho Chi Minh City (HCMC). To determine 1) at national level between 2011 and 2013, the relationship between human immunodeficiency virus (HIV) testing, uptake of TB-HIV interventions and adverse treatment outcomes among TB-HIV patients; and 2) in HCMC in 2013, patient characteristics associated with adverse outcomes. An ecological study reviewing aggregate nationwide data and a retrospective cohort review in HCMC. Nationwide, from 2011 to 2013, HIV testing increased in TB patients from 58% to 68% and antiretroviral therapy (ART) increased in TB-HIV patients from 54% to 63%. Adverse treatment outcomes in TB-HIV patients increased from 24% to 27%, largely due to transfer out (5-9% increase) and death. The Northern and Highland regions showed poor uptake of TB-HIV interventions. In HCMC, 303 (27%) of 1110 TB-HIV patients had adverse outcomes, with higher risks observed in those with previously treated TB, those diagnosed as HIV-positive before TB onset and those never placed on cotrimoxazole or ART. Despite improving HIV testing rates and TB-HIV interventions, adverse outcomes in TB-HIV patients remain at about 26%. Characteristics predicting higher risk of adverse outcomes must be addressed if Viet Nam wishes to end the TB epidemic by 2030.

  20. Active targeted HIV testing and linkage to care among men who have sex with men attending a gay sauna in Thailand.

    Science.gov (United States)

    Khawcharoenporn, Thana; Apisarnthanarak, Anucha; Phanuphak, Nittaya

    2017-03-01

    Existing data on the feasibility of human immunodeficiency virus (HIV) testing and counseling (HTC) and linkage to care among men who have sex with men (MSM) in hotspots are currently limited. A prospective study on active targeted HTC and linkage to care among MSM (≥18 years old) was conducted at a gay sauna in Thailand from November 2013 to October 2015. HIV risks and risk perception were evaluated through an anonymous survey. HIV testing with result notification and care appointment arrangement were provided on-site. Of the 358 participants; median age was 30 years; 206/358(58%) were at high risk for HIV acquisition; 148/358(41%) accepted HTC, all of whom either had prior negative HIV tests [98/148 (66%)] or had not known their HIV status [50/148 (34%)]. The three most common reasons for declining HTC were prior HIV testing within 6 months (48%), not ready (19%) and perceiving self as no risk (11%). Of the 262 moderate- and high-risk participants, 172 (66%) had false perception of low HIV risk which was significantly associated with declining HTC. Among the 148 participants undergoing HTC, 25 (17%) were HIV-infected. Having false perception of low risk (P = 0.004) and age antiretroviral therapy. The active targeted HTC and facilitating care establishment was feasible among MSM attending the gay sauna but required strategies to improve accuracy of HIV-risk perception and linkage to care.

  1. Selective histonedeacetylase inhibitor M344 intervenes in HIV-1 latency through increasing histone acetylation and activation of NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Hao Ying

    Full Text Available Histone deacetylase (HDAC inhibitors present an exciting new approach to activate HIV production from latently infected cells to potentially enhance elimination of these cells and achieve a cure. M344, a novel HDAC inhibitor, shows robust activity in a variety of cancer cells and relatively low toxicity compared to trichostatin A (TSA. However, little is known about the effects and action mechanism of M344 in inducing HIV expression in latently infected cells.Using the Jurkat T cell model of HIV latency, we demonstrate that M344 effectively reactivates HIV-1 gene expression in latently infected cells. Moreover, M344-mediated activation of the latent HIV LTR can be strongly inhibited by a NF-κB inhibitor aspirin. We further show that M344 acts by increasing the acetylation of histone H3 and histone H4 at the nucleosome 1 (nuc-1 site of the HIV-1 long terminal repeat (LTR and by inducing NF-κB p65 nuclear translocation and direct RelA DNA binding at the nuc-1 region of the HIV-1 LTR. We also found that M344 synergized with prostratin to activate the HIV-1 LTR promoter in latently infected cells.These results suggest the potential of M344 in anti-latency therapies and an important role for histone modifications and NF-κB transcription factors in regulating HIV-1 LTR gene expression.

  2. Anti-viral drug treatment along with immune activator IL-2: a control-based mathematical approach for HIV infection

    Science.gov (United States)

    Nath Chatterjee, Amar; Roy, Priti Kumar

    2012-02-01

    Recent development in antiretroviral treatment against HIV can help AIDS patients to fight against HIV. But the question that whether the disease is to be partially or totally eradicated from HIV infected individuals still remains unsolved. Usually, the most effective treatment for the disease is HAART which can only control the disease progression. But as the immune system becomes weak, the patients can not fight against other diseases. Immune cells are activated and proliferated by IL-2 after the identification of antigen. IL-2 production is impaired in HIV positive patients and intermitted administration of immune activator IL-2 together with HAART which is a more effective treatment to fight against the disease. Thus, its expediency is essential and is yet to be explored. In this article we anticipated a mathematical model of the effect of IL-2 together with RTIs therapy in HIV positive patients. Our analytical as well as numerical study shows that the optimal schedule of treatment for best result is to be obtained by systematic drug therapy. But at the last stage of treatment, the infection level raises again due to minimisation of drug dosage. Thus we study the perfect adherence of the drugs and found out if RTIs are taken with sufficient interval then for fixed interval of IL-2 therapy, certain amount of drug dosages may be able to sustain the immune system at pre-infection stage and the infected CD4+T cells are going towards extinction.

  3. The conflation of gender and sex: Gaps and opportunities in HIV data among transgender women and MSM.

    Science.gov (United States)

    Poteat, Tonia; German, Danielle; Flynn, Colin

    2016-01-01

    Historically, HIV studies have conflated men who have sex with men (MSM) with transgender (trans) women, explicitly excluded trans individuals, or included sample sizes of trans people that are too small to reach meaningful conclusions. Despite the heavy burden of HIV among trans women, conflation of this population with MSM has limited the information available on the social and behavioural factors that increase HIV vulnerability among trans women and how these factors may differ from MSM. Using data sets from quantitative studies among MSM (n = 645) and trans women (n = 89), as well as qualitative in-depth interviews with 30 trans women in Baltimore, we explore what these data tell us about similarities and differences in HIV vulnerability between the two groups and where they leave gaps in our understanding. We conclude with implications for data collection and intervention development.

  4. Inhibitory Effects of Ethyl Acetate Extract of Andrographis paniculata on NF-κB Trans-Activation Activity and LPS-Induced Acute Inflammation in Mice

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    Wen-Wan Chao

    2011-01-01

    Full Text Available This study was to investigate anti-inflammatory effect of Andrographis paniculata (Burm. f. Nees (Acanthaceae (AP. The effects of ethyl acetate (EtOAc extract from AP on the level of inflammatory mediators were examined first using nuclear factor kappa B (NF-κB driven luciferase assay. The results showed that AP significantly inhibited NF-κB luciferase activity and tumor necrosis factor α (TNF-α, interleukin 6 (IL-6, macrophage inflammatory protein-2 (MIP-2 and nitric oxide (NO secretions from lipopolysaccharide (LPS/interferon-γ stimulated Raw264.7 cells. To further evaluate the anti-inflammatory effects of AP in vivo, BALB/c mice were tube-fed with 0.78 (AP1, 1.56 (AP2, 3.12 (AP3 and 6.25 (AP4 mg kg−1 body weight (BW/day in soybean oil, while the control and PDTC (pyrrolidine dithiocarbamate, an anti-inflammatory agent groups were tube-fed with soybean oil only. After 1 week of tube-feeding, the PDTC group was injected with 50 mg kg−1 BW PDTC and 1 h later, all of the mice were injected with 15 mg kg−1 BW LPS. The results showed that the AP1, AP2, AP3 and PDTC groups, but not AP4, had significantly higher survival rate than the control group. Thus, the control, AP1, AP2, AP3 and PDTC groups were repeated for in vivo parameters. The results showed that the AP and PDTC groups had significantly lower TNF-α, IL-12p40, MIP-2 or NO in serum or peritoneal macrophages and infiltration of inflammatory cells into the lung of mice. The AP1 group also had significantly lower MIP-2 mRNA expression in brain. This study suggests that AP can inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages.

  5. Radical feminists & trans activists truce

    OpenAIRE

    Mackay, F.

    2014-01-01

    #GenderWeek: Truce! When radical feminists and trans feminists empathise\\ud Feminist Times\\ud By Finn Mackay \\ud read all #GenderWeek articles.\\ud We wanted to explore the ground between the polarised, entrenched positions in the so-called “TERF-war”. Radical feminists on one pole, trans-inclusionary feminists and trans activists on the other. The disputed territory being women-only space, language and the ever changing legal framework surrounding gender.\\ud Entrenchment leads to stalemate. S...

  6. A real-time view of the TAR:Tat:P-TEFb complex at HIV-1 transcription sites

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    Knezevich Anna

    2007-05-01

    Full Text Available Abstract HIV-1 transcription is tightly regulated: silent in long-term latency and highly active in acutely-infected cells. Transcription is activated by the viral protein Tat, which recruits the elongation factor P-TEFb by binding the TAR sequence present in nascent HIV-1 RNAs. In this study, we analyzed the dynamic of the TAR:Tat:P-TEFb complex in living cells, by performing FRAP experiments at HIV-1 transcription sites. Our results indicate that a large fraction of Tat present at these sites is recruited by Cyclin T1. We found that in the presence of Tat, Cdk9 remained bound to nascent HIV-1 RNAs for 71s. In contrast, when transcription was activated by PMA/ionomycin, in the absence of Tat, Cdk9 turned-over rapidly and resided on the HIV-1 promoter for only 11s. Thus, the mechanism of trans-activation determines the residency time of P-TEFb at the HIV-1 gene, possibly explaining why Tat is such a potent transcriptional activator. In addition, we observed that Tat occupied HIV-1 transcription sites for 55s, suggesting that the TAR:Tat:P-TEFb complex dissociates from the polymerase following transcription initiation, and undergoes subsequent cycles of association/dissociation.

  7. HIV Status Does Not Influence Outcome in Patients With Classical Hodgkin Lymphoma Treated With Chemotherapy Using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the Highly Active Antiretroviral Therapy Era

    Science.gov (United States)

    Montoto, Silvia; Shaw, Kate; Okosun, Jessica; Gandhi, Shreyans; Fields, Paul; Wilson, Andrew; Shanyinde, Milensu; Cwynarski, Kate; Marcus, Robert; de Vos, Johannes; Young, Anna Marie; Tenant-Flowers, Melinda; Orkin, Chloe; Johnson, Margaret; Chilton, Daniella; Gribben, John G.; Bower, Mark

    2012-01-01

    Purpose The prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the HAART era according to HIV serostatus to establish whether this also holds true for HL. Patients and Methods From 1997 to 2010, 224 patients newly diagnosed with HL, of whom 93 were HIV positive, were consecutively treated with ABVD chemotherapy. HIV-positive patients had more high-risk disease according to the International Prognostic Score (IPS) than HIV-negative patients (IPS ≥ 3: 68% v 26%, respectively; P < .001). Forty-seven HIV-positive patients had a CD4 count less than 200/μL, and 92 patients received HAART during chemotherapy. Results The complete response rate was 74% for HIV-positive patients and 79% for HIV-negative patients (P = not significant). After a median follow-up of 60 months (range, 8 to 174 months), 23 patients (16 HIV-negative and seven HIV-positive patients) have experienced relapse at a median time of 6 months (range, 1 to 106 months). Five-year event-free survival (EFS) was 59% (95% CI, 47% to 70%) for HIV-positive patients and 66% (95% CI, 57% to 74%) for HIV-negative patients (P = not significant). Five-year overall survival (OS) was 81% (95% CI, 69% to 89%) and 88% (95% CI, 80% to 93%) for HIV-positive and HIV-negative patients, respectively (P = not significant). HIV status did not predict OS or EFS on multivariate analysis including IPS and HIV status. Conclusion This mature study demonstrates that HIV-positive patients with HL have more extensive disease with more adverse prognostic factors than HIV-negative patients, but when treated with ABVD, HIV infection does not adversely affect OS or EFS. PMID:23045581

  8. Monocyte-lymphocyte fusion induced by the HIV-1 envelope generates functional heterokaryons with an activated monocyte-like phenotype

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    Martínez-Méndez, David; Rivera-Toledo, Evelyn; Ortega, Enrique; Licona-Limón, Ileana; Huerta, Leonor, E-mail: leonorhh@biomedicas.unam.mx

    2017-03-01

    Enveloped viruses induce cell-cell fusion when infected cells expressing viral envelope proteins interact with target cells, or through the contact of cell-free viral particles with adjoining target cells. CD4{sup +} T lymphocytes and cells from the monocyte-macrophage lineage express receptors for HIV envelope protein. We have previously reported that lymphoid Jurkat T cells expressing the HIV-1 envelope protein (Env) can fuse with THP-1 monocytic cells, forming heterokaryons with a predominantly myeloid phenotype. This study shows that the expression of monocytic markers in heterokaryons is stable, whereas the expression of lymphoid markers is mostly lost. Like THP-1 cells, heterokaryons exhibited FcγR-dependent phagocytic activity and showed an enhanced expression of the activation marker ICAM-1 upon stimulation with PMA. In addition, heterokaryons showed morphological changes compatible with maturation, and high expression of the differentiation marker CD11b in the absence of differentiation-inducing agents. No morphological change nor increase in CD11b expression were observed when an HIV-fusion inhibitor blocked fusion, or when THP-1 cells were cocultured with Jurkat cells expressing a non-fusogenic Env protein, showing that differentiation was not induced merely by cell-cell interaction but required cell-cell fusion. Inhibition of TLR2/TLR4 signaling by a TIRAP inhibitor greatly reduced the expression of CD11b in heterokaryons. Thus, lymphocyte-monocyte heterokaryons induced by HIV-1 Env are stable and functional, and fusion prompts a phenotype characteristic of activated monocytes via intracellular TLR2/TLR4 signaling. - Highlights: • Jurkat T cells expressing the HIV-1 envelope fuse with THP-1 monocytes. • Heterokaryons display a dominant myeloid phenotype and monocyte function. • Heterokaryons exhibit activation features in the absence of activation agents. • Activation is not due to cell-cell interaction but requires cell-cell fusion. • The

  9. Monocyte-lymphocyte fusion induced by the HIV-1 envelope generates functional heterokaryons with an activated monocyte-like phenotype

    International Nuclear Information System (INIS)

    Martínez-Méndez, David; Rivera-Toledo, Evelyn; Ortega, Enrique; Licona-Limón, Ileana; Huerta, Leonor

    2017-01-01

    Enveloped viruses induce cell-cell fusion when infected cells expressing viral envelope proteins interact with target cells, or through the contact of cell-free viral particles with adjoining target cells. CD4"+ T lymphocytes and cells from the monocyte-macrophage lineage express receptors for HIV envelope protein. We have previously reported that lymphoid Jurkat T cells expressing the HIV-1 envelope protein (Env) can fuse with THP-1 monocytic cells, forming heterokaryons with a predominantly myeloid phenotype. This study shows that the expression of monocytic markers in heterokaryons is stable, whereas the expression of lymphoid markers is mostly lost. Like THP-1 cells, heterokaryons exhibited FcγR-dependent phagocytic activity and showed an enhanced expression of the activation marker ICAM-1 upon stimulation with PMA. In addition, heterokaryons showed morphological changes compatible with maturation, and high expression of the differentiation marker CD11b in the absence of differentiation-inducing agents. No morphological change nor increase in CD11b expression were observed when an HIV-fusion inhibitor blocked fusion, or when THP-1 cells were cocultured with Jurkat cells expressing a non-fusogenic Env protein, showing that differentiation was not induced merely by cell-cell interaction but required cell-cell fusion. Inhibition of TLR2/TLR4 signaling by a TIRAP inhibitor greatly reduced the expression of CD11b in heterokaryons. Thus, lymphocyte-monocyte heterokaryons induced by HIV-1 Env are stable and functional, and fusion prompts a phenotype characteristic of activated monocytes via intracellular TLR2/TLR4 signaling. - Highlights: • Jurkat T cells expressing the HIV-1 envelope fuse with THP-1 monocytes. • Heterokaryons display a dominant myeloid phenotype and monocyte function. • Heterokaryons exhibit activation features in the absence of activation agents. • Activation is not due to cell-cell interaction but requires cell-cell fusion. • The

  10. Identification of anti-HIV active dicaffeoylquinic- and tricaffeoylquinic acids in Helichrysum populifolium by NMR-based metabolomic guided fractionation.

    Science.gov (United States)

    Heyman, Heino Martin; Senejoux, François; Seibert, Isabell; Klimkait, Thomas; Maharaj, Vinesh Jaichand; Meyer, Jacobus Johannes Marion

    2015-06-01

    South Africa being home to more than 35% of the world's Helichrysum species (c.a. 244) of which many are used in traditional medicine, is seen potentially as a significant resource in the search of new anti-HIV chemical entities. It was established that five of the 30 Helichrysum species selected for this study had significant anti-HIV activity ranging between 12 and 21 μg/mL (IC50) by using an in-house developed DeCIPhR method on a full virus model. Subsequent toxicity tests also revealed little or no toxicity for these active extracts. With the use of NMR-based metabolomics, the search for common chemical characteristics within the plant extract was conducted, which resulted in specific chemical shift areas identified that could be linked to the anti-HIV activity of the extracts. The NMR chemical shifts associated with the activity were identified to be 2.56-3.08 ppm, 5.24-6.28 ppm, 6.44-7.04 ppm and 7.24-8.04 ppm. This activity profile was then used to guide the fractionation process by narrowing down and focusing the fractionation and purification processes to speed up the putative identification of five compounds with anti-HIV activity in the most active species, Helichrysum populifolium. The anti-HIV compounds identified for the first time from H. populifolium were three dicaffeoylquinic acid derivatives, i.e. 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid as well as two tricaffeoylquinic acid derivatives i.e. 1,3,5-tricaffeoylquinic acid and either 5-malonyl-1,3,4-tricaffeoylquinic or 3-malonyl-1,4,5-tricaffeoylquinic acid, with the latter being identified for the first time in the genus. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. A influência dos ácidos graxos trans na disfunção da célula endotelial e o possível efeito terapêutico do exercício sobre o tecido endotelial como forma de prevenção ou regressão da aterosclerose Influence of trans fatty acids on endothelial cell dysfunction and possible therapeutic effects of physical activity on endothelial tissue for prevention or regression of atherosclerosis

    Directory of Open Access Journals (Sweden)

    Laureane Nunes Masi

    2009-06-01

    Full Text Available O endotélio atua ativamente na regulação do tônus vascular, sintetizando e liberando substâncias vasoativas. A inflamação e os fatores de risco cardiovasculares alteram a homeostase vascular, levando à disfunção endotelial e possível formação de placas de ateroma. O aumento das concentrações plasmáticas de ácidos graxos livres pode causar lipotoxicidade vascular, disfunção do endotélio e, finalmente, aterosclerose. Dieta rica em lipídeos contendo ácidos graxos trans tem correlação positiva com a progressão de doenças cardiovasculares. Mudanças no estilo de vida, na adoção de dieta balanceada e atividade física são estratégias para a prevenção de doenças cardiovasculares e a reabilitação de pacientes. Nesta revisão, discutimos a influência benéfica do exercício físico em aspectos importantes da disfunção endotelial causados pelos ácidos graxos trans, incluindo evidências recentes e/ou ainda não exploradas. Discutimos também quais seriam os mecanismos envolvidos no comprometimento funcional da célula endotelial frente ao aumento de ácidos graxos trans na circulação.The endothelium actively participates in the regulation of vascular tone through the synthesis and release of vasoactive mediators. Inflammation and cardiovascular risk factors affect vascular homeostasis, causing endothelial dysfunction and atheromatous plaque formation. Increased free fatty acid concentrations may result in vascular lipotoxicity, endothelium dysfunction and, ultimately, atherosclerosis. A lipid-rich diet including trans fatty acids has a positive correlation with the progression of cardiovascular diseases. Lifestyle changes, such as eating a well-balanced diet and participating in regular physical activity, have been proposed to prevent cardiovascular diseases and improve rehabilitation. In this review, we discuss the beneficial effects of regular exercise on important aspects of endothelial dysfunction caused by

  12. HIV-1 Myristoylated Nef Treatment of Murine Microglial Cells Activates Inducible Nitric Oxide Synthase, NO2 Production and Neurotoxic Activity.

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    Giorgio Mangino

    Full Text Available The potential role of the human immunodeficiency virus-1 (HIV-1 accessory protein Nef in the pathogenesis of neuroAIDS is still poorly understood. Nef is a molecular adapter that influences several cellular signal transduction events and membrane trafficking. In human macrophages, Nef expression induces the production of extracellular factors (e.g. pro-inflammatory chemokines and cytokines and the recruitment of T cells, thus favoring their infection and its own transfer to uninfected cells via exosomes, cellular protrusions or cell-to-cell contacts. Murine cells are normally not permissive for HIV-1 but, in transgenic mice, Nef is a major disease determinant. Both in human and murine macrophages, myristoylated Nef (myr+Nef treatment has been shown to activate NF-κB, MAP kinases and interferon responsive factor 3 (IRF-3, thereby inducing tyrosine phosphorylation of signal transducers and activator of transcription (STAT-1, STAT-2 and STAT-3 through the production of proinflammatory factors.We report that treatment of BV-2 murine microglial cells with myr+Nef leads to STAT-1, -2 and -3 tyrosine phosphorylation and upregulates the expression of inducible nitric oxide synthase (iNOS with production of nitric oxide. We provide evidence that extracellular Nef regulates iNOS expression through NF-κB activation and, at least in part, interferon-β (IFNβ release that acts in concert with Nef. All of these effects require both myristoylation and a highly conserved acidic cluster in the viral protein. Finally, we report that Nef induces the release of neurotoxic factors in the supernatants of microglial cells.These results suggest a potential role of extracellular Nef in promoting neuronal injury in the murine model. They also indicate a possible interplay between Nef and host factors in the pathogenesis of neuroAIDS through the production of reactive nitrogen species in microglial cells.

  13. Nucleolar protein trafficking in response to HIV-1 Tat: rewiring the nucleolus.

    Science.gov (United States)

    Jarboui, Mohamed Ali; Bidoia, Carlo; Woods, Elena; Roe, Barbara; Wynne, Kieran; Elia, Giuliano; Hall, William W; Gautier, Virginie W

    2012-01-01

    The trans-activator Tat protein is a viral regulatory protein essential for HIV-1 replication. Tat trafficks to the nucleoplasm and the nucleolus. The nucleolus, a highly dynamic and structured membrane-less sub-nuclear compartment, is the site of rRNA and ribosome biogenesis and is involved in numerous cellular functions including transcriptional regulation, cell cycle control and viral infection. Importantly, transient nucleolar trafficking of both Tat and HIV-1 viral transcripts are critical in HIV-1 replication, however, the role(s) of the nucleolus in HIV-1 replication remains unclear. To better understand how the interaction of Tat with the nucleolar machinery contributes to HIV-1 pathogenesis, we investigated the quantitative changes in the composition of the nucleolar proteome of Jurkat T-cells stably expressing HIV-1 Tat fused to a TAP tag. Using an organellar proteomic approach based on mass spectrometry, coupled with Stable Isotope Labelling in Cell culture (SILAC), we quantified 520 proteins, including 49 proteins showing significant changes in abundance in Jurkat T-cell nucleolus upon Tat expression. Numerous proteins exhibiting a fold change were well characterised Tat interactors and/or known to be critical for HIV-1 replication. This suggests that the spatial control and subcellular compartimentaliation of these cellular cofactors by Tat provide an additional layer of control for regulating cellular machinery involved in HIV-1 pathogenesis. Pathway analysis and network reconstruction revealed that Tat expression specifically resulted in the nucleolar enrichment of proteins collectively participating in ribosomal biogenesis, protein homeostasis, metabolic pathways including glycolytic, pentose phosphate, nucleotides and amino acids biosynthetic pathways, stress response, T-cell signaling pathways and genome integrity. We present here the first differential profiling of the nucleolar proteome of T-cells expressing HIV-1 Tat. We discuss how these

  14. Mother-to-child transmission of human immunodeficiency virus (HIV) among HIV-infected pregnant women on highly active anti-retroviral therapy with premature rupture of membranes at term.

    Science.gov (United States)

    Eleje, George Uchenna; Edokwe, Emeka Stephen; Ikechebelu, Joseph Ifeanyichukwu; Onubogu, Chinyere Ukamaka; Ugochukwu, Ebele Francesca; Okam, Princeston Chukwuemeka; Ibekwe, Adaobi Maryann

    2018-01-01

    To determine mother-to-child transmission (MTCT) rate and associated risk factors of human immune-deficiency virus (HIV) among HIV-infected pregnant women with term premature rupture of membranes (PROM) in comparison with those without PROM at term. All optimally managed HIV-positive pregnant women of Nnamdi Azikiwe University Teaching Hospital, on highly active anti-retroviral therapy (HAART) who had PROM at term were enrolled. Maternal HIV-1 viral load was not assessed. Follow up was for a minimum of 18 months for evidence of HIV infection. Of the 121 women with PROM at term, 46 (38.0%) were HIV sero-positive, 22/46 (47.8%) of which had their babies followed up till 18 months. The mean latency period was 10.5 ± 5.3 h in PROM group. Apart from duration of PROM (OR = 0.01; 95%CI = 0.00-0.13; p  0.05). Of the 22 (47.8%) babies followed-up in the PROM group and 13 in non-PROM group, none tested positive to HIV, given an MTCT rate of 0%. MTCT rate was 0% following term PROM and in women without PROM. Since maternal HIV-1 viral load was not assessed, we need to be critical while interpreting the findings.

  15. Signal transduction and HIV transcriptional activation after exposure to ultraviolet light and other DNA-damaging agents

    International Nuclear Information System (INIS)

    Valerie, K.; Laster, W.S.; Luhua Cheng; Kirkham, J.C.; Reavey, Peter; Kuemmerle, N.B.

    1996-01-01

    Short wavelength (254 nm) ultraviolet light (UVC) radiation was much more potent in activating transcription of human immunodeficiency virus 1 (HIV) reporter genes stably integrated into the genomes of human and monkey cells than ionizing radiation (IR) from a 137 Cs source at similarly cytotoxic doses. A similar differential was also observed when c-jun transcription levels were examined. However, these transcription levels do not correlate with activation of nuclear factor (NF)-kB and AP-1 measured by band-shift assays, i.e. both types of radiation produce similar increases in NF-kB and AP-1 activity, suggesting existence of additional levels of regulation during these responses. Because of the well-established involvement of cytoplasmic signaling pathways in the cellular response to tumor necrosis factor-α (TNF-α), UVC, and IR using other types of assays, the role of TNF-α in the UVC response of HIV and c-jun was investigated in our cell system. We demonstrate that UVC and TNF-α activate HIV gene expression in a synergistic fashion, suggesting that it is unlikely that TNF-α is involved in UVC activation of HIV transcription in stably transfected HeLa cells. Moreover, maximum TNF-α stimulation resulted in one order of magnitude lower levels of HIV expression than that observed after UVC exposure. We also observed an additive effect of UVC and TNF-α on c-jun steady-state mRNA levels, suggestive of a partial overlap in activation mechanism of c-jun by UVC and TNF-α; yet these responses are distinct to some extent. Our results indicate that the HIV, and to some extent also the c-jun, transcriptional responses to UVC are not the result of TNF-α stimulation and subsequent downstream cytoplasmic signaling events in HeLa cells. In addition to the new data, this report also summarizes our current views regarding UVC-induced activations of HIV gene expression in stably transfected cells. (Author)

  16. Immunological Response of Hiv-Infected Children to Highly Active Antiretoviral Therapy at Gondar University Hospital, North-Western Ethiopia.

    Science.gov (United States)

    Kokeb, Mehretie; Degu, Getu

    2016-01-01

    The effectiveness of highly active antiretroviral therapy (HAART) in children has not been well studied specially in developing countries where the burden of HIV is high. This study was aimed to assess the immunologic response of HIV-infected children to HAART at Pediatric ART Clinic Gondar University Hospital. Institution based cross-sectional study was conducted at the Pediatric ART Clinic Gondar University Hospital from March 01-April 30, 2014. The study included 283 HIV-infected children who were on HAART for 6 months and above. Medical records of HIV-infected children were reviewed using pre-tested questionnaire. CD4 count/percent was collected every 6 months retrospectively. For all statistical significance tests, the cut-off value was pimmunological response. The study revealed that there was good Immunological response to ART, and that the maximum response was in the 1(st) 6 months of ART. Low CD4 count at initiation, undisclosed HIV status and lack of good adherence were found to cause low immunological response to HAART.

  17. Graves' Disease as a Manifestation of Immune Reconstitution in HIV-Infected Individuals after Initiation of Highly Active Antiretroviral Therapy

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    Samad Rasul

    2011-01-01

    Full Text Available Graves' disease after the initiation of highly active antiretroviral therapy (HAART in certain HIV-1-infected individuals has been described as an immune reconstitution inflammatory syndrome (IRIS. This phenomenon should be suspected in individuals who present with clinical deterioration and a presentation suggestive of hyperthyroidism despite good virological and immunological response to HAART. Signs and symptoms of hyperthyroidism may be discrete or overt and typically develop 8–33 months after initiating therapy. One to two percent of HIV-infected patients can present with overt thyroid disease. Relatively few cases of Graves' IRIS have been reported in the literature to date. We describe four cases of Graves' IRIS in HIV-infected patients who were started on HAART therapy.

  18. Cloning, Expression and Purification of the Recombinant HIV-1 Tat-Nef Fusion Protein in Prokaryotic Expression System

    OpenAIRE

    Somayeh Kadkhodayan; Shiva Irani; Seyed Mehdi Sadat; Fatemeh Fotouhi; Azam Bolhassani

    2016-01-01

    Abstract Background: Nef is one of the HIV-1 critical proteins, because it is essential for viral replication and AIDS disease progression and induction of immune response against it can partially inhibit viral infection. Moreover, a domain of the HIV-1 Trans-Activator of Transcription (Tat, 48-60 aa) could act as a cell penetrating peptide (CPP). In current study, cloning and expression of Tat-Nef fusion protein was performed in E. coli for the first time. The protein expression was confi...

  19. Excision of HIV-1 proviral DNA by recombinant cell permeable tre-recombinase.

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    Lakshmikanth Mariyanna

    Full Text Available Over the previous years, comprehensive studies on antiretroviral drugs resulted in the successful introduction of highly active antiretroviral therapy (HAART into clinical practice for treatment of HIV/AIDS. However, there is still need for new therapeutic approaches, since HAART cannot eradicate HIV-1 from the infected organism and, unfortunately, can be associated with long-term toxicity and the development of drug resistance. In contrast, novel gene therapy strategies may have the potential to reverse the infection by eradicating HIV-1. For example, expression of long terminal repeat (LTR-specific recombinase (Tre-recombinase has been shown to result in chromosomal excision of proviral DNA and, in consequence, in the eradication of HIV-1 from infected cell cultures. However, the delivery of Tre-recombinase currently depends on the genetic manipulation of target cells, a process that is complicating such therapeutic approaches and, thus, might be undesirable in a clinical setting. In this report we demonstrate that E.coli expressed Tre-recombinases, tagged either with the protein transduction domain (PTD from the HIV-1 Tat trans-activator or the translocation motif (TLM of the Hepatitis B virus PreS2 protein, were able to translocate efficiently into cells and showed significant recombination activity on HIV-1 LTR sequences. Tre activity was observed using episomal and stable integrated reporter constructs in transfected HeLa cells. Furthermore, the TLM-tagged enzyme was able to excise the full-length proviral DNA from chromosomal integration sites of HIV-1-infected HeLa and CEM-SS cells. The presented data confirm Tre-recombinase activity on integrated HIV-1 and provide the basis for the non-genetic transient application of engineered recombinases, which may be a valuable component of future HIV eradication strategies.

  20. Proof of activity with AMD11070, an orally bioavailable inhibitor of CXCR4-tropic HIV type 1.

    Science.gov (United States)

    Moyle, Graeme; DeJesus, Edwin; Boffito, Marta; Wong, Rebecca S; Gibney, Colleen; Badel, Karin; MacFarland, Ron; Calandra, Gary; Bridger, Gary; Becker, Stephen

    2009-03-15

    The X4 Antagonist Concept Trial investigates the safety and antiviral activity of AMD11070, a potent inhibitor of X4-tropic human immunodeficiency virus (HIV) in vitro in HIV-infected patients harboring X4-tropic virus. Patients enrolled in the study had an X4 virus population 2000 relative luminescence units (rlu; by the Monogram Trofile Assay) and an HIV-1 RNA level 5000 copies/mL. Patients received AMD11070 monotherapy for 10 days. Coreceptor tropism, plasma HIV-1 RNA level, and CD4 cell count were measured at study entry, on day 5, and on day 10. Daily predose and serial samples on the last day of treatment were obtained for determination of plasma AMD11070 concentration. Ten patients were given AMD11070 monotherapy (200 mg to 8 patients and 100 mg to 2 patients) twice daily for 10 days. The median baseline CD4 cell count was 160 cells/mm(3), and the median HIV-1 RNA level was 91,447 copies/mL. Four of 9 evaluable patients achieved a reduction in X4 virus population of >or= rlu. The median change in X4 virus population at the end of treatment was -0.22 log(10) rlu (range, -1.90 to 0.23 log(10) rlu). Three of 4 patients who responded to therapy showed a tropism shift from dual- or mixed-tropic viruses to exclusively R5 virus by day 10. There were no drug-related serious adverse events, adverse events of greater than grade 2, or laboratory abnormalities. These results demonstrate the activity of AMD11070, the first oral CXCR4 antagonist, against X4-tropic HIV-1. The drug was well tolerated, with no serious safety concerns. AMD11070 is on clinical hold because of histologic changes to the liver observed in long-term animal studies; additional preclinical safety assessments are pending.

  1. The HIV-1 Vpu protein induces apoptosis in Drosophila via activation of JNK signaling.

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    Christelle Marchal

    Full Text Available The genome of the human immunodeficiency virus type 1 (HIV-1 encodes the canonical retroviral proteins, as well as additional accessory proteins that enhance the expression of viral genes, the infectivity of the virus and the production of virions. The accessory Viral Protein U (Vpu, in particular, enhances viral particle production, while also promoting apoptosis of HIV-infected human T lymphocytes. Some Vpu effects rely on its interaction with the ubiquitin-proteasome protein degradation system, but the mechanisms responsible for its pro-apoptotic effects in vivo are complex and remain largely to be elucidated.We took advantage of the Drosophila model to study the effects of Vpu activity in vivo. Expression of Vpu in the developing Drosophila wing provoked tissue loss due to caspase-dependent apoptosis. Moreover, Vpu induced expression of the pro-apoptotic gene reaper, known to down-regulate Inhibitor of Apoptosis Proteins (IAPs which are caspase-antagonizing E3 ubiquitin ligases. Indeed, Vpu also reduced accumulation of Drosophila IAP1 (DIAP1. Though our results demonstrate a physical interaction between Vpu and the proteasome-addressing SLIMB/β-TrCP protein, as in mammals, both SLIMB/βTrCP-dependent and -independent Vpu effects were observed in the Drosophila wing. Lastly, the pro-apoptotic effect of Vpu in this tissue was abrogated upon inactivation of the c-Jun N-terminal Kinase (JNK pathway. Our results in the fly thus provide the first functional evidence linking Vpu pro-apoptotic effects to activation of the conserved JNK pathway.

  2. HIV/STI Prevention Among Heterosexually Active Black Adolescents With Mental Illnesses: Focus Group Findings for Intervention Development.

    Science.gov (United States)

    Brawner, Bridgette M; Jemmott, Loretta Sweet; Wingood, Gina; Reason, Janaiya; Mack, Niya

    Heterosexually active Black adolescents with mental illnesses are at increased risk for sexually transmitted infections (STIs), including HIV. However, few HIV/STI prevention interventions exist for this demographic. We held seven focus groups (N = 33) to elucidate social, cultural, and psychological factors that influence HIV/STI risk-related sexual behaviors in this understudied population. Seven themes emerged: (a) Blackness and media portrayals, (b) Blackness as a source of cultural resilience and pride, (c) psychosocial determinants of condom use, (d) consequences of engaging in sexual activity, (e) attitudes and beliefs toward sexual behaviors, (f) benefits of sexual activity, and (g) coping mechanisms. Participants also supported the feasibility of and interest in HIV/STI prevention programs integrated with mental health treatment. Transportation, potential breaches of confidentiality, and time were noted barriers to participation. Psychoeducational, skills-based programs are needed to address the sequelae of mental illnesses as they relate to the sexual decision-making process in adolescents. Copyright © 2017 Association of Nurses in AIDS Care. Published by Elsevier Inc. All rights reserved.

  3. Novel 3′-Processing Integrase Activity Assay by Real-Time PCR for Screening and Identification of HIV-1 Integrase Inhibitors

    Directory of Open Access Journals (Sweden)

    Supachai Sakkhachornphop

    2015-01-01

    Full Text Available The 3′-end processing (3′P of each viral long terminal repeat (LTR during human immunodeficiency virus type-1 (HIV-1 integration is a vital step in the HIV life cycle. Blocking the 3′P using 3′P inhibitor has recently become an attractive strategy for HIV-1 therapeutic intervention. Recently, we have developed a novel real-time PCR based assay for the detection of 3′P activity in vitro. The methodology usually involves biotinylated HIV-1 LTR, HIV-1 integrase (IN, and specific primers and probe. In this novel assay, we designed the HIV-1 LTR substrate based on a sequence with a homology to HIV-1 LTR labeled at its 3′ end with biotin on the sense strand. Two nucleotides at the 3′ end were subsequently removed by IN activity. Only two nucleotides labeled biotin were captured on an avidin-coated tube; therefore, inhibiting the binding of primers and probe results in late signals in the real-time PCR. This novel assay has successfully detected both the 3′P activity of HIV-1 IN and the anti-IN activity by Raltegravir and sodium azide agent. This real-time PCR assay has been shown to be effective and inexpensive for a high-throughput screening of novel IN inhibitors.

  4. Antiviral Activity of HIV gp120 Targeting Bispecific T Cell Engager (BiTE®) Antibody Constructs.

    Science.gov (United States)

    Brozy, Johannes; Schlaepfer, Erika; Mueller, Christina K S; Rochat, Mary-Aude; Rampini, Silvana K; Myburgh, Renier; Raum, Tobias; Kufer, Peter; Baeuerle, Patrick A; Muenz, Markus; Speck, Roberto F

    2018-05-02

    Today's gold standard in HIV therapy is the combined antiretroviral therapy (cART). It requires strict adherence by patients and life-long medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency, but cannot cure patients. The bispecific T cell engaging (BiTE®) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. We here generated BiTE® antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1+2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3ϵ scFv. These engineered human BiTE® antibody constructs showed engagement of T cells for redirected lysis of HIV gp120-transfected CHO cells. Furthermore, they substantially inhibited HIV-1 replication in PBMCs as well as in macrophages co-cultured with autologous CD8+ T-cells, the most potent being the human CD4(1+2) BiTE® antibody construct and the CD4(1+2)L17b BiTE® antibody construct. The CD4(1+2) h BiTE® antibody construct promoted HIV infection of human CD4-/CD8+ T cells. In contrast, the neutralizing B12 and the VRC01 BiTE® antibody constructs as well as the CD4(1+2)L17b BiTE® antibody construct did not. Thus, BiTE® antibody constructs targeting HIV gp120 are very promising for constraining HIV and warrant further development as novel antiviral therapy with curative potential. Importance HIV is a chronic infection well controlled with the current cART. However, we lack cure of HIV, and the HIV pandemic goes on. Here we showed in vitro and ex vivo t hat a bispecific T-cell engaging (BiTE®) antibody construct targeting HIV gp120 resulted in substantially reduced HIV replication. In addition, these BiTE® antibody constructs display efficient killing of gp120 expressing cells and inhibited replication in ex vivo

  5. Persistence of Activated and Adaptive-Like NK Cells in HIV+ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    Anna C. Hearps

    2017-06-01

    Full Text Available Innate immune dysfunction persists in HIV+ individuals despite effective combination antiretroviral therapy (cART. We recently demonstrated that an adaptive-like CD56dim NK cell population lacking the signal transducing protein FcRγ is expanded in HIV+ individuals. Here, we analyzed a cohort of HIV+ men who have sex with men (MSM, n = 20 at baseline and following 6, 12, and 24 months of cART and compared them with uninfected MSM (n = 15 to investigate the impact of cART on NK cell dysfunction. Proportions of NK cells expressing markers of early (CD69+ and late (HLA-DR+/CD38+ activation were elevated in cART-naïve HIV+ MSM (p = 0.004 and 0.015, respectively, as were FcRγ− NK cells (p = 0.003. Using latent growth curve modeling, we show that cART did not reduce levels of FcRγ− NK cells (p = 0.115 or activated HLA-DR+/CD38+ NK cells (p = 0.129 but did reduce T cell and monocyte activation (p < 0.001 for all. Proportions of FcRγ− NK cells were not associated with NK cell, T cell, or monocyte activation, suggesting different factors drive CD56dim FcRγ− NK cell expansion and immune activation in HIV+ individuals. While proportions of activated CD69+ NK cells declined significantly on cART (p = 0.003, the rate was significantly slower than the decline of T cell and monocyte activation, indicating a reduced potency of cART against NK cell activation. Our findings indicate that 2 years of suppressive cART have no impact on CD56dim FcRγ− NK cell expansion and that NK cell activation persists after normalization of other immune parameters. This may have implications for the development of malignancies and co-morbidities in HIV+ individuals on cART.

  6. Regulated production and anti-HIV type 1 activities of cytidine deaminases APOBEC3B, 3F, and 3G.

    Science.gov (United States)

    Rose, Kristine M; Marin, Mariana; Kozak, Susan L; Kabat, David

    2005-07-01

    APOBEC3G and 3F (A3G and A3F) cytidine deaminases incorporate into retroviral cores where they lethally hypermutate nascent DNA reverse transcripts. As substantiated here, the viral infectivity factor (Vif) encoded by human immunodeficiency virus type-1 (HIV-1) binds A3G and A3F and induces their degradation, thereby precluding their incorporation into viral progeny. Previous evidence suggested that A3G is expressed in H9 and other nonpermissive cells that contain this antiviral defense but not in several permissive cells, and that overexpression of A3G or A3F makes permissive cells nonpermissive. Using a broader panel of cell lines, we confirmed a correlation between A3G and cellular abilities to inactivate HIV-1(Deltavif). However, there was a quantitative discrepancy because several cells with weak antiviral activities had similar amounts of wild-type A3G mRNA and protein compared to H9 cells. Antiviral activity of H9 cells was also attenuated in some conditions. These quantitative discrepancies could not be explained by the presence of A3F or other A3G paralogs in some of the cell lines. Thus, A3A, A3B, and A3C had weak but significant anti-HIV-1 activities and did not dominantly interfere with A3G or A3F antiviral functions. Control of A3G synthesis by the protein kinase C/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway was also similar in permissive and nonpermissive cells. A3G in highly permissive cells is degraded by Vif, suggesting that it is not in a sequestered site, and is specifically incorporated in low amounts into HIV-1(Deltavif). Although A3G and/or A3F inactivate HIV-1(Deltavif) and are neutralized by Vif, the antiviral properties of cell lines are also influenced by other cellular and viral factors.

  7. Maraviroc is associated with latent HIV-1 reactivation through NF-κB activation in resting CD4+ T cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy.

    Science.gov (United States)

    Madrid-Elena, Nadia; García-Bermejo, María Laura; Serrano-Villar, Sergio; Díaz-de Santiago, Alberto; Sastre, Beatriz; Gutiérrez, Carolina; Dronda, Fernando; Coronel Díaz, María; Domínguez, Ester; López-Huertas, María Rosa; Hernández-Novoa, Beatriz; Moreno, Santiago

    2018-02-14

    Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency reversing potential of maraviroc and the mechanisms involved, we performed a phase-II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (Eudra CT: 2012-003215-66). All patients completed full maraviroc dosing and follow up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signalling pathways involved in the viral reactivation. An increase in HIV-1 transcription in resting CD4 + T-cells, estimated by HIV-1 unspliced RNA, was observed. Moreover, activation of the NF-κB transcription factor was observed in these cells. In contrast, AP-1 and NFAT activity was not detected. To elucidate the mechanism of NF-κB activation by maraviroc, we have evaluated in HeLa P4 C5 cells, which stably express CCR5, if maraviroc could be acting as a partial CCR5-agonist, with no other mechanisms or pathways involved. Our results show that maraviroc can induce NF-κB activity and NF-κB target genes expression by CCR5 binding, since the use of TAK779, a CCR5 inhibitor, blocked NF-κB activation and functionality. Taken together, we show that maraviroc may have a role in the activation of latent virus transcription through the activation of NF-κB as a result of binding CCR5. Our results strongly support a novel use of maraviroc as a potential latency reversal agent in HIV-1-infected patients. IMPORTANCE HIV-1 persistence in a small pool of long-lived latently infected resting CD4 + T-cells is a major barrier to viral eradication in HIV-1-infected patients on antiretroviral therapy. A potential strategy to cure HIV-1-infection is the use of latency reversing agents to eliminate the reservoirs established in resting CD4 + T-cells. As no drug has been shown to be completely

  8. A novel simple QSAR model for the prediction of anti-HIV activity using multiple linear regression analysis.

    Science.gov (United States)

    Afantitis, Antreas; Melagraki, Georgia; Sarimveis, Haralambos; Koutentis, Panayiotis A; Markopoulos, John; Igglessi-Markopoulou, Olga

    2006-08-01

    A quantitative-structure activity relationship was obtained by applying Multiple Linear Regression Analysis to a series of 80 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine (HEPT) derivatives with significant anti-HIV activity. For the selection of the best among 37 different descriptors, the Elimination Selection Stepwise Regression Method (ES-SWR) was utilized. The resulting QSAR model (R (2) (CV) = 0.8160; S (PRESS) = 0.5680) proved to be very accurate both in training and predictive stages.

  9. Mother-to-child HIV transmissions in Israel, 1985-2011.

    Science.gov (United States)

    Mor, Z; Sheffer, R; Chemtob, D

    2017-07-01

    Mother-to-child transmission (MTCT) is the leading cause of paediatric HIV-infection in Israel. This study aimed to assess MTCT rates and analyse temporal changes in relation to highly active antiretroviral therapy (HAART) introduction in 1996. This historical prospective study included all HIV-infected women who delivered in Israel between 1988 and 2011. Demographic, clinical, laboratory and therapy characteristics were compared between HIV-infected newborns with all others, and between infants born before and after 1996. Of all 796 infants born in Israel to HIV-infected women, 25 (3·1%) were infected. MTCT rates decreased significantly after HAART introduction compared with infants who were born before 1996 (16·3% vs. 1·7%). Mothers who infected vertically were more likely to be younger, Ethiopian-born, delivered trans-vaginally, not treated with HAART during pregnancy/labour and delivered before 1996 compared with mothers who did not transmit the HIV to their neonates. Newborns who did not receive antiretroviral therapy postpartum were more commonly HIV-infected and their mortality rate was higher. In conclusion, HAART during pregnancy/labour decreased MTCT significantly. Most MTCT in Israel was recorded among Ethiopian migrants, yet, in decreasing rates. Continuous efforts should be employed to encourage early HIV testing and allow effective HAART to pregnant women who belong to a key risk-group.

  10. Multi-target activity of Hemidesmus indicus decoction against innovative HIV-1 drug targets and characterization of Lupeol mode of action.

    Science.gov (United States)

    Esposito, Francesca; Mandrone, Manuela; Del Vecchio, Claudia; Carli, Ilaria; Distinto, Simona; Corona, Angela; Lianza, Mariacaterina; Piano, Dario; Tacchini, Massimo; Maccioni, Elias; Cottiglia, Filippo; Saccon, Elisa; Poli, Ferruccio; Parolin, Cristina; Tramontano, Enzo

    2017-08-31

    Despite the availability of several anti-retrovirals, there is still an urgent need for developing novel therapeutic strategies and finding new drugs against underexplored HIV-1 targets. Among them, there are the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) function and the cellular α-glucosidase, involved in the control mechanisms of N-linked glycoproteins formation in the endoplasmic reticulum. It is known that many natural compounds, such as pentacyclic triterpenes, are a promising class of HIV-1 inhibitors. Hence, here we tested the pentacyclic triterpene Lupeol, showing that it inhibits the HIV-1 RT-associated RNase H function. We then performed combination studies of Lupeol and the active site RNase H inhibitor RDS1759, and blind docking calculations, demonstrating that Lupeol binds to an HIV-1 RT allosteric pocket. On the bases of these results and searching for potential multitarget active drug supplement, we also investigated the anti-HIV-1 activity of Hemidesmus indicus, an Ayurveda medicinal plant containing Lupeol. Results supported the potential of this plant as a valuable multitarget active drug source. In fact, by virtue of its numerous active metabolites, H. indicus was able to inhibit not only the RT-associated RNase H function, but also the HIV-1 RT-associated RNA-dependent DNA polymerase activity and the cellular α-glucosidase. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Minocycline attenuates HIV-1 infection and suppresses chronic immune activation in humanized NOD/LtsZ-scidIL-2Rγnull mice

    Science.gov (United States)

    Singh, Maneesh; Singh, Pratibha; Vaira, Dolores; Amand, Mathieu; Rahmouni, Souad; Moutschen, Michel

    2014-01-01

    More than a quarter of a century of research has established chronic immune activation and dysfunctional T cells as central features of chronic HIV infection and subsequent immunodeficiency. Consequently, the search for a new immunomodulatory therapy that could reduce immune activation and improve T-cell function has been increased. However, the lack of small animal models for in vivo HIV study has hampered progress. In the current study, we have investigated a model of cord blood haematopoietic progenitor cells (CB-HPCs) -transplanted humanized NOD/LtsZ-scidIL-2Rγnull mice in which progression of HIV infection is associated with widespread chronic immune activation and inflammation. Indeed, HIV infection in humanized NSG mice caused up-regulation of several T-cell immune activation markers such as CD38, HLA-DR, CD69 and co-receptor CCR5. T-cell exhaustion markers PD-1 and CTLA-4 were found to be significantly up-regulated on T cells. Moreover, increased plasmatic levels of lipopolysaccharide, sCD14 and interleukin-10 were also observed in infected mice. Treatment with minocycline resulted in a significant decrease of expression of cellular and plasma immune activation markers, inhibition of HIV replication and improved T-cell counts in HIV-infected humanized NSG mice. The study demonstrates that minocycline could be an effective, low-cost adjunctive treatment to regulate chronic immune activation and replication of HIV. PMID:24409837

  12. Upregulation of Glucose Uptake and Hexokinase Activity of Primary Human CD4+ T Cells in Response to Infection with HIV-1

    Directory of Open Access Journals (Sweden)

    Maia Kavanagh Williamson

    2018-03-01

    Full Text Available Infection of primary CD4+ T cells with HIV-1 coincides with an increase in glycolysis. We investigated the expression of glucose transporters (GLUT and glycolytic enzymes in human CD4+ T cells in response to infection with HIV-1. We demonstrate the co-expression of GLUT1, GLUT3, GLUT4, and GLUT6 in human CD4+ T cells after activation, and their concerted overexpression in HIV-1 infected cells. The investigation of glycolytic enzymes demonstrated activation-dependent expression of hexokinases HK1 and HK2 in human CD4+ T cells, and a highly significant increase in cellular hexokinase enzyme activity in response to infection with HIV-1. HIV-1 infected CD4+ T cells showed a marked increase in expression of HK1, as well as the functionally related voltage-dependent anion channel (VDAC protein, but not HK2. The elevation of GLUT, HK1, and VDAC expression in HIV-1 infected cells mirrored replication kinetics and was dependent on virus replication, as evidenced by the use of reverse transcription inhibitors. Finally, we demonstrated that the upregulation of HK1 in HIV-1 infected CD4+ T cells is independent of the viral accessory proteins Vpu, Vif, Nef, and Vpr. Though these data are consistent with HIV-1 dependency on CD4+ T cell glucose metabolism, a cellular response mechanism to infection cannot be ruled out.

  13. TransAlta 2003 annual report

    International Nuclear Information System (INIS)

    2004-01-01

    This annual report presents financial information from TransAlta Corp., along with a review of its operations throughout 2003 and a summary of the how the electric utility has performed in terms of power generation, independent power producers, transmission and energy marketing. TransAlta is one of the largest non-regulated power generation and wholesale marketing companies in Canada. It's assets include coal-fired, gas-fired, hydro and renewable generation facilities in Canada, the United States, Mexico and Australia. Reported earnings in 2003 were $1.26 per share compared to $1.17 in 2002. The strong first quarter was followed by harsh market conditions, low water levels which affected hydro production, and pricing restrictions in Ontario that reduced contribution from the Sarnia plant. This report outlines the utility's progress in increasing revenue and producing more power. In 2003, unplanned outages were reduced by 7 per cent and injury frequency rate was reduced by 27 per cent. The installation of 114 wind turbines in Fort Macleod, Alberta, increased TransAlta's renewable energy capacity to 3.7 per cent in 2003. The wind farm produces 75 MW of electricity, enough to power more than 32,500 homes annually. This report summarized the company's energy resource activities and presented an operations review as well as consolidated financial statements and common share information. This included the utility's assets, liabilities, revenues, expenses and cash flows. Revenue and expenditure statements were summarized by source. refs., tabs., figs

  14. TransCanada Corporation 2003 annual report

    International Nuclear Information System (INIS)

    2004-01-01

    This annual report presents financial information from TransCanada Corp., along with a review of its operations throughout 2003 and a summary of the how the company performed in terms of providing natural gas transmission and power services in North America. In 2003, TransCanada increased earnings from continuing operations by 7 per cent. It maintained a strong cash flow and continued to strengthen its balance sheet. More than 1.2 billion was invested and dividends were increased by 7 per cent in January 2004, for a total return to shareholders of 27 per cent, including dividends. In 2003, TransCanada also increased its ownership interest in Foothills Pipe Lines Ltd. to 100 per cent from 50 per cent. It secured a position in the Mackenzie Gas Pipeline Project and progressed the development of multiple liquefied natural gas projects in the northeast United States and eastern Canada. The company acquired 31.6 per cent interest in Bruce Power, adding nearly 1,500 megawatts base load generation to its portfolio. Plans are underway for cogeneration plants in Quebec, New Brunswick and Alberta. This report summarized the company's energy resource activities and presented an operations review as well as consolidated financial statements and common share information. This included the utility's assets, liabilities, revenues, expenses and cash flows. Revenue and expenditure statements were summarized by source. tabs., figs

  15. TransCanada Corporation 2004 annual report

    International Nuclear Information System (INIS)

    2005-01-01

    TransCanada is a leading North American energy company dealing with natural gas transmission, power generation and marketing opportunities. Financial information from TransCanada was presented in this annual report along with a review of its operations in 2004 and a summary of how the company performed in terms of providing natural gas transmission and power services in North America. In 2004, TransCanada increased earnings from continuing operations and maintained a strong cash flow and continued to strengthen its balance sheet. Achievements in 2004 included the acquisition of the Gas Transmission Northwest Pipeline System and the North Baja Pipeline System; the purchase of hydroelectric generation assets in New England with a total generating capacity of more than 500 MW; and the completed construction of two new gas-fired cogeneration plants, the 165 MW MacKay River facility in Alberta and the 90 MW Grandview facility in New Brunswick. The challenges in 2004 included the performance of the company's existing asset-based businesses and the new initiatives to produce another year of solid operating and financial results. This report summarized the company's energy resource activities and presented an operations review as well as consolidated financial statements and common share information. This included the utility's assets, liabilities, revenues, expenses and cash flows. Revenue and expenditure statements were summarized by source. tabs., figs

  16. GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Masayuki; Miguel Salcedo-Gómez, Pedro; Yedidi, Ravikiran S.; Delino, Nicole S.; Nakata, Hirotomo; Venkateswara Rao, Kalapala; Ghosh, Arun K.; Mitsuya, Hiroaki

    2017-09-25

    We report that GRL-09510, a novel HIV-1 protease inhibitor (PI) containing a newly-generated P2-crown-tetrahydrofuranylurethane (Crwn-THF), a P2'-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC50: 0.0014–0.0028 μM) with minimal cytotoxicity (CC50: 39.0 μM). Similarly, GRL-09510 efficiently blocked the replication of HIV-1NL4-3 variants, which were capable of propagating at high-concentrations of atazanavir, lopinavir, and amprenavir (APV). GRL-09510 was also potent against multi-drug-resistant clinical HIV-1 variants and HIV-2ROD. Under the selection condition, where HIV-1NL4-3 rapidly acquired significant resistance to APV, an integrase inhibitor raltegravir, and a GRL-09510 congener (GRL-09610), no variants highly resistant against GRL-09510 emerged over long-term in vitro passage of the virus. Crystallographic analysis demonstrated that the Crwn-THF moiety of GRL-09510 forms strong hydrogen-bond-interactions with HIV-1 protease (PR) active-site amino acids and is bulkier with a larger contact surface, making greater van der Waals contacts with PR than the bis-THF moiety of darunavir. The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants, that the newly generated P2-Crwn-THF moiety confers highly desirable anti-HIV-1 potency. The use of the novel Crwn-THF moiety sheds lights in the design of novel PIs.

  17. Structured intermittent interruption of chronic HIV infection treatment with highly active antiretroviral therapy: effects on leptin and TNF-alpha.

    Science.gov (United States)

    Arjona, M Montes de Oca; Pérez-Cano, R; Garcia-Juárez, R; Martín-Aspas, A; del Alamo, C Fernández Gutiérrez; Girón-González, J A

    2006-04-01

    The changes in nutritional parameters and adipocytokines after structured intermittent interruption of highly active antiretroviral treatment of patients with chronic HIV infection are analyzed. Twenty-seven patients with chronic HIV infection (median CD4+ T cell count/microl: nadir, 394; at the beginning of structured interruptions, 1041; HIV viral load: nadir, 41,521 copies/ml; at the beginning of structured interruptions triglycerides, cholesterol, leptin, and tumor necrosis factor and its soluble receptors I and II were determined. After the three cycles of intermittent interruptions of therapy, no significant differences in CD4+ T cell count/microl, viral load, or serum concentrations of cholesterol or triglycerides with reference to baseline values were found. A near-significant higher fatty mass (skinfold thicknesses, at the end, 121 mm, at the beginning, 100 mm, p = 0.100), combined with a significant increase of concentration of leptin (1.5 vs. 4.7 ng/ml, p = 0,044), as well as a decrease in serum concentrations of soluble receptors of tumor necrosis factor (TNFRI, 104 vs. 73 pg/ml, p = 0.022; TNFRII 253 vs. 195 pg/ml, p = 0.098) were detected. Structured intermittent interruption of highly active antiretroviral treatment of patients with chronic HIV infection induces a valuable positive modification in markers of lipid turnover and adipose tissue mass.

  18. Markers of Microbial Translocation and Immune Activation Predict Cognitive Processing Speed in Heavy-Drinking Men Living with HIV

    Directory of Open Access Journals (Sweden)

    Mollie A. Monnig

    2017-09-01

    Full Text Available HIV infection and alcohol use disorder are associated with deficits in neurocognitive function. Emerging evidence points to pro-inflammatory perturbations of the gut-brain axis as potentially contributing to neurocognitive impairment in the context of HIV and chronic heavy alcohol use. This study examined whether plasma markers of microbial translocation (LPS from the gastrointestinal tract and related immune activation (sCD14, EndoCAb were associated with neurocognition in 21 men living with HIV who were virally suppressed on antiretroviral therapy. All participants met federal criteria for heavy drinking and were enrolled in a randomized controlled trial (RCT of a brief alcohol intervention. This secondary analysis utilized blood samples and cognitive scores (learning, memory, executive function, verbal fluency, and processing speed obtained at baseline and three-month follow-up of the RCT. In generalized estimating equation models, LPS, sCD14, and EndoCAb individually were significant predictors of processing speed. In a model with all biomarkers, higher LPS and sCD14 both remained significant predictors of lower processing speed. These preliminary findings suggest that inflammation stemming from HIV and/or alcohol could have negative effects on the gut-brain axis, manifested as diminished processing speed. Associations of microbial translocation and immune activation with processing speed in heavy-drinking PLWH warrant further investigation in larger-scale studies.

  19. Vitamin A and beta-carotene concentrations in adults with HIV/AIDS on highly active antiretroviral therapy.

    Science.gov (United States)

    Kaio, Daniella Junko; Rondó, Patricia Helen Carvalho; Souza, José Maria Pacheco; Firmino, Aline Vale; Luzia, Liania Alves; Segurado, Aluisio Augusto

    2013-01-01

    Micronutrient deficiency is a common condition in HIV-infected individuals and may occur in all stages of the disease. The objective of this cross-sectional study was to compare the concentrations of vitamin A and beta-carotene, micronutrients related to immunity and oxidative stress, in 182 adults with HIV/AIDS, under different highly active antiretroviral therapy (HAART) regimens. Patients were divided into 3 groups according to their HAART regimen: combination of nucleoside analog reverse transcriptase inhibitors (NRTIs) and non-NRTIs; combination of NRTIs, protease inhibitors, and ritonavir; combination of NRTIs and other classes. Multiple linear regression analysis determined the effect of the treatment regimen, time of use, and compliance with the regimen, on vitamin A and beta-carotene concentrations, controlling for the following variables: gender, age, educational level, smoking, physical activity, body mass index, time of infection with HIV, presence of comorbidities, CD4(+) T lymphocyte count, total cholesterol and fractions, and triglyceride levels. There was no significant difference in vitamin A or beta-carotene concentrations in patients under the different HAART regimens. However, approximately 4% of the patients had deficient/low concentrations of vitamin A (<0.70 μmol/L), and 98% showed concentrations of beta-carotene <1.0 μmol/L. In conclusion, HIV/AIDS patients in this region will not benefit from vitamin A supplementation, independently of the HAART regimen utilized, but beta-carotene may be of importance, considering its antioxidant effect.

  20. trans-(Cl)-[Ru(5,5'-diamide-2,2'-bipyridine)(CO)2 Cl2 ]: Synthesis, Structure, and Photocatalytic CO2 Reduction Activity.

    Science.gov (United States)

    Kuramochi, Yusuke; Fukaya, Kyohei; Yoshida, Makoto; Ishida, Hitoshi

    2015-07-06

    A series of trans-(Cl)-[Ru(L)(CO)2 Cl2 ]-type complexes, in which the ligands L are 2,2'-bipyridyl derivatives with amide groups at the 5,5'-positions, are synthesized. The C-connected amide group bound to the bipyridyl ligand through the carbonyl carbon atom is twisted with respect to the bipyridyl plane, whereas the N-connected amide group is in the plane. DFT calculations reveal that the twisted structure of the C-connected amide group raises the level of the LUMO, which results in a negative shift of the first reduction potential (Ep ) of the ruthenium complex. The catalytic abilities for CO2 reduction are evaluated in photoreactions (λ>400 nm) with the ruthenium complexes (the catalyst), [Ru(bpy)3 ](2+) (bpy=2,2'-bipyridine; the photosensitizer), and 1-benzyl-1,4-dihydronicotinamide (the electron donor) in CO2 -saturated N,N-dimethylacetamide/water. The logarithm of the turnover frequency increases by shifting Ep a negative value until it reaches the reduction potential of the photosensitizer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

    International Nuclear Information System (INIS)

    Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira; Aiamkitsumrit, Benjamas; Fassnacht, Ryan; Kashanchi, Fatah; Ochem, Alex; Simon, Gary L.; Karn, Jonathan; Hauser, Kurt F.; Tyagi, Mudit

    2015-01-01

    Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. - Highlights: • Cocaine induces the initiation phase of HIV transcription by activating NF-ĸB. • Cocaine induced NF-ĸB phosphorylation promotes its interaction with P300. • Cocaine enhances the elongation phase of HIV transcription by stimulating MSK1. • Cocaine activated MSK1 catalyzes the phosphorylation of histone H3 at its Ser10. • Cocaine induced H3S10 phosphorylation facilitates the recruitment of P-TEFb at LTR

  2. Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

    Energy Technology Data Exchange (ETDEWEB)

    Sahu, Geetaram; Farley, Kalamo [Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC (United States); El-Hage, Nazira [Virginia Commonwealth University, Richmond, VA (United States); Aiamkitsumrit, Benjamas; Fassnacht, Ryan [Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC (United States); Kashanchi, Fatah [George Mason University, Manassas, VA (United States); Ochem, Alex [ICGEB, Wernher and Beit Building, Anzio Road, Observatory, 7925 Cape Town (South Africa); Simon, Gary L. [Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC (United States); Karn, Jonathan [Case Western Reserve University, Cleveland, OH (United States); Hauser, Kurt F. [Virginia Commonwealth University, Richmond, VA (United States); Tyagi, Mudit, E-mail: tmudit@email.gwu.edu [Division of Infectious Diseases, Department of Medicine, George Washington University, Washington, DC (United States); Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037 (United States)

    2015-09-15

    Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. - Highlights: • Cocaine induces the initiation phase of HIV transcription by activating NF-ĸB. • Cocaine induced NF-ĸB phosphorylation promotes its interaction with P300. • Cocaine enhances the elongation phase of HIV transcription by stimulating MSK1. • Cocaine activated MSK1 catalyzes the phosphorylation of histone H3 at its Ser10. • Cocaine induced H3S10 phosphorylation facilitates the recruitment of P-TEFb at LTR.

  3. Anti-HIV and immunomodulation activities of cacao mass lignin-carbohydrate complex.

    Science.gov (United States)

    Sakagami, Hiroshi; Kawano, Michiyo; Thet, May Maw; Hashimoto, Ken; Satoh, Kazue; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Haishima, Yuji; Maeda, Yuuichi; Sakurai, Koji

    2011-01-01

    Recently, a prominent antiviral and macrophage stimulatory activity of cacao lignin-carbohydrate complex (LCC) has been reported. However, the solubility and sterility of LCC have not been considered yet. In the present study, complete solubilisation and sterilisation was achieved by autoclaving under mild alkaline conditions and the previously reported biological activities were re-examined. LCCs were obtained by 1% NaOH extraction and acid precipitation, and a repeated extraction-precipitation cycle. Nitric oxide (NO) and cytokine productions were assayed by the Griess method and ELISA, respectively. Inducible NO synthase (iNOS) expression was determined by Western blot analysis. Superoxide anion, hydroxyl radical and nitric oxide radical-scavenging activity was determined by ESR spectroscopy. Cacao mass LCC showed reproducibly higher anti-HIV activity than cacao husk LCC. Cacao mass LCC, up to 62.5 μg/ml, did not stimulate mouse macrophage-like cells (RAW264.7 and J774.1) to produce NO, nor did it induce iNOS protein, in contrast to lipopolysaccharide (LPS). Cacao mass LCC and LPS synergistically stimulated iNOS protein expression, suggesting a different point of action. Cacao mass LCC induced tumour necrosis factor-α production markedly less than LPS, and did not induce interleukin-1β, interferon-α or interferon-γ. ESR spectroscopy showed that cacao mass LCC, but not LPS, scavenged NO produced from NOC-7. This study demonstrated several new biological activities of LCCs distinct from LPS and further confirmed the promising antiviral and immunomodulating activities of LCCs.

  4. A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel.

    Directory of Open Access Journals (Sweden)

    Marla J Keller

    2011-01-01

    Full Text Available Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001 and fit a sigmoid E(max pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development

  5. Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection.

    Science.gov (United States)

    Palmer, Clovis S; Duette, Gabriel A; Wagner, Marc C E; Henstridge, Darren C; Saleh, Suah; Pereira, Candida; Zhou, Jingling; Simar, David; Lewin, Sharon R; Ostrowski, Matias; McCune, Joseph M; Crowe, Suzanne M

    2017-10-01

    High glucose transporter 1 (Glut1) surface expression is associated with increased glycolytic activity in activated CD4+ T cells. Phosphatidylinositide 3-kinases (PI3K) activation measured by p-Akt and OX40 is elevated in CD4+Glut1+ T cells from HIV+ subjects. TCR engagement of CD4+Glut1+ T cells from HIV+ subjects demonstrates hyperresponsive PI3K-mammalian target of rapamycin signaling. High basal Glut1 and OX40 on CD4+ T cells from combination antiretroviral therapy (cART)-treated HIV+ patients represent a sufficiently metabolically active state permissive for HIV infection in vitro without external stimuli. The majority of CD4+OX40+ T cells express Glut1, thus OX40 rather than Glut1 itself may facilitate HIV infection. Furthermore, infection of CD4+ T cells is limited by p110γ PI3K inhibition. Modulating glucose metabolism may limit cellular activation and prevent residual HIV replication in 'virologically suppressed' cART-treated HIV+ persons. © 2017 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  6. Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation.

    Science.gov (United States)

    Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar; Gisslen, Magnus; Palmer, Sarah; Price, Richard W

    2014-09-24

    Though combination antiretroviral therapy reduces the concentration of HIV-1 RNA in both plasma and cerebrospinal fluid (CSF) below the detection limit of clinical assays, low levels of HIV-1 RNA are frequently detectable in plasma using more sensitive assays. We examined the frequency and magnitude of persistent low-level HIV-1 RNA in CSF and its relation to the central nervous system (CNS) immune activation. CSF and plasma HIV-1 RNA were measured using the single-copy assay with a detection limit of 0.3 copies/ml in 70 CSF and 68 plasma samples from 45 treated HIV-1-infected patients with less than 40 copies/ml of HIV-1 RNA in both fluids by standard clinical assays. We also measured CSF neopterin to assess intrathecal immune activation. Theoretical drug exposure was estimated using the CNS penetration-efficacy score of treatment regimens. CSF HIV-1 RNA was detected in 12 of the 70 CSF samples (17%) taken after up to 10 years of suppressive therapy, compared to 39 of the 68 plasma samples (57%) with a median concentration of less than 0.3 copies/ml in CSF compared to 0.3 copies/ml in plasma (P < 0.0001). CSF samples with detectable HIV-1 RNA had higher CSF neopterin levels (mean 8.2 compared to 5.7 nmol/l; P = 0.0085). Patients with detectable HIV-1 RNA in CSF did not differ in pretreatment plasma HIV-1 RNA levels, nadir CD4 cell count or CNS penetration-efficacy score. Low-level CSF HIV-1 RNA and its association with elevated CSF neopterin highlight the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury.

  7. Regional differences in astrocyte activation in HIV-associated dementia Diferencias regionales en la activación astrocitaria en demencia asociada a HIV

    Directory of Open Access Journals (Sweden)

    María C. Vanzani

    2006-04-01

    Full Text Available Since astrogliosis is a histological marker usually observed in HIV-associated dementia (HIV-D, we decided to investigate the potential relationship between the expression of glial fibrillary acidic protein (GFAP and the regional distribution of cells positive (+ for this specific marker of astrocyte activation. Histological sections of brain tissues obtained at necropsy from 5 HIV-D patients and 5 age-matched controls without history of neuropsychiatric illness were immunostained with peroxidase. Mean numbers of GFAP(+ astrocytes were significantly increased in entorhinal cortex, hippocampus and subcortical white matter of patients, but values in frontal cortex and basal ganglia were similar to those of controls. In contrast, surface density of immunoreactive GFAP was significantly increased in all tested brain areas from all patients, including unusually affected regions such as entorhinal cortex and hippocampus. Therefore, such consistent finding of hypertrophic astrocytes, ranging from highest cell percentajes in subcortical white matter to lowest in basal ganglia indicates that quantification of surface density in GFAP (+ cells appears to be a more reliable approach to score gliosis than the counting of their cell nuclei. Because astrocyte activation involves both protective and detrimental effects on adjacent neuronal subsets, the evidence of regional differences in this reactive potential highlights the importance of accurately defining their contribution to the neuropathogenesis not only of HIV-D, but of a wide range of neurodegenerative disorders.Siendo la astrogliosis un signo histológico habitualmente presente en demencia asociada a HIV, se investigó la eventual relación entre expresión de proteína gliofibrilar ácida (GFAP y localización regional de células positivas para ese marcador específico de la activación astrocitaria. Por inmunoperoxidasa, se procesaron cortes histológicos de tejidos cerebrales obtenidos por

  8. A Survey of Plants with Anti-HIV Active Compounds and their Modes ...

    African Journals Online (AJOL)

    Background: Several limitations of current antiretroviral therapy (ART) programmes will continue to push patients towards the use of plants to manage HIV/AIDS. However, evidence about the use of anti-HIV plants is anecdotal. Objectives: Search the literature for research articles that document plants with anti-HIV ...

  9. Tuberculosis Screening and Active Tuberculosis among HIV-Infected Persons in a Canadian Tertiary Care Centre

    Directory of Open Access Journals (Sweden)

    Paul Brassard

    2009-01-01

    Full Text Available RATIONALE: HIV infection increases the risk of reactivation of latent tuberculosis (TB. The present study evaluates how latent TB is detected and treated to determine the effectiveness of screening in HIV-infected patients with diverse risk profiles.

  10. Suppression of HIV-1 viral load after multiple changes in high active ...

    African Journals Online (AJOL)

    1-infected patients. However, the virus persists ... chronological changes in HIV viral load and CD4+ T-cell count, and treatment outcomes of multiple combinations of .... Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the ...

  11. HIV infection results in ventral-striatal reward system hypo-activation during cue processing

    NARCIS (Netherlands)

    Plessis, Stéfan du; Vink, Matthijs; Joska, John A; Koutsilieri, Eleni; Bagadia, Asif; Stein, Dan J; Emsley, Robin

    2015-01-01

    OBJECTIVE: Functional MRI has thus far demonstrated that HIV has an impact on frontal-striatal systems involved in executive functioning. The potential impact of HIV on frontal-striatal systems involved in reward processing has yet to be examined by functional MRI. This study therefore aims to

  12. Synergistic activity profile of carbosilane dendrimer G2-STE16 in combination with other dendrimers and antiretrovirals as topical anti-HIV-1 microbicide.

    Science.gov (United States)

    Sepúlveda-Crespo, Daniel; Lorente, Raquel; Leal, Manuel; Gómez, Rafael; De la Mata, Francisco J; Jiménez, José Luis; Muñoz-Fernández, M Ángeles

    2014-04-01

    Polyanionic carbosilane dendrimers represent opportunities to develop new anti-HIV microbicides. Dendrimers and antiretrovirals (ARVs) acting at different stages of HIV replication have been proposed as compounds to decrease new HIV infections. Thus, we determined the potential use of our G2-STE16 carbosilane dendrimer in combination with other carbosilane dendrimers and ARVs for the use as topical microbicide against HIV-1. We showed that these combinations obtained 100% inhibition and displayed a synergistic profile against different HIV-1 isolates in our model of TZM.bl cells. Our results also showed their potent activity in the presence of an acidic vaginal or seminal fluid environment and did not activate an inflammatory response. This study is the first step toward exploring the use of different anionic carbosilane dendrimers in combination and toward making a safe microbicide. Therefore, our results support further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicide. This paper describes the first steps toward the use of anionic carbosilane dendrimers in combination with antivirals to address HIV-1, paving the way to further studies on dendrimer/dendrimer or dendrimer/ARV combinations as topical anti-HIV-1 microbicides. © 2014.

  13. Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yadong; Dong, Shiyi; Wang, Weicai; Wang, Jianning [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Wang, Miao [Department of Oral and Maxillofacial Surgery, Kiang Wu Hospital, Macao (China); Chen, Mu [Department of Stomatology, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen (China); Hou, Jinsong [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Huang, Hongzhang, E-mail: drhuang52@163.com [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China)

    2016-08-26

    Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway. - Highlights: • atRA exposure on E12.0 induced MEE persistence and cleft palate. • Notch1 was up-regulated in MEE cells in the atRA-treated embryos. • atRA inhibits MEE degradation, which in turn induces cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway.

  14. Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

    International Nuclear Information System (INIS)

    Zhang, Yadong; Dong, Shiyi; Wang, Weicai; Wang, Jianning; Wang, Miao; Chen, Mu; Hou, Jinsong; Huang, Hongzhang

    2016-01-01

    Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway. - Highlights: • atRA exposure on E12.0 induced MEE persistence and cleft palate. • Notch1 was up-regulated in MEE cells in the atRA-treated embryos. • atRA inhibits MEE degradation, which in turn induces cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway.

  15. Nutritional assessment and lipid profile in HIV-infected children and adolescents treated with highly active antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Marina Hjertquist Tremeschin

    2011-06-01

    Full Text Available INTRODUCTION: HIV-infected children and adolescents treated with highly active antiretroviral therapy (HAART regimens that include a protease inhibitor (PI can show significant improvements in clinical outcomes, nutritional status and quality of life. The study aimed to report nutritional and metabolic alterations for pediatric patients continuously exposed to HAART and for healthy controls for up to 1 year. METHODS: Clinical, anthropometric, lipid profile and food intake data were collected prospectively over approximately 12-months for each patient. RESULTS: Fifty-one individuals were studied, of these, 16 were healthy. After 12 months follow-up, HIV-positive individuals remained below the healthy control group parameters. No change was observed concerning food intake. Triglyceride serum levels were higher in patients using protease inhibitor at the onset of the study [PI groups: 114 (43 - 336, and 136 (63 - 271 versus control group: 54.5 (20 - 162; p = 0.003], but after twelve months follow-up, only the group using protease inhibitor for up to two months presented higher values [140 (73 - 273 versus 67.5 (33 - 117; p = 0.004]. HDL-cholesterol was lower in HIV-positive individuals [HIV-positive groups: 36 (27 - 58 and 36 (23 - 43; control 49.5 (34 - 69; p = 0.004]. CONCLUSIONS: HIV-infected children and adolescents treated with highly active antiretroviral therapy showed compromised nutritional parameters compared to a paired healthy control group. Individuals using protease inhibitor presented worse triglyceride serum levels compared to their healthy counterparts.

  16. Evaluation of the Effects of S-Allyl-L-cysteine, S-Methyl-L-cysteine, trans-S-1-Propenyl-L-cysteine, and Their N-Acetylated and S-Oxidized Metabolites on Human CYP Activities.

    Science.gov (United States)

    Amano, Hirotaka; Kazamori, Daichi; Itoh, Kenji

    2016-01-01

    Three major organosulfur compounds of aged garlic extract, S-allyl-L-cysteine (SAC), S-methyl-L-cysteine (SMC), and trans-S-1-propenyl-L-cysteine (S1PC), were examined for their effects on the activities of five major isoforms of human CYP enzymes: CYP1A2, 2C9, 2C19, 2D6, and 3A4. The metabolite formation from probe substrates for the CYP isoforms was examined in human liver microsomes in the presence of organosulfur compounds at 0.01-1 mM by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Allicin, a major component of garlic, inhibited CYP1A2 and CYP3A4 activity by 21-45% at 0.03 mM. In contrast, a CYP2C9-catalyzed reaction was enhanced by up to 1.9 times in the presence of allicin at 0.003-0.3 mM. SAC, SMC, and S1PC had no effect on the activities of the five isoforms, except that S1PC inhibited CYP3A4-catalyzed midazolam 1'-hydroxylation by 31% at 1 mM. The N-acetylated metabolites of the three compounds inhibited the activities of several isoforms to a varying degree at 1 mM. N-Acetyl-S-allyl-L-cysteine and N-acetyl-S-methyl-L-cysteine inhibited the reactions catalyzed by CYP2D6 and CYP1A2, by 19 and 26%, respectively, whereas trans-N-acetyl-S-1-propenyl-L-cysteine showed weak to moderate inhibition (19-49%) of CYP1A2, 2C19, 2D6, and 3A4 activities. On the other hand, both the N-acetylated and S-oxidized metabolites of SAC, SMC, and S1PC had little effect on the reactions catalyzed by the five isoforms. These results indicated that SAC, SMC, and S1PC have little potential to cause drug-drug interaction due to CYP inhibition or activation in vivo, as judged by their minimal effects (IC 50 >1 mM) on the activities of five major isoforms of human CYP in vitro.

  17. Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: Are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy?

    International Nuclear Information System (INIS)

    Fraunholz, Ingeborg; Rabeneck, Daniela; Gerstein, Johanna; Jaeck, Katharina; Haberl, Annette; Weiss, Christian; Roedel, Claus

    2011-01-01

    Purpose: To report treatment compliance, toxicity and clinical outcome of chemoradiotherapy (CRT) for anal carcinoma in HIV-negative vs. HIV-positive patients treated with highly active antiretroviral therapy. Material and methods: Between 1997 and 2008, 25 HIV-positive and 45 HIV-negative patients received CRT (50.4 Gy at 1.8 Gy/fraction plus 5.4-10.8 Gy boost; 5-fluorouracil, 1000 mg/m 2 , Days 1-4 and 29-32, mitomycin C, 10 mg/m 2 , Days 1 and 29). Median follow-up was 51 (range, 3-235) months. Results: HIV-positive patients were significantly younger (mean age, 47 vs. 57 years, p < 0.001) and predominantly male (92% vs. 29%, p < 0.001). CRT could be completed in all patients with a reduction of chemotherapy and/or RT-interruption in 28% and 8%, respectively, in HIV-positive patients, and in 9% and 11%, respectively, in HIV-negative patients. Acute Grade 3/4-toxicity occurred in 44% vs. 49% (p = 0.79). Initial complete response (84% vs. 93%, p = 0.41), 5-year rates of local control (65% vs. 78%, p = 0.44), cancer-specific (78% vs. 90%, p = 0.17) and overall survival (71% vs. 77%, p = 0.76) were not significantly different. Conclusion: HIV-positive patients with anal cancer can be treated with standard CRT, with the same tolerability and toxicity as HIV-negative patients. Long-term local control and survival rates are not significantly different between these groups.

  18. Trans fatty acid isomers and the trans-9/trans-11 index in fat containing foods

    Science.gov (United States)

    Kuhnt, Katrin; Baehr, Melanie; Rohrer, Carsten; Jahreis, Gerhard

    2011-01-01

    To determine trans fatty acid (TFA) distribution of contemporary foods, especially regarding individual trans octadecenoic acids (trans C18:1), 339 German foods of six categories (semi-solid fats, deep-fried potato products, bakery products, confectioneries, instant products and butter) were analysed using two GC methods. Results showed a high variation of TFA content between and within the categories containing between 0 and 40.5% of FAME except in butter, which is a source of natural TFA. The mean TFA values were below 2.0% of FAME, however, bakery products contained 4.5% and butter fat 3.2%, respectively. In addition, the distribution of individual trans C18:1 differed. In samples containing ruminant fat (butter and various confectioneries), vaccenic acid (t11-C18:1, t11) predominated, while in foods containing industrially hydrogenated fats, elaidic acid (trans-9, t9-) and t10-C18:1 were the major trans isomers.. This was reflected by a low t9/t11 index of 0.3 and 0.5 in butter and ruminant fat containing confectioneries, respectively, whilst the highest index was observed in shortenings and deep-fried potato products at 5.2 and 6.8, respectively. In conclusion, the TFA content of foods available on the German market is generally declining, but substantial variations are present. The t9/t11 index could be used as an indicator to determine ruminant fat. Practical applications: A number of studies provide evidence that a high TFA intake, particularly of industrial origin, adversely affects human health. The TFA content of foods could be reduced due to the introduction of several mandatory regulations and modifications regarding the hydrogenation process of oils. The most abundant dietary TFA are the isomers of trans C18:1. Unfortunately, the differentiation of these isomers is not yet very common, though the trans C18:1 profile differs depending on its origin (bacterial hydrogenation in the rumen or industrial hydrogenation). To date, data for TFA content

  19. A new activity of anti-HIV and anti-tumor protein GAP31: DNA adenosine glycosidase - Structural and modeling insight into its functions

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hui-Guang [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Huang, Philip L. [American Biosciences, Boston, MA 02114 (United States); Zhang, Dawei; Sun, Yongtao [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Chen, Hao-Chia [Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892 (United States); Zhang, John [Department of Chemistry, New York University, New York, NY 10003 (United States); Huang, Paul L. [Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114 (United States); Kong, Xiang-Peng, E-mail: xiangpeng.kong@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States); Lee-Huang, Sylvia, E-mail: sylvia.lee-huang@med.nyu.edu [Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States)

    2010-01-01

    We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

  20. PEPFAR support of alcohol-HIV prevention activities in Namibia and Botswana: a framework for investigation, implementation and evaluation.

    Science.gov (United States)

    Glenshaw, M; Deluca, N; Adams, R; Parry, C; Fritz, K; Du Preez, V; Voetsch, K; Lekone, P; Seth, P; Bachanas, P; Grillo, M; Kresina, T F; Pick, B; Ryan, C; Bock, N

    2016-01-01

    The association between harmful use of alcohol and HIV infection is well documented. To address this dual epidemic, the US President's Emergency Plan for AIDS Relief (PEPFAR) developed and implemented a multi-pronged approach primarily in Namibia and Botswana. We present the approach and preliminary results of the public health investigative and programmatic activities designed, initiated and supported by PEPFAR to combat the harmful use of alcohol and its association as a driver of HIV morbidity and mortality from 2008 to 2013. PEPFAR supported comprehensive alcohol programming using a matrix model approach that combined the socio-ecological framework and the Alcohol Misuse Prevention and Intervention Continuum. This structure enabled seven component objectives: (1) to quantify harmful use of alcohol through rapid assessments; (2) to develop and evaluate alcohol-based interventions; (3) to promote screening programs and alcohol abuse resource services; (4) to support stakeholder networks; (5) to support policy interventions and (6) structural interventions; and (7) to institutionalize universal prevention messages. Targeted PEPFAR support for alcohol activities resulted in several projects to address harmful alcohol use and HIV. Components are graphically conceptualized within the matrix model, demonstrating the intersections between primary, secondary and tertiary prevention activities and individual, interpersonal, community, and societal factors. Key initiative successes included leveraging alcohol harm prevention activities that enabled projects to be piloted in healthcare settings, schools, communities, and alcohol outlets. Primary challenges included the complexity of multi-sectorial programming, varying degrees of political will, and difficulties monitoring outcomes over the short duration of the program.

  1. Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-κB and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR

    Science.gov (United States)

    Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira; Aiamkitsumrit, Benjamas; Fassnacht, Ryan; Kashanchi, Fatah; Ochem, Alex; Simon, Gary L.; Karn, Jonathan; Hauser, Kurt F.; Tyagi, Mudit

    2015-01-01

    Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-κB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-κB at 276th serine residue. These modifications enhance the interaction of NF-κB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. PMID:25980739

  2. Exposure to apoptotic activated CD4+ T cells induces maturation and APOBEC3G-mediated inhibition of HIV-1 infection in dendritic cells.

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    Venkatramanan Mohanram

    Full Text Available Dendritic cells (DCs are activated by signaling via pathogen-specific receptors or exposure to inflammatory mediators. Here we show that co-culturing DCs with apoptotic HIV-infected activated CD4(+ T cells (ApoInf or apoptotic uninfected activated CD4(+ T cells (ApoAct induced expression of co-stimulatory molecules and cytokine release. In addition, we measured a reduced HIV infection rate in DCs after co-culture with ApoAct. A prerequisite for reduced HIV infection in DCs was activation of CD4(+ T cells before apoptosis induction. DCs exposed to ApoAct or ApoInf secreted MIP-1α, MIP-1β, MCP-1, and TNF-α; this effect was retained in the presence of exogenous HIV. The ApoAct-mediated induction of co-stimulatory CD86 molecules and reduction of HIV infection in DCs were partially abrogated after blocking TNF-α using monoclonal antibodies. APOBEC3G expression in DCs was increased in co-cultures of DCs and ApoAct but not by apoptotic resting CD4(+ T cells (ApoRest. Silencing of APOBEC3G in DC abrogated the HIV inhibitory effect mediated by ApoAct. Sequence analyses of an env region revealed significant induction of G-to-A hypermutations in the context of GG or GA dinucleotides in DNA isolated from DCs exposed to HIV and ApoAct. Thus, ApoAct-mediated DC maturation resulted in induction of APOBEC3G that was important for inhibition of HIV-infection in DCs. These findings underscore the complexity of differential DC responses evoked upon interaction with resting as compared with activated dying cells during HIV infection.

  3. Early initiation of highly active antiretroviral therapy fails to reverse immunovirological abnormalities in gut-associated lymphoid tissue induced by acute HIV infection.

    Science.gov (United States)

    Tincati, Camilla; Biasin, Mara; Bandera, Alessandra; Violin, Michela; Marchetti, Giulia; Piacentini, Luca; Vago, Gian Luca; Balotta, Claudia; Moroni, Mauro; Franzetti, Fabio; Clerici, Mario; Gori, Andrea

    2009-01-01

    During the acute phase of HIV infection, large CD4+ T-cell depletion occurs in the gastrointestinal tract. The kinetics of CD4+ T-cell decrease and highly active antiretroviral therapy (HAART)-mediated immune reconstitution were evaluated. Rectosigmoid colonic (RSC) biopsies and blood samples of nine patients with acute HIV infection were collected. CD4+ T-cell count, HIV RNA, intracellular HIV DNA and messenger RNA cytokine expression were evaluated before and after 6 months of HAART. All nine patients presented symptomatic retroviral infection. Early HAART was associated with a sustained and comparable reduction of HIV RNA in plasma, peripheral blood mononuclear cells (PBMCs) and RSC biopsies. HIV DNA decreased in PBMCs, but was only marginally reduced in RSC biopsies. Comparisons between reduction rates of HIV DNA in these two compartments confirmed that HIV DNA clearance was less efficient in RSC biopsies compared with PBMCs. Assessment of immunological profiles in PBMCs and RSC biopsies showed that the T-helper (Th)1-like/Th2-like ratio was sharply decreased in RSC biopsies and increased in PBMCs throughout the study period. A persistent Th2-like profile was detected in RSC biopsies. Efficient clearing of HIV DNA observed in PBMCs correlated with the establishment of a more favourable Th1-like profile. A less efficient clearance of intracellular HIV DNA following early introduction of HAART is associated with persistent immunological impairment in gut-associated lymphoid tissue (GALT), which is reflected by the skewed expression of cytokines in this reservoir. The present study shows that early initiation of HAART, in the short-term, is not effective in containing the establishment of HIV infection and in reversing associated immunological GALT abnormalities.

  4. Activity and Safety of Synthetic Lectins Based on Benzoboroxole-Functionalized Polymers for Inhibition of HIV Entry

    Science.gov (United States)

    Mahalingam, Alamelu; Geonnotti, Anthony R.; Balzarini, Jan; Kiser, Patrick F.

    2011-01-01

    Lectins derived from plant and microbial sources constitute a vital class of entry inhibitors that target the oligomannose residues on the HIV envelope gp120. Despite their potency and specificity, success of lectin-based entry inhibitors may be impeded by issues in regards to economical production, formulation and potential mitogenicity. Therefore, there exists a gap in the HIV therapeutics pipeline that underscores the need for mass producible, synthetic, broad-spectrum, and biocomptabile inhibitors of HIV entry. Here, we present the development of a polymeric synthetic lectin, based on benzoboroxole (BzB), which exhibits weak affinity (~25 M−1) for non-reducing sugars, similar to those found on the HIV envelope. High molecular weight BzB-functionalized polymers demonstrated antiviral activity that increased with an increase in ligand density and molecular weight of the polymer construct; revealing that polyvalency improves activity. Polymers showed significant increase in activity from 25 to 75 mol% BzB functionalization with EC50 of 15 μM and 15 nM, respectively. A further increase in mole functionalization to 90% resulted in an increase of the EC50 (59 ± 5 nM), likely due to the elongated rigid structure of the polymer chain compelled by electrostatic repulsion between the boronic acid groups. An increase in molecular weight of the polymer at 50 mol% BzB functionalization showed a gradual but significant increase in antiviral activity, with the highest activity seen with the 382 kDa polymer (EC50 of 1.1 ± 0.5 nM in CEM cells and 11 ± 3 nM in TZM-bl cells). Supplementing the polymer backbone with 10 mol% sulfonic acid not only increased the aqueous solubility of the polymers by at least 50-fold, but also demonstrated a synergistic increase in anti-HIV activity (4.0 ± 1.5 nM in TZM-bl cells), possibly due to electrostatic interactions between the negatively charged polymer backbone and the positively charged V3-loop in the gp120. The benzoboroxole

  5. Aminotransferase elevation in HIV/hepatitis B virus co-infected patients treated with two active hepatitis B virus drugs.

    Science.gov (United States)

    Jain, Mamta K; Parekh, Nimisha K; Hester, Jill; Lee, William M

    2006-12-01

    Discerning drug hepatotoxicity from viral hepatitis flares remains an ongoing problem unique to patients coinfected with HIV and hepatitis B (HBV). We present three such coinfected patients who have been on two anti-HBV agents, lamivudine and tenofovir disoproxil fumarate simultaneously, as part of highly active antiretroviral therapy (HAART). All three developed significant aminotransferase elevations 6-12 weeks after initiation of HAART despite being on two active HBV drugs. Two of the three patients were initially thought to have drug-related hepatotoxicity from HIV medications. It seems more likely that all three patients demonstrated hepatitis B reactivation of differing severity as the result of varying degrees of immune recovery. Distinguishing clearly between drug-related hepatotoxicity and hepatitis reactivation may be difficult but is important as their clinical management differs.

  6. Aaptamine Derivatives with Antifungal and Anti-HIV-1 Activities from the South China Sea Sponge Aaptos aaptos

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    Hao-Bing Yu

    2014-12-01

    Full Text Available Five new alkaloids of aaptamine family, compounds (1–5 and three known derivatives (6–8, have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1–2 are characterized with triazapyrene lactam skeleton, whereas compounds 4–5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7–8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.

  7. Mutation for nonsyndromic mental retardation in the trans-2-enoyl-CoA reductase TER gene involved in fatty acid elongation impairs the enzyme activity and stability, leading to change in sphingolipid profile.

    Science.gov (United States)

    Abe, Kensuke; Ohno, Yusuke; Sassa, Takayuki; Taguchi, Ryo; Çalışkan, Minal; Ober, Carole; Kihara, Akio

    2013-12-20

    Very long-chain fatty acids (VLCFAs, chain length >C20) exist in tissues throughout the body and are synthesized by repetition of the fatty acid (FA) elongation cycle composed of four successive enzymatic reactions. In mammals, the TER gene is the only gene encoding trans-2-enoyl-CoA reductase, which catalyzes the fourth reaction in the FA elongation cycle. The TER P182L mutation is the pathogenic mutation for nonsyndromic mental retardation. This mutation substitutes a leucine for a proline residue at amino acid 182 in the TER enzyme. Currently, the mechanism by which the TER P182L mutation causes nonsyndromic mental retardation is unknown. To understand the effect of this mutation on the TER enzyme and VLCFA synthesis, we have biochemically characterized the TER P182L mutant enzyme using yeast and mammalian cells transfected with the TER P182L mutant gene and analyzed the FA elongation cycle in the B-lymphoblastoid cell line with the homozygous TER P182L mutation (TER(P182L/P182L) B-lymphoblastoid cell line). We have found that TER P182L mutant enzyme exhibits reduced trans-2-enoyl-CoA reductase activity and protein stability, thereby impairing VLCFA synthesis and, in turn, altering the sphingolipid profile (i.e. decreased level of C24 sphingomyelin and C24 ceramide) in the TER(P182L/P182L) B-lymphoblastoid cell line. We have also found that in addition to the TER enzyme-catalyzed fourth reaction, the third reaction in the FA elongation cycle is affected by the TER P182L mutation. These findings provide new insight into the biochemical defects associated with this genetic mutation.

  8. The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity.

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    Rui Jia

    Full Text Available The interferon-inducible transmembrane (IFITM proteins inhibit a wide range of viruses. We previously reported the inhibition of human immunodeficiency virus type 1 (HIV-1 strain BH10 by human IFITM1, 2 and 3. It is unknown whether other HIV-1 strains are similarly inhibited by IFITMs and whether there exists viral countermeasure to overcome IFITM inhibition. We report here that the HIV-1 NL4-3 strain (HIV-1NL4-3 is not restricted by IFITM1 and its viral envelope glycoprotein is partly responsible for this insensitivity. However, HIV-1NL4-3 is profoundly inhibited by an IFITM1 mutant, known as Δ(117-125, which is deleted of 9 amino acids at the C-terminus. In contrast to the wild type IFITM1, which does not affect HIV-1 entry, the Δ(117-125 mutant diminishes HIV-1NL4-3 entry by 3-fold. This inhibition correlates with the predominant localization of Δ(117-125 to the plasma membrane where HIV-1 entry occurs. In spite of strong conservation of IFITM1 among most species, mouse IFITM1 is 19 amino acids shorter at its C-terminus as compared to human IFITM1 and, like the human IFITM1 mutant Δ(117-125, mouse IFITM1 also inhibits HIV-1 entry. This is the first report illustrating the role of viral envelope protein in overcoming IFITM1 restriction. The results also demonstrate the importance of the C-terminal region of IFITM1 in modulating the antiviral function through controlling protein subcellular localization.

  9. Social-Ecological, Motivational and Volitional Factors for Initiating and Maintaining Physical Activity in the Context of HIV.

    Science.gov (United States)

    Ley, Clemens; Barrio, María Rato; Leach, Lloyd

    2015-01-01

    Sport and exercise can have several health benefits for people living with HIV. These benefits can be achieved through different types of physical activity, adapting to disease progression, motivation and social-ecological options. However, physical activity levels and adherence to exercise are generally low in people living with HIV. At the same time, high drop-out rates in intervention studies are prevalent; even though they often entail more favourable conditions than interventions in the natural settings. Thus, in the framework of an intervention study, the present study aims to explore social-ecological, motivational and volitional correlates of South African women living with HIV with regard to physical activity and participation in a sport and exercise health promotion programme. The qualitative data was produced in the framework of a non-randomised pre-post intervention study that evaluated structure, processes and outcomes of a 10-week sport and exercise programme. All 25 participants of the programme were included in this analysis, independent of compliance. Data was produced through questionnaires, participatory group discussions, body image pictures, research diaries and individual semi-structured interviews. All participants lived in a low socioeconomic, disadvantaged setting. Hence, the psychological correlates are contextualised and social-ecological influences on perception and behaviour are discussed. The results show the importance of considering social-cultural and environmental influences on individual motives, perceptions and expectancies, the fear of disclosure and stigmatisation, sport and exercise-specific group dynamics and self-supporting processes. Opportunities and strategies to augment physical activity and participation in sport and exercise programmes in the context of HIV are discussed.

  10. Oligo-carrageenan kappa-induced reducing redox status and activation of TRR/TRX system increase the level of indole-3-acetic acid, gibberellin A3 and trans-zeatin in Eucalyptus globulus trees.

    Science.gov (United States)

    González, Alberto; Contreras, Rodrigo A; Zúiga, Gustavo; Moenne, Alejandra

    2014-08-20

    Eucalyptus globulus trees treated with oligo-carrageenan (OC) kappa showed an increase in NADPH, ascorbate and glutathione levels and activation of the thioredoxin reductase (TRR)/thioredoxin (TRX) system which enhance photosynthesis, basal metabolism and growth. In order to analyze whether the reducing redox status and the activation of thioredoxin reductase (TRR)/thioredoxin (TRX) increased the level of growth-promoting hormones, trees were treated with water (control), with OC kappa, or with inhibitors of ascorbate synthesis, lycorine, glutathione synthesis, buthionine sulfoximine (BSO), NADPH synthesis, CHS-828, and thioredoxin reductase activity, auranofine, and with OC kappa, and cultivated for four additional months. Eucalyptus trees treated with OC kappa showed an increase in the levels of the auxin indole 3-acetic acid (IAA), gibberellin A3 (GA3) and the cytokinin trans-zeatin (t-Z) as well as a decrease in the level of the brassinosteroid epi-brassinolide (EB). In addition, treatment with lycorine, BSO, CHS-828 and auranofine inhibited the increase in IAA, GA3 and t-Z as well as the decrease in EB levels. Thus, the reducing redox status and the activation of TRR/TRX system induced by OC kappa increased the levels of IAA, GA3 and t-Z levels determining, at least in part, the stimulation of growth in Eucalyptus trees.

  11. Lignosulfonic acid exhibits broadly anti-HIV-1 activity--potential as a microbicide candidate for the prevention of HIV-1 sexual transmission.

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    Min Qiu

    Full Text Available Some secondary metabolites from plants show to have potent inhibitory activities against microbial pathogens, such as human immunodeficiency virus (HIV, herpes simplex virus (HSV, Treponema pallidum, Neisseria gonorrhoeae, etc. Here we report that lignosulfonic acid (LSA, a polymeric lignin derivative, exhibits potent and broad activity against HIV-1 isolates of diverse subtypes including two North America strains and a number of Chinese clinical isolates values ranging from 21.4 to 633 nM. Distinct from other polyanions, LSA functions as an entry inhibitor with multiple targets on viral gp120 as well as on host receptor CD4 and co-receptors CCR5/CXCR4. LSA blocks viral entry as determined by time-of-drug addiction and cell-cell fusion assays. Moreover, LSA inhibits CD4-gp120 interaction by blocking the binding of antibodies specific for CD4-binding sites (CD4bs and for the V3 loop of gp120. Similarly, LSA interacts with CCR5 and CXCR4 via its inhibition of specific anti-CCR5 and anti-CXCR4 antibodies, respectively. Interestingly, the combination of LSA with AZT and Nevirapine exhibits synergism in viral inhibition. For the purpose of microbicide development, LSA displays low in vitro cytotoxicity to human genital tract epithelial cells, does not stimulate NF-κB activation and has no significant up-regulation of IL-1α/β and IL-8 as compared with N-9. Lastly, LSA shows no adverse effect on the epithelial integrity and the junctional protein expression. Taken together, our findings suggest that LSA can be a potential candidate for tropical microbicide.

  12. Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells.

    Science.gov (United States)

    Bomsel, Morgane; Ganor, Yonatan

    2017-12-01

    The neuroimmune dialogue between peripheral neurons and Langerhans cells (LCs) within mucosal epithelia protects against incoming pathogens. LCs rapidly internalize human immunodeficiency virus type 1 (HIV-1) upon its sexual transmission and then trans -infect CD4 + T cells. We recently found that the neuropeptide calcitonin gene-related peptide (CGRP), secreted mucosally from peripheral neurons, inhibits LC-mediated HIV-1 trans -infection. In this study, we investigated the mechanism of CGRP-induced inhibition, focusing on HIV-1 degradation in LCs and its interplay with trans -infection. We first show that HIV-1 degradation occurs in endolysosomes in untreated LCs, and functionally blocking such degradation with lysosomotropic agents results in increased trans -infection. We demonstrate that CGRP acts via its cognate receptor and at a viral postentry step to induce faster HIV-1 degradation, but without affecting the kinetics of endolysosomal degradation. We reveal that unexpectedly, CGRP shifts HIV-1 degradation from endolysosomes toward the proteasome, providing the first evidence for functional HIV-1 proteasomal degradation in LCs. Such efficient proteasomal degradation significantly inhibits the first phase of trans -infection, and proteasomal, but not endolysosomal, inhibitors abrogate CGRP-induced inhibition. Together, our results establish that CGRP controls the HIV-1 degradation mode in LCs. The presence of endogenous CGRP within innervated mucosal tissues, especially during the sexual response, to which CGRP contributes, suggests that HIV-1 proteasomal degradation predominates in vivo Hence, proteasomal, rather than endolysosomal, HIV-1 degradation in LCs should be enhanced clinically to effectively restrict HIV-1 trans -infection. IMPORTANCE During sexual transmission, HIV-1 is internalized and degraded in LCs, the resident antigen-presenting cells in mucosal epithelia. Yet during trans -infection, infectious virions escaping degradation are transferred

  13. Potential Role of Vδ2+ γδ T Cells in Regulation of Immune Activation in Primary HIV Infection

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    Nupur Bhatnagar

    2017-09-01

    Full Text Available Although conventional regulatory T cells (Tregs are sufficient in controlling low residual T-cell activation in ART-treated patients, they are not efficient in controlling exaggerated immune activation associated with high levels of HIV replication in primary HIV infection (PHI. Our previous data suggested that double negative (DN T cells including mainly γδ DN T cells play a role in the control of immune activation in PHI. Since γδ T cells are capable of exerting regulatory functions, we investigated their implication as Tregs in PHI as well as chronic HIV infection (CHI. In a cross-sectional study of 58 HIV-infected patients, in the primary and the chronic phase either ART-treated or untreated (UT, we analyzed phenotype and cytokine production of γδ T cells using flow cytometry. Cytokine production was assessed following in vitro stimulation with isopentenyl pyrophosphate or plate-bound anti-CD3/anti-CD28 monoclonal antibodies. We found that the proportion of γδ T cells negatively correlated with CD8 T-cell activation in PHI patients. Furthermore, we found that in these patients, the Vδ2 receptor bearing (Vδ2+ γδ T cells were strongly activated, exhibited low terminal differentiation, and produced the anti-inflammatory cytokine, TGF-β. In contrast, in UT-CHI, we observed a remarkable expansion of γδ T cells, where the Vδ2+ γδ T cells comprised of an elevated proportion of terminally differentiated cells producing high levels of IFN-γ but very low levels of TGF-β. We also found that this loss of regulatory feature of γδ T cells in CHI was a lasting impairment as we did not find recovery of TGF-β production even in ART-CHI patients successfully treated for more than 5 years. Our data therefore suggest that during the primary HIV infection, Vδ2+ γδ T cells may act as Tregs controlling immune activation through production of TGF-β. However, in CHI, γδ T cells transform from an anti-inflammatory into pro

  14. Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid.

    Science.gov (United States)

    Martínez-Gualda, Belén; Sun, Liang; Rivero-Buceta, Eva; Flores, Aida; Quesada, Ernesto; Balzarini, Jan; Noppen, Sam; Liekens, Sandra; Schols, Dominique; Neyts, Johan; Leyssen, Pieter; Mirabelli, Carmen; Camarasa, María-José; San-Félix, Ana

    2017-03-01

    We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  15. HIV-1 transgenic rat CD4+ T cells develop decreased CD28 responsiveness and suboptimal Lck tyrosine dephosphorylation following activation

    International Nuclear Information System (INIS)

    Yadav, Anjana; Pati, Shibani; Nyugen, Anhthu; Barabitskaja, Oxana; Mondal, Prosanta; Anderson, Michael; Gallo, Robert C.; Huso, David L.; Reid, William

    2006-01-01

    Impaired CD4+ T cell responses, resulting in dysregulated T-helper 1 (Th1) effector and memory responses, are a common result of HIV-1 infection. These defects are often preceded by decreased expression and function of the α/β T cell receptor (TCR)-CD3 complex and of co-stimulatory molecules including CD28, resulting in altered T cell proliferation, cytokine secretion and cell survival. We have previously shown that HIV Tg rats have defective development of T cell effector function and generation of specific effector/memory T cell subsets. Here we identify abnormalities in activated HIV-1 Tg rat CD4+ T cells that include decreased pY505 dephosphorylation of Lck (required for Lck activation), decreased CD28 function, reduced expression of the anti-apoptotic molecule Bcl-xL, decreased secretion of the mitogenic lympokine interleukin-2 (IL-2) and increased activation induced apoptosis. These events likely lead to defects in antigen-specific signaling and may help explain the disruption of Th1 responses and the generation of specific effector/memory subsets in transgenic CD4+ T cells

  16. Policing practices as a structural determinant for HIV among sex workers: a systematic review of empirical findings.

    Science.gov (United States)

    Footer, Katherine Ha; Silberzahn, Bradley E; Tormohlen, Kayla N; Sherman, Susan G

    2016-01-01

    Sex workers are disproportionately infected with HIV worldwide. Significant focus has been placed on understanding the structural determinants of HIV and designing related interventions. Although there is growing international evidence that policing is an important structural HIV determinant among sex workers, the evidence has not been systematically reviewed. We conducted a systematic review of quantitative studies to examine the effects of policing on HIV and STI infection and HIV-related outcomes (condom use; syringe use; number of clients; HIV/STI testing and access) among cis and trans women sex workers. Databases included PubMed, Embase, Scopus, Sociological Abstracts, Popline, Global Health (OVID), Web of Science, IBSS, IndMed and WHOLIS. We searched for studies that included police practices as an exposure for HIV or STI infection or HIV-related outcomes. Of the 137 peer-reviewed articles identified for full text review, 14 were included, representing sex workers' experiences with police across five settings. Arrest was the most commonly explored measure with between 6 and 45% of sex workers reporting having ever been arrested. Sexual coercion was observed between 3 and 37% of the time and police extortion between 12 and 28% across studies. Half the studies used a single measure to capture police behaviours. Studies predominantly focused on "extra-legal policing practices," with insufficient attention to the role of "legal enforcement activities". All studies found an association between police behaviours and HIV or STI infection, or a related risk behaviour. The review points to a small body of evidence that confirms policing practices as an important structural HIV determinant for sex workers, but studies lack generalizability with respect to identifying those police behaviours most relevant to women's HIV risk environment.

  17. Enhanced activity of carbosilane dendrimers against HIV when combined with reverse transcriptase inhibitor drugs: searching for more potent microbicides

    Directory of Open Access Journals (Sweden)

    Vacas-Córdoba E

    2014-07-01

    Full Text Available Enrique Vacas-Córdoba,1–3 Marta Galán,3,4 Francisco J de la Mata,3,4 Rafael Gómez,3,4 Marjorie Pion,1–3 M Ángeles Muñoz-Fernández1–3 1Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 2Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain; 3Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN, Madrid, Spain; 4Dendrimers for Biomedical Applications Group (BioInDen, University of Alcalá, Madrid, Spain Abstract: Self-administered topical microbicides or oral preexposure prophylaxis could be very helpful tools for all risk groups to decrease the human immunodeficiency virus (HIV-1 infection rates. Up until now, antiretrovirals (ARVs have been the most advanced microbicide candidates. Nevertheless, the majority of clinical trials has failed in HIV-1 patients. Nanotechnology offers suitable approaches to develop novel antiviral agents. Thereby, new nanosystems, such as carbosilane dendrimers, have been shown to be safe and effective compounds against HIV with great potential as topical microbicides. In addition, because most of the attempts to develop effective topical microbicides were unsuccessful, combinatorial strategies could be a valid approach when designing new microbicides. We evaluated various combinations of anionic carbosilane dendrimers with sulfated (G3-S16 and naphthyl sulfonated (G2-NF16 ended groups with different ARVs against HIV-1 infection. The G3-S16 and G2-NF16 dendrimers showed a synergistic or additive activity profile with zidovudine, efavirenz, and tenofovir in the majority of the combinations tested against the X4 and R5 tropic HIV-1 in cell lines, as well as in human primary cells. Therefore, the combination of ARVs and polyanionic carbosilane dendrimers enhances the antiviral potency of the individual compounds, and our findings support further clinical research on combinational approaches as

  18. Enteric parasitic infections in HIV/AIDS patients before and after the highly active antiretroviral therapy

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    Tatiana Paschoalette Rodrigues Bachur

    Full Text Available Enteroparasites are related to gastrointestinal alterations among patients with HIV/AIDS, some causing severe manifestations in the period before the institution of the highly active antiretroviral therapy (HAART. The prevalence of enteroparasitoses in patients with HIV/AIDS seen at two hospitals in Ceará , Brazil, was compared in the pre-HAART (Group 1; n = 482 and HAART (Group 2; n = 100 eras. Fecal parasitologic examinations (FPE were performed using the direct, Lutz, Baermann-Moraes and modified Ziehl-Neelsen methods. The following parasites were detected in Groups 1 and 2, respectively: Strongyloides stercoralis - 30.1% and 11% (p<0.0001, Ascaris lumbricoides - 15.6% and 2% (p<0.0001, hookworms - 13.7% and 2% (p<0.0001, Trichuris trichiura - 13.1% and 1% (p<0.0001, Hymenolepis nana - 0 and 1% (p = 0.1718, Giardia duodenalis - 7.9% and 1% (p = 0.0076, Entamoeba histolytica/dispar - 3.3% and 1% (p = 0.3301, Isospora belli - 4.8% and 1% (p = 0.0993, Cryptosporidium sp. - 8.1% and 0 (p = 0.0007, and non-pathogenic protozoans as well. There was a significant reduction in the prevalence of enteroparasites between the eras (63.9% to 24%; p<0.0001. In the HAART era, the following observations were made: greater frequency of enteroparasites in patients without antiretroviral therapy (p = 0.0575, as in those with AIDS (p = 0.08, and diarrhea (36% of the patients; lack of association with positive FPE (p = 0.626; and non-detection of Cryptosporidium sp. Strongyloides stercoralis showed an elevated prevalence in the two eras and was more frequent in men (32.41% than women (19.04% of Group 1 (p = 0.018, a finding suggesting the transmission of the helminth through sodomy. The advent of the HAART modified the profile of opportunistic infections, including parasites, probably due to the reconstitution of cellular immunity and the direct action of HAART on the parasites.

  19. A Survey of Plants with Anti-HIV Active Compounds and their Modes ...

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    proteins, alkaloids, and biflavonoids inhibit various ... several plant families and species contain anti-HIV .... articles reviewed, only about a third were included .... membranes against free .... Pedersen, B.K. Low plasma level of adiponectin.

  20. The impact of pregnancy on anti-HIV activity of cervicovaginal secretions.

    Science.gov (United States)

    Hughes, Brenna L; Dutt, Riana; Raker, Christina; Barthelemy, Melody; Rossoll, Richard M; Ramratnam, Bharat; Wira, Charles R; Cu-Uvin, Susan

    2016-12-01

    Mucosal immunity of the female genital tract plays a critical role in defense against sexually transmitted infections like HIV. Pregnancy is associated with both structural and immunologic alterations in the genital mucosa, but the impact of these changes on its ability to suppress HIV infection is unknown. Current epidemiologic data are conflicting as to whether pregnancy increases the risk of HIV acquisition. The purpose of this study was to define the association between antimicrobial peptides and chemokines in cervicovaginal secretions and in vitro HIV infectivity among pregnant and nonpregnant women. Forty pregnant and 37 nonpregnant women were enrolled in a prospective longitudinal cohort study at a single tertiary care women's hospital in Providence, RI. Cervicovaginal lavage was performed at each study visit. For pregnant women, study visits occurred once per trimester, and there was an optional postpartum visit. For nonpregnant women, study visits occurred across a single cycle that was timed to occur in the proliferative, ovulatory, and secretory phases based on the presumption of a regular menstrual cycle. The impact of cervicovaginal lavage on HIV infectivity was evaluated using a TZM-bl assay and compared between pregnant and nonpregnant women for each visit. The previously validated TZM-bl assay, which uses a luciferase reporting gene to indicate HIV infection of TZM-bl cells, was measured with a luminometer with higher relative light units that indicate greater levels of in vitro HIV infection. Immune mediators were measured with a multiplex bead assay. HIV infectivity and median concentration of each mediator were compared between pregnant and nonpregnant groups with the Wilcoxon rank sum test. Cervicovaginal fluid from pregnant and nonpregnant women significantly decreased HIV infectivity in both groups compared with positive control (virus only; PHIV infectivity in both groups across all visits, except at the postpartum visit in the pregnant

  1. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation

    Science.gov (United States)

    Yang, Hung-Chih; Xing, Sifei; Shan, Liang; O’Connell, Karen; Dinoso, Jason; Shen, Anding; Zhou, Yan; Shrum, Cynthia K.; Han, Yefei; Liu, Jun O.; Zhang, Hao; Margolick, Joseph B.; Siliciano, Robert F.

    2009-01-01

    The development of highly active antiretroviral therapy (HAART) to treat individuals infected with HIV-1 has dramatically improved patient outcomes, but HAART still fails to cure the infection. The latent viral reservoir in resting CD4+ T cells is a major barrier to virus eradication. Elimination of this reservoir requires reactivation of the latent virus. However, strategies for reactivating HIV-1 through nonspecific T cell activation have clinically unacceptable toxicities. We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4+ T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4+ T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthalene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-κB without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge latent virus. Our study expands the number of classes of latency-reversing therapeutics and demonstrates the utility of this in vitro model for finding strategies to eradicate HIV-1 infection. PMID:19805909

  2. Trans-nationalisation Processes in the Ukrainian Economy

    Directory of Open Access Journals (Sweden)

    Bolharova Natalya K.

    2013-12-01

    Full Text Available The article considers main processes of trans-nationalisation of Ukrainian economy, identifies specific features of trans-national production and explains some theoretical aspects of these issues. It provides main stages of theoretical comprehension of activity of trans-national corporations (TNC, specific features of the theory of competitive advantages of TNC and specifies the basic ones of them. The article conducts analysis of flows of direct foreign investments into the Ukrainian economy. It shows distribution of direct foreign investments into Ukraine by main countries-investors, regions-recipients and types of economic activity. It conducts review and analysis of the modern state of trans-national corporations of foreign origin in the Ukrainian market. It considers functioning of domestic TNC in Ukraine and main tendencies of entering of Ukrainian companies into the world environment and also identifies directions of further development of these phenomena. Prospects of further studies in this direction are identification of the degree of trans-nationalisation processes in the Ukrainian economy and identification of the positive effect, in particular, synergy from integration and globalisation.

  3. Merck Ad5/HIV induces broad innate immune activation that predicts CD8⁺ T-cell responses but is attenuated by preexisting Ad5 immunity.

    Science.gov (United States)

    Zak, Daniel E; Andersen-Nissen, Erica; Peterson, Eric R; Sato, Alicia; Hamilton, M Kristina; Borgerding, Joleen; Krishnamurty, Akshay T; Chang, Joanne T; Adams, Devin J; Hensley, Tiffany R; Salter, Alexander I; Morgan, Cecilia A; Duerr, Ann C; De Rosa, Stephen C; Aderem, Alan; McElrath, M Juliana

    2012-12-11

    To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity.

  4. Active methamphetamine use is associated with transmitted drug resistance to non-nucleoside reverse transcriptase inhibitors in individuals with HIV infection of unknown duration.

    Science.gov (United States)

    Cachay, Edward R; Moini, Niousha; Kosakovsky Pond, Sergei L; Pesano, Rick; Lie, Yolanda S; Aiem, Heidi; Butler, David M; Letendre, Scott; Mathews, Wm Christopher; Smith, Davey M

    2007-01-01

    Frequent methamphetamine use among recently HIV infected individuals is associated with transmitted drug resistance (TDR) to non-nucleoside reverse transcriptase inhibitors (NNRTI); however, the reversion time of TDR to drug susceptible HIV may exceed 3 years. We assessed whether recreational substance use is associated with detectable TDR among individuals newly diagnosed with HIV infection of unknown duration. Cross-sectional analysis. Subjects were enrolled at the University California, San Diego Early Intervention Program. Demographic, clinical and substance use data were collected using structured interviews. Genotypic resistance testing was performed using GeneSeq, Monogram Biosciences. We analyzed the association between substance use and TDR using bivariate analyses and the corresponding transmission networks using phylogenetic models. Between April 2004 and July 2006, 115 individuals with genotype data were enrolled. The prevalence of alcohol, marijuana and methamphetamine use were 98%, 71% and 64% respectively. Only active methamphetamine use in the 30 days prior to HIV diagnosis was independently associated with TDR to NNRTI (OR: 6.6; p=0.002). Despite not knowing the duration of their HIV infection, individuals reporting active methamphetamine use in the 30 days prior to HIV diagnosis are at an increased risk of having HIV strains that are resistant to NNRTI.

  5. Active Methamphetamine Use is Associated with Transmitted Drug Resis-tance to Non-Nucleoside Reverse Transcriptase Inhibitors in Individuals with HIV Infection of Unknown Duration

    Science.gov (United States)

    Cachay, Edward R; Moini, Niousha; Kosakovsky Pond, Sergei L; Pesano, Rick; Lie, Yolanda S; Aiem, Heidi; Butler, David M; Letendre, Scott; Mathews, Wm. Christopher; Smith, Davey M

    2007-01-01

    Background: Frequent methamphetamine use among recently HIV infected individuals is associated with transmitted drug resistance (TDR) to non-nucleoside reverse transcriptase inhibitors (NNRTI); however, the reversion time of TDR to drug susceptible HIV may exceed 3 years. We assessed whether recreational substance use is associated with detectable TDR among individuals newly diagnosed with HIV infection of unknown duration. Design: Cross-sectional analysis. Methods: Subjects were enrolled at the University California, San Diego Early Intervention Program. Demographic, clinical and substance use data were collected using structured interviews. Genotypic resistance testing was performed using GeneSeq™, Monogram Biosciences. We analyzed the association between substance use and TDR using bivariate analyses and the corresponding transmission networks using phylogenetic models. Results: Between April 2004 and July 2006, 115 individuals with genotype data were enrolled. The prevalence of alcohol, marijuana and methamphetamine use were 98%, 71% and 64% respectively. Only active methamphetamine use in the 30 days prior to HIV diagnosis was independently associated with TDR to NNRTI (OR: 6.6; p=0.002). Conclusion: Despite not knowing the duration of their HIV infection, individuals reporting active methamphetamine use in the 30 days prior to HIV diagnosis are at an increased risk of having HIV strains that are resistant to NNRTI. PMID:18923691

  6. Human Paraoxonase-1 Activity Is Related to the Number of CD4+ T-Cells and Is Restored by Antiretroviral Therapy in HIV-1-Infected Individuals

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    Luciana Morganti Ferreira Maselli

    2014-01-01

    Full Text Available Background. Paraoxonase-1 (PON1 activity is suggested to be altered in individuals infected with human immunodeficiency virus type-1 (HIV-1. We investigated PON1 activity in individuals receiving different regimens of highly active antiretroviral therapy (HAART. Methods. PON1 activity was evaluated in 91 HIV-1 seronegative and 624 HIV-1 infected individuals (115 were not undergoing therapy (ART-naïve, and 509 were receiving HAART. HIV-1 infected individuals were treated with the following: efavirenz (EFV; n=195 or nevirapine (NVP; n=95 or lopinavir/ritonavir (LOP/r; n=219. Serum levels of total cholesterol (TC, HDL, and low-density lipoprotein (LDL fractions and the atherogenic indices (AI, TC : HDL, and LDL : HDL ratios were determined. Results. PON1 activity (U/L was lower in the ART-naïve group compared with the other groups. PON1 activity correlated with CD4+ T-cell number of ART-naïve group (r=0,121; P=0,014. The LOP/r group showed a reduction in HDL and an increase in AI (TC : HDL ratio in comparison with other groups. Conclusion. PON1 activity was reduced in untreated individuals, but not in individuals receiving HAART. PON1 activity correlated with the number of CD4+ T-cells. The findings suggest that the activity of PON1 is associated with the immune status of HIV-1 infected individuals.

  7. Synergistic activity profile of griffithsin in combination with tenofovir, maraviroc and enfuvirtide against HIV-1 clade C

    International Nuclear Information System (INIS)

    Ferir, Geoffrey; Palmer, Kenneth E.; Schols, Dominique

    2011-01-01

    Griffithsin (GRFT) is possibly the most potent anti-HIV peptide found in natural sources. Due to its potent and broad-spectrum antiviral activity and unique safety profile it has great potential as topical microbicide component. Here, we evaluated various combinations of GRFT against HIV-1 clade B and clade C isolates in primary peripheral blood mononuclear cells (PBMCs) and in CD4 + MT-4 cells. In all combinations tested, GRFT showed synergistic activity profile with tenofovir, maraviroc and enfuvirtide based on the median effect principle with combination indices (CI) varying between 0.34 and 0.79 at the calculated EC 95 level. Furthermore, the different glycosylation patterns on the viral envelope of clade B and clade C gp120 had no observable effect on the synergistic interactions. Overall, we can conclude that the evaluated two-drug combination increases their antiviral potency and supports further clinical investigations in pre-exposure prophylaxis for GRFT combinations in the context of HIV-1 clade C infection.

  8. HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers.

    Science.gov (United States)

    Pai, Sara I; Jack Lee, J; Carey, Thomas E; Westra, William H; Ferrone, Soldano; Moore, Charles; Mosunjac, Marina B; Shin, Dong M; Ferris, Robert L

    2018-02-01

    Human immunodeficiency virus (HIV)-infected individuals are at increased risk for developing several non-AIDS related malignancies and are often excluded from cancer immunotherapy regimens. To evaluate the immune competence of this cancer patient population, we evaluated HLA class I antigen presenting machinery (APM) component expression and PD-1:PD-L1 pathway upregulation in HIV(+) and HIV(-) head and neck cancers (HNCs). Sixty-two HIV(+) and 44 matched HIV(-) controls diagnosed with HNC between 1991 and 2011 from five tertiary care referral centers in the United States were identified. HLA class I APM component, PD-1, and PD-L1 expression were analyzed by immunohistochemical staining with monoclonal antibodies (mAbs). Clinical data was abstracted from the medical records. There was no significant difference between the cases and controls in LMP2, TAP1, HLA-A and HLA-B/C, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1 within the tumor microenvironment. LMP2, HLA-A and HLA-B/C expression were significantly associated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = .004, p = .026, and p = .006, respectively) but not in the HIV(-) controls. In addition, HLA-A expression was significantly associated with PD-L1 expression in the HIV(+) HNC cases only (p = .029). HIV-infected individuals diagnosed with HNC do not have any detectable defects in HLA class I APM component expression and in PD-1:PD-L1 pathway activation. Given the current successes of HAART therapy in maintaining immune cell counts, HIV(+) patients diagnosed with cancer may benefit from the recently FDA-approved immune checkpoint blockade therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Rate of candidiasis among HIV-infected children in Spain in the era of highly active antiretroviral therapy (1997-2008).

    Science.gov (United States)

    Álvaro-Meca, Alejandro; Jensen, Julia; Micheloud, Dariela; Díaz, Asunción; Gurbindo, Dolores; Resino, Salvador

    2013-03-04

    Candidiasis is the most common opportunistic infection seen in human immunodeficiency virus (HIV)-infected individuals. The aim of our study was to estimate the candidiasis rate and evaluate its trend in HIV-infected children in Spain during the era of highly active antiretroviral therapy (HAART) compared to HIV-uninfected children. We carried out a retrospective study. Data were obtained from the records of the Minimum Basic Data Set from hospitals in Spain. All HIV-infected children were under 17 years of age, and a group of HIV-uninfected children with hospital admissions matching the study group by gender and age were randomly selected. The follow-up period (1997-2008) was divided into three calendar periods: a) From 1997 to 1999 for early-period HAART; b) from 2000 to 2002 for mid-period HAART; and c) from 2003 to 2008 for late-period HAART. Among children with hospital admissions, HIV-infected children had much higher values than HIV-uninfected children during each of the three calendar periods for overall candidiasis rates (150.0 versus 6.1 events per 1,000 child hospital admissions/year (p candidiasis rate (events per 1,000 HIV-infected children/year) decreased from 1997-1999 to 2000-2002 (18.8 to 10.6; p candidiasis, both non-ICM and ICM rates experienced significant decreases from 1997-1999 to 2003-2008 (15.9 to 5.7 (p candidiasis rate still remains higher than in the general population (from 1997 to 2008), candidiasis diagnoses have decreased among HIV-infected children throughout the HAART era, and it has ceased to be a major health problem among children with HIV infection.

  10. Rate of candidiasis among HIV-infected children in Spain in the era of highly active antiretroviral therapy (1997–2008)

    Science.gov (United States)

    2013-01-01

    Background Candidiasis is the most common opportunistic infection seen in human immunodeficiency virus (HIV)-infected individuals. The aim of our study was to estimate the candidiasis rate and evaluate its trend in HIV-infected children in Spain during the era of highly active antiretroviral therapy (HAART) compared to HIV-uninfected children. Methods We carried out a retrospective study. Data were obtained from the records of the Minimum Basic Data Set from hospitals in Spain. All HIV-infected children were under 17 years of age, and a group of HIV-uninfected children with hospital admissions matching the study group by gender and age were randomly selected. The follow-up period (1997–2008) was divided into three calendar periods: a) From 1997 to 1999 for early-period HAART; b) from 2000 to 2002 for mid-period HAART; and c) from 2003 to 2008 for late-period HAART. Results Among children with hospital admissions, HIV-infected children had much higher values than HIV-uninfected children during each of the three calendar periods for overall candidiasis rates (150.0 versus 6.1 events per 1,000 child hospital admissions/year (p candidiasis rate (events per 1,000 HIV-infected children/year) decreased from 1997–1999 to 2000–2002 (18.8 to 10.6; p candidiasis, both non-ICM and ICM rates experienced significant decreases from 1997–1999 to 2003–2008 (15.9 to 5.7 (p candidiasis rate still remains higher than in the general population (from 1997 to 2008), candidiasis diagnoses have decreased among HIV-infected children throughout the HAART era, and it has ceased to be a major health problem among children with HIV infection. PMID:23510319

  11. Beneficial effects of physical activity in an HIV-infected woman with lipodystrophy: a case report

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    de Oliveira Leandro

    2011-09-01

    Full Text Available Abstract Introduction Lipodystrophy is common in patients infected with human immunodeficiency virus receiving highly active antiretroviral therapy, and presents with morphologic changes and metabolic alterations that are associated with depressive behavior and reduced quality of life. We examined the effects of exercise training on morphological changes, lipid profile and quality of life in a woman with human immunodeficiency virus presenting with lipodystrophy. Case presentation A 31-year-old Latin-American Caucasian woman infected with human immunodeficiency virus participated in a 12-week progressive resistance exercise training program with an aerobic component. Her weight, height, skinfold thickness, body circumferences, femur and humerus diameter, blood lipid profile, maximal oxygen uptake volume, exercise duration, strength and quality of life were assessed pre-exercise and post-exercise training. After 12 weeks, she exhibited reductions in her total subcutaneous fat (18.5%, central subcutaneous fat (21.0%, peripheral subcutaneous fat (10.7%, waist circumference (WC (4.5%, triglycerides (9.9%, total cholesterol (12.0% and low-density lipoprotein cholesterol (8.6%. She had increased body mass (4.6%, body mass index (4.37%, humerus and femur diameter (3.0% and 2.3%, respectively, high-density lipoprotein cholesterol (16.7%, maximal oxygen uptake volume (33.3%, exercise duration (37.5% and strength (65.5%. Quality of life measures improved mainly for psychological and physical measures, independence and social relationships. Conclusions These findings suggest that supervised progressive resistance exercise training is a safe and effective treatment for evolving morphologic and metabolic disorders in adults infected with HIV receiving highly active antiretroviral therapy, and improves their quality of life.

  12. Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study

    Science.gov (United States)

    Associations between abnormal body fat distribution and clinical variables are poorly understood in pediatric HIV disease. Our objective was to compare total body fat and its distribution in perinatally HIV-infected and HIV-exposed but uninfected (HEU) children and to evaluate associations with clin...

  13. Trans Asian Railway

    DEFF Research Database (Denmark)

    Petr, Petr; Schramm, Hans-Joachim; Prockl, Günter

    -structured in depth interviews of key actors in the Czech Republic, the paper examines the perception of container inland transport chains of a diverse range of market players that are active in such a landlocked market in Central and East Europe (CEE). The research questions whether competitive pricing, service time...... reliability and transit time determine changes in service supply by freight forwarders. It investigates the position taken by their customers and shipping lines in regard to TAR links. Although the empirical evidence is limited to a sample of market players in the Czech Republic, the results support valuable...

  14. A narrative review of research on the effects of physical activity on people living with HIV and opportunities for health promotion in disadvantaged settings.

    Science.gov (United States)

    Ley, Clemens; Barrio, María Rato

    2012-06-01

    The article explores different types and effects of physical activity for people living with HIV. Considering the lack of studies done in African contexts and the disparity between research settings and natural settings, a narrative review of the literature was conducted and contextualised to South Africa. Various physical, psychological and social-cultural constraints impair the wellbeing of people living with HIV, in part by restricting their participation in physical activities. Apart from the well-studied immediate physiological benefits on health, we argue that physical-sportive group activities, such as sport or recreational games, can improve psychosocial factors and generate holistic health effects for people living with HIV. Group-activity effects could improve individuals' motivation and adherence to participating in physical activities, provided that positive interaction and non-stigmatisation are guaranteed. However, most studies in this field have been limited to the benefits of aerobic exercise and resistance training. There has been little research on the types and different effects of physical activity and adherence to physical activity of people living with HIV in African contexts. Based on an analysis of the different types and effects, we suggest opportunities for and challenges to implementing physical activities for people living with HIV, especially in disadvantaged settings, and also identify gaps in the research to date.

  15. Sialoadhesin expressed on IFN-induced monocytes binds HIV-1 and enhances infectivity.

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    Hans Rempel

    2008-04-01

    Full Text Available HIV-1 infection dysregulates the immune system and alters gene expression in circulating monocytes. Differential gene expression analysis of CD14(+ monocytes from subjects infected with HIV-1 revealed increased expression of sialoadhesin (Sn, CD169, Siglec 1, a cell adhesion molecule first described in a subset of macrophages activated in chronic inflammatory diseases.We analyzed sialoadhesin expression on CD14(+ monocytes by flow cytometry and found significantly higher expression in subjects with elevated viral loads compared to subjects with undetectable viral loads. In cultured CD14(+ monocytes isolated from healthy individuals, sialoadhesin expression was induced by interferon-alpha and interferon-gamma but not tumor necrosis factor-alpha. Using a stringent binding assay, sialoadhesin-expressing monocytes adsorbed HIV-1 through interaction with the sialic acid residues on the viral envelope glycoprotein gp120. Furthermore, monocytes expressing sialoadhesin facilitated HIV-1 trans infection of permissive cells, which occurred in the absence of monocyte self-infection.Increased sialoadhesin expression on CD14(+ monocytes occurred in response to HIV-1 infection with maximum expression associated with high viral load. We show that interferons induce sialoadhesin in primary CD14(+ monocytes, which is consistent with an antiviral response during viremia. Our findings suggest that circulating sialoadhesin-expressing monocytes are capable of binding HIV-1 and effectively delivering virus to target cells thereby enhancing the distribution of HIV-1. Sialoadhesin could disseminate HIV-1 to viral reservoirs during monocyte immunosurveillance or migration to sites of inflammation and then facilitate HIV-1 infection of permissive cells.

  16. Barriers and facilitators to HIV and sexually transmitted infections testing for gay, bisexual, and other transgender men who have sex with men.

    Science.gov (United States)

    Scheim, Ayden I; Travers, Robb

    2017-08-01

    Transgender men who have sex with men (trans MSM) may be at elevated risk for HIV and other sexually transmitted infections (STI), and therefore require access to HIV and STI testing services. However, trans people often face stigma, discrimination, and gaps in provider competence when attempting to access health care and may therefore postpone, avoid, or be refused care. In this context, quantitative data have indicated low access to, and uptake of, HIV testing among trans MSM. The present manuscript aimed to identify trans MSM's perspectives on barriers and facilitators to HIV and STI testing. As part of a community-based research project investigating HIV risk and resilience among trans MSM, 40 trans MSM aged 18 and above and living in Ontario, Canada participated in one-on-one qualitative interviews in 2013. Participants described a number of barriers to HIV and other STI testing. These included both trans-specific and general difficulties in accessing sexual health services, lack of trans health knowledge among testing providers, limited clinical capacity to meet STI testing needs, and a perceived gap between trans-inclusive policies and their implementation in practice. Two major facilitators were identified: access to trusted and flexible testing providers, and integration of testing with ongoing monitoring for hormone therapy. Based on these findings, we provide recommendations for enhancing access to HIV and STI testing for this key population.

  17. Antibacterial Activity and Membrane-Disruptive Mechanism of 3-p-trans-Coumaroyl-2-hydroxyquinic Acid, a Novel Phenolic Compound from Pine Needles of Cedrus deodara, against Staphylococcus aureus

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    Yanping Wu

    2016-08-01

    Full Text Available Recently, we reported that a novel phenolic compound isolated from Cedrus deodara, 3-p-trans-coumaroyl-2-hydroxyquinic acid (CHQA, exhibits a potent antioxidant activity. The present study aimed to evaluate the antibacterial activity of CHQA against eleven food-borne pathogens and to elucidate its mechanism of action against Staphylococcus aureus. The results from minimum inhibitory concentration (MIC determinations showed that CHQA exhibited moderate inhibitory effects on all of the tested pathogens with MIC values ranging from 2.5–10 mg/mL. Membrane potential measurements and flow cytometric analysis demonstrated that CHQA damaged the cytoplasmic membrane of S. aureus, causing a significant membrane hyperpolarization with a loss of membrane integrity. Moreover, CHQA induced an increase in membrane fluidity and conformational changes in membrane protein of S. aureus, suggesting that CHQA probably acts on the cell membrane by interactions with membrane lipid and protein. Transmission electron microscopic observations further confirmed that CHQA disrupted the cell membrane of S. aureus and caused severe morphological changes, which even led to leakage of intracellular constituents. These findings indicated that CHQA could have the potential to serve as a natural antibacterial agent to control and prevent the growth of pathogens in food and in food-processing environments.

  18. Resilience does not explain the dissociation between chronic pain and physical activity in South Africans living with HIV

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    Antonia L. Wadley

    2016-09-01

    Full Text Available Pain burden is high in people living with HIV (PLWH, but the effect of this pain on functionality is equivocal. Resilience, the ability to cope with adversity, may promote adaptation to pain, so we hypothesised that higher resilience would correlate with less pain-related impairment of activity. We recruited 197 black South African PLWH, 99 with chronic pain (CP and 98 patients without. We measured pain intensity and interference using the Brief Pain Inventory, and resilience using the Resilience Scale. Participants were generally highly resilient. Greater resilience correlated with better health-related quality of life, but not with pain intensity or interference. We also measured physical activity objectively, by actigraphy, in a subset of patients (37 with chronic pain and 31 without chronic pain, who wore accelerometers for two weeks. There was no difference in duration or intensity of activity between those with and without pain, and activity was not associated with resilience. In this sample, pain was not associated with altered physical activity. Resilience did not explain differences in pain intensity or pain interference but was associated with improved quality of life. Financial stresses and the fear of HIV stigma may have driven patients to conceal pain and to suppress its expected impairment of activity.

  19. Starch plus sunflower oil addition to the diet of dry dairy cows results in a trans-11 to trans-10 shift of biohydrogenation.

    Science.gov (United States)

    Zened, A; Enjalbert, F; Nicot, M C; Troegeler-Meynadier, A

    2013-01-01

    Trans fatty acids (FA), exhibit different biological properties. Among them, cis-9,trans-11 conjugated linoleic acid has some interesting putative health properties, whereas trans-10,cis-12 conjugated linoleic acid has negative effects on cow milk fat production and would negatively affect human health. In high-yielding dairy cows, a shift from trans-11 to trans-10 pathway of biohydrogenation (BH) can occur in the rumen of cows receiving high-concentrate diets, especially when the diet is supplemented with unsaturated fat sources. To study this shift, 4 rumen-fistulated nonlactating Holstein cows were assigned to a 4×4 Latin square design with 4 different diets during 4 periods. Cows received 12 kg of dry matter per day of 4 diets based on corn silage during 4 successive periods: a control diet (22% starch, diet supplemented with wheat plus barley (35% starch, diet supplemented with 5% of sunflower oil (20% starch, 7.6% crude fat), and a high-starch plus sunflower oil diet (33% starch, 7.3% crude fat). Five hours after feeding, proportions of trans-11 BH isomers greatly increased in the rumen content with the addition of sunflower oil, without change in ruminal pH compared with the control diet. Addition of starch to the control diet had no effect on BH pathways but decreased ruminal pH. The addition of a large amount of starch in association with sunflower oil increased trans-10 FA at the expense of trans-11 FA in the rumen content, revealing a trans-11 to trans-10 shift. Interestingly, with this latter diet, ruminal pH did not change compared with a single addition of starch. This trans-11 to trans-10 shift occurred progressively, after a decrease in the proportion of trans-11 FA in the rumen, suggesting that this shift could result from a dysbiosis in the rumen in favor of trans-10-producing bacteria at the expense of those producing trans-11 or a modification of bacterial activities. Copyright © 2013 American Dairy Science Association. Published by Elsevier

  20. The equine herpesvirus-1 IR3 gene that lies antisense to the sole immediate-early (IE) gene is trans-activated by the IE protein, and is poorly expressed to a protein

    International Nuclear Information System (INIS)

    Ahn, Byung Chul; Breitenbach, Jonathan E.; Kim, Seong K.; O'Callaghan, Dennis J.

    2007-01-01

    The unique IR3 gene of equine herpesvirus 1 (EHV-1) is expressed as a late 1.0-kb transcript. Previous studies confirmed the IR3 transcription initiation site and tentatively identified other cis-acting elements specific to IR3 such as a TATA box, a 443 base pair 5'untranslated region (UTR), a 285 base pair open reading frame (ORF), and a poly adenylation (A) signal [Holden, V.R., Harty, R.N., Yalamanchili, R.R., O'Callaghan, D.J., 1992. The IR3 gene of equine herpesvirus type 1: a unique gene regulated by sequences within the intron of the immediate-early gene. DNA Seq. 3, 143-152]. Transient transfection assays revealed that the IR3 promoter is strongly trans-activated by the IE protein (IEP) and that coexpression of the IEP with the early EICP0 and IR4 regulatory proteins results in maximal trans-activation of the IR3 promoter. Gel shift assays revealed that the IEP directly binds to the IR3 promoter region. Western blot analysis showed that the IR3 protein produced in E. coli was detected by antibodies to IR3 synthetic peptides; however, the IR3 protein was not detected in EHV-1 infected cell extracts by these same anti-IR3 antibodies, even though the IR3 transcript was detected by northern blot. These findings suggest that the IR3 may not be expressed to a protein. Expression of an IR3/GFP fusion gene was not observed, but expression of a GFP/IR3 fusion gene was detected by fluorescent microscopy. In further attempts to detect the IR3/GFP fusion protein using anti-GFP antibody, western blot analysis showed that the IR3/GFP fusion protein was not detected in vivo. Interestingly, a truncated form of the GFP/IR3 protein was synthesized from the GFP/IR3 fusion gene. However, GFP/IR3 and IR3/GFP fusion proteins of the predicted sizes were synthesized by in vitro coupled transcription and translation of the fusion genes, suggesting poor expression of the IR3 protein in vivo. The possible role of the IR3 transcript in EHV-1 infection is discussed

  1. All-trans retinoic acid inhibits KIT activity and induces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein

    Directory of Open Access Journals (Sweden)

    Taguchi Takahiro

    2010-12-01

    Full Text Available Abstract Background Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for irresectable and metastasized gastrointestinal stromal tumor (GIST patients. Unfortunately, most patients responding to imatinib will eventually exhibit imatinib-resistance, the cause of which is not fully understood. The serious clinical problem of imatinib-resistance demands alternative therapeutic strategy. This study was conducted to investigate the effect of all-trans retinoic acid (ATRA on GIST cell lines. Methods Cell proliferation was determined by trypan blue dye exclusion test. Western blot analysis was performed to test the expression of activated KIT, its downstream proteins, and apoptosis associated proteins. The cytotoxic interactions of imatinib with ATRA were evaluated using the isobologram of Steel and Peckham. Results and conclusion In this work, for the first time we have demonstrated that ATRA affected on cell proliferation of GIST-T1 and GIST-882 cell line through inhibition of cell growth in a dose dependent manner and induced apoptosis. High dose of ATRA induced morphologic change in GIST-T1 cells, rounded-up cells, and activated the caspase-3 protein. In further examination, we found that the ATRA-induced apoptosis in GIST-T1 cells was accompanied by the down-regulated expression of survivin and up-regulated expression of Bax protein. Moreover, ATRA suppressed the activity of KIT protein in GIST-T1 cells and its downstream signal, AKT activity, but not MAPK activity. We also have demonstrated that combination of ATRA with imatinib showed additive effect by isobologram, suggesting that the combination of ATRA and imatinib may be a novel potential therapeutic option for GIST treatment. Furthermore, the scracht assay result suggested that ATRA was a potential reagent to prevent the invasion or metastasis of GIST cells.

  2. Prevalence of Metabolic Syndrome in Patients with HIV in the Era of Highly Active Antiretroviral Therapy.

    Science.gov (United States)

    Lombo, Bernardo; Alkhalil, Imran; Golden, Marjorie P; Fotjadhi, Irma; Ravi, Sreedhar; Virata, Michael; Lievano, Marta; Diez, Jose; Ghantous, Andre; Donohue, Thomas

    2015-05-01

    Since the introduction of combination antiretroviral therapy (cART) as the standard of care for HIV disease, there has been a precipitous decline in the death rate due to HIV/ AIDS. The purpose of this study was to report the prevalence of metabolic syndrome in HIV infected patients. Retrospective, cross-sectional, observational study of 259 patients with HIV infection treated with cART from an urban community hospital. Metabolic syndrome prevalence was defined using the International Diabetes Federation (IDF) and the U.S. National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Study patients were included regardless of the duration of cART. The prevalence of metabolic syndrome was 27% using IDF criteria and 26% using ATP III criteria. Logistic regression analysis found an association between treatment with the protease inhibitor darunavir and metabolic syndrome. (OR 3.32 with 95% confidence interval between 1.54 and 7.15). There is a high prevalence of metabolic syndrome and obesity in HIV patients treated with cART, especially those taking the protease inhibitor darunavir.

  3. Random Number Generation in HIV Disease: Associations with Neuropsychological Functions and Activities of Daily Living.

    Science.gov (United States)

    Sheppard, David P; Woods, Steven Paul; Doyle, Katie L; Verduzco, Marizela

    2017-02-01

    HIV is associated with frontostriatal dysregulation and executive dysfunction. This study evaluated whether HIV-infected individuals evidence deficits in random number generation (RNG), which is a strategic task requiring paced, rule-guided production of digits. In total, 74 HIV+ adults and 54 seronegative comparison participants completed a comprehensive research neuropsychological battery. Participants produced a random digit sequence by avoiding any order and using numbers 1 through 10 for 100 s at a pace of 1 digit/s. Outcomes included intrusions, repetitions, seriation (1-2-3-4), and cycling (median length of gaps between repeating digits). HIV disease was associated with higher levels of seriation and cycling (ps  .10). Among HIV+ individuals, higher seriation was associated with neuropsychological performance including poorer auditory attention, verbal learning, and delayed memory, whereas higher cycling scores were associated with poorer delayed memory and verbal fluency (ps random sequences, which showed medium associations with higher order verbal abilities and may contribute to greater declines in everyday functioning outcomes. Future studies might examine RNG's role in health behaviors such as medical decision-making or medication adherence. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Etiology of spontaneous pneumothorax in 105 HIV-infected patients without highly active antiretroviral therapy

    International Nuclear Information System (INIS)

    Rivero, Antonio; Perez-Camacho, Ines; Lozano, Fernando; Santos, Jesus; Camacho, Angela; Serrano, Ascencion; Cordero, Elisa; Jimenez, Francisco; Torres-Tortosa, Manuel; Torre-Cisneros, Julian

    2009-01-01

    Introduction: Spontaneous pneumothorax (SP) is a frequent complication in non-treated HIV-infected patients as a complication of opportunistic infections and tumours. Objective: To analyse the aetiology of SP in non-treated HIV patients. Patients and methods: Observational study of SP cases observed in a cohort of 9831 of non-treated HIV-infected patients attended in seven Spanish hospitals. Results: 105 patients (1.06%) developed SP. The aetiological cause was identified in 89 patients. The major causes identified were: bacterial pneumonia (36 subjects, 34.3%); Pneumocystis jiroveci pneumonia (PJP) (31 patients, 29.5%); and pulmonary tuberculosis (17 cases, 15.2%). The most common cause of SP in drugs users was bacterial pneumonia (40%), whereas PJP was more common (65%) in sexual transmitted HIV-patients. The most common cause of bilateral SP was PJP (62.5%) whereas unilateral SP was most commonly associated with bacterial pneumonia (40.2%). The most common cause of SP in patients with a CD4+ lymphocyte count >200 cells/ml and in patients without AIDS criteria was bacterial pneumonia. PJP was the more common cause in patients with a CD4+ lymphocyte count <200 cells/ml or with AIDS. Conclusion: The incidence of SP in non-treated HIV-infected patients was 1.06%. The aetiology was related to the patients risk practices and to their degree of immunosuppression. Bacterial pneumonia was the most common cause of SP.

  5. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... NIDA Director's Page Organization Legislative Activities Advisory Boards & ... "HIV/AIDS." HIV can be transferred between people if an infected person's blood or other bodily fluid comes in contact with ...

  6. Interleukin-7 induces HIV replication in primary naive T cells through a nuclear factor of activated T cell (NFAT)-dependent pathway

    International Nuclear Information System (INIS)

    Managlia, Elizabeth Z.; Landay, Alan; Al-Harthi, Lena

    2006-01-01

    Interleukin (IL)-7 plays several roles critical to T cell maturation, survival, and homeostasis. Because of these functions, IL-7 is under investigation as an immune-modulator for therapeutic use in lymphopenic clinical conditions, including HIV. We reported that naive T cells, typically not permissive to HIV, can be productively infected when pre-treated with IL-7. We evaluated the mechanism by which IL-7-mediates this effect. IL-7 potently up-regulated the transcriptional factor NFAT, but had no effect on NFκB. Blocking NFAT activity using a number of reagents, such as Cyclosporin A, FK-506, or the NFAT-specific inhibitor known as VIVIT peptide, all markedly reduced IL-7-mediated induction of HIV replication in naive T cells. Additional neutralization of cytokines present in IL-7-treated cultures and/or those that have NFAT-binding sequences within their promotors indicated that IL-10, IL-4, and most significantly IFNγ, all contribute to IL-7-induction of HIV productive replication in naive T cells. These data clarify the mechanism by which IL-7 can overcome the block to HIV productive infection in naive T cells, despite their quiescent cell status. These findings are relevant to the treatment of HIV disease and understanding HIV pathogenesis in the naive CD4+ T cell compartment, especially in light of the vigorous pursuit of IL-7 as an in vivo immune modulator

  7. Associations between HIV, highly active anti-retroviral therapy, and hypertensive disorders of pregnancy among maternal deaths in South Africa 2011-2013.

    Science.gov (United States)

    Sebitloane, Hannah M; Moodley, Jagidesa; Sartorius, Benn

    2017-02-01

    To explore potential relationships between HIV and highly active anti-retroviral therapy (HAART), and hypertensive disorders of pregnancy (HDP). A retrospective secondary analysis of maternal-deaths data from the 2011-2013 Saving Mothers Report from South Africa. The incidence of HIV infection amongst individuals who died owing to HDP was determined and comparisons were made based on HIV status and the use of HAART. Among 4452 maternal deaths recorded in the Saving Mothers report, a lower risk of a maternal deaths being due to HDP was observed among women who had HIV infections compared with women who did not have HIV (relative risk [RR] 0.57, 95% confidence interval [CI] 0.51-0.64). Further, reduced odds of death being due to HDP were recorded among women with AIDS not undergoing HAART compared with women with HIV who did not require treatment (RR 0.42, 95% CI 0.3-0.58). Notably, among all women with AIDS, a greater risk of death due to HDP was demonstrated among those who received HAART compared with those who did not (RR 1.15, 95% CI 1.02-1.29). HIV and AIDS were associated with a decreased risk of HDP being the primary cause of death; the use of HAART increased this risk. © 2016 International Federation of Gynecology and Obstetrics.

  8. Modeling the Effects of Vorinostat In Vivo Reveals both Transient and Delayed HIV Transcriptional Activation and Minimal Killing of Latently Infected Cells.

    Science.gov (United States)

    Ke, Ruian; Lewin, Sharon R; Elliott, Julian H; Perelson, Alan S

    2015-10-01

    Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Furthermore, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.

  9. Stimuli-sensitive thiolated hyaluronic acid based nanofibers: synthesis, preclinical safety and in vitro anti-HIV activity.

    Science.gov (United States)

    Agrahari, Vivek; Meng, Jianing; Ezoulin, Miezan Jm; Youm, Ibrahima; Dim, Daniel C; Molteni, Agostino; Hung, Wei-Ting; Christenson, Lane K; Youan, Bi-Botti C

    2016-11-01

    To develop a seminal enzyme bioresponsive, mucoadhesive nanofibers (NFs) as safe and effective nanocarriers for the prevention of HIV vaginal transmission. A novel thiolated hyaluronic acid (HA-SH) polymer was synthesized to fabricate tenofovir (TFV)-loaded electrospun NFs (HA-SH-NFs) and characterized in vitro/in vivo. A triggered drug release (87% w/w) from the engineered HA-SH-NFs (mean diameter ∼75 nm) occured within 1 h under the influence of seminal hyaluronidase enzyme. HA-SH-NFs were noncytotoxic, induced no damage on the C57BL/6 mice genital-tract and other organs. No significant CD45 cell-infiltration and changes in cytokines level in cervicovaginal tissues were observed. HA-SH-NFs significantly enhanced both TFV retention and bioavailability in vaginal tissue compared with the 1% TFV-gel. The anti-HIV activity of TFV (on pseudotyped virus followed by luciferase assay) was not adversely affected by the electrospinning process. HA-SH-NFs developed in this study could potentially serve as a safe nanotemplate for topical intravaginal delivery of HIV/AIDS microbicides.

  10. Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes

    International Nuclear Information System (INIS)

    Ketas, Thomas J.; Schader, Susan M.; Zurita, Juan; Teo, Esther; Polonis, Victoria; Lu Min; Klasse, Per Johan; Moore, John P.

    2007-01-01

    Inhibitors of viral entry are under consideration as topical microbicides to prevent HIV-1 sexual transmission. Small molecules targeting HIV-1 gp120 (BMS-378806) or CCR5 (CMPD167), and a peptide fusion inhibitor (C52L), each blocks vaginal infection of macaques by a SHIV. A microbicide, however, must be active against multiple HIV-1 variants. We therefore tested BMS-C (a BMS-378806 derivative), CMPD167, C52L and the CXCR4 ligand AMD3465, alone and in combination, against 25 primary R5, 12 X4 and 7 R5X4 isolates from subtypes A-G. At high concentrations (0.1-1 μM), the replication of most R5 isolates in human donor lymphocytes was inhibited by > 90%. At lower concentrations, double and triple combinations were more effective than individual inhibitors. Similar results were obtained with X4 viruses when AMD3465 was substituted for CMPD167. The R5X4 viruses were inhibited by combining AMD3465 with CMPD167, or by the coreceptor-independent compounds. Thus, combining entry inhibitors may improve microbicide effectiveness

  11. Prevalence of oral soft tissue lesions in HIV-infected minority children treated with highly active antiretroviral therapies.

    Science.gov (United States)

    Flanagan, M A; Barasch, A; Koenigsberg, S R; Fine, D; Houpt, M

    2000-01-01

    This project studied the prevalence of oral soft tissue disease in HIV-infected children treated with highly active antiretroviral therapy (HAART). Thirty-eight HIV-infected children participated in the study. Twenty-three of these patients were treated with HAART while 14 received exclusively reverse transcriptase inhibitors (RTI) and served as controls. The children were examined three times at approximately one-month intervals while their health history and laboratory data were abstracted from medical charts. Analyses were performed to determine differences in lesion prevalence between treatment groups as well as between lesion and no lesion groups with regard to immune differences. Thirty patients (79%) had oral lesions detected in at least one visit. There were no differences in specific lesion prevalence between HAART compared with RTI-treated children. However, a trend for more oral candidiasis in the latter group was observed. Subjects with oral soft tissue lesions had lower CD4 counts (P = 0.04) and percentage (P = 0.01) but similar viral loads when compared to patients without oral soft tissue disease. HAART does not appear to significantly affect oral soft tissue disease prevalence in HIV-infected children. Presence of lesions was associated with decreased immunity and may signal advancing disease.

  12. [Isolation, idetification and anti-HIV-1 integrase activity of culturable endophytic fungi from Tibetan medicinal plant Phlomis younghusbandii Mukerjee].

    Science.gov (United States)

    Zhang, Da-Wei; Zhao, Ming-Ming; Chen, Juan; Li, Chao; Guo, Shun-Xing

    2013-05-01

    A total of 52 endophytic fungi were isolated from roots and stems of Tibetan medicinal plant Phlomis younghusbandii Mukerjee. These fungal isolates were molecularly identified based on ITS sequnces and 28S sequences distributed to 12 genera, including Phoma, Chaetosphaeronema, Fusarium and Leptosphaeria, etc. Among them, the dominant genus was Phoma. Extracts of all strains were evaluated for anti-HIV-1 integrase activity by using soluable integrase expressed in E. coli BL21 (DE3). The results showed that seven samples from five fungal endophytes PHY-24, PHY-38, PHY-40, PHY-51, PHY-53, which belonged to genus Chaetosphaeronema, inhibited strand transfer reaction catalyzed by HIV-1 integrase with IC50 values, of 6.60, 5.20, 2.86, 7.86, 4.47, 4.56 and 3.23 microg x mL(-1) respectively. In conclusion, the endophytic fungi of Phlomis younghusbandii Mukerjee are valuable for further screening anti-HIV-1 integrase agents.

  13. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy

    NARCIS (Netherlands)

    Rodger, Alison J.; Cambiano, Valentina; Bruun, Tina; Vernazza, Pietro; Collins, Simon; van Lunzen, Jan; Corbelli, Giulio Maria; Estrada, Vicente; Geretti, Anna Maria; Beloukas, Apostolos; Asboe, David; Viciana, Pompeyo; Gutiérrez, Félix; Clotet, Bonaventura; Pradier, Christian; Gerstoft, Jan; Weber, Rainer; Westling, Katarina; Wandeler, Gilles; Prins, Jan M.; Rieger, Armin; Stoeckle, Marcel; Kümmerle, Tim; Bini, Teresa; Ammassari, Adriana; Gilson, Richard; Krznaric, Ivanka; Ristola, Matti; Zangerle, Robert; Handberg, Pia; Antela, Antonio; Allan, Sris; Phillips, Andrew N.; Lundgren, Jens; Pompeyo, V.; Trastoy, M.; Palacio, R.; Gutiérrez, F.; Masiá, M.; Padilla, S.; Robledano, C.; Clotet, B.; Coll, P.; Peña, J.; Estrada, V.; Rodrigo, M.; Santiago, E.; Rivero, A.; Antela, A.; Losada, E.

    2016-01-01

    IMPORTANCE A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. OBJECTIVE To evaluate the rate of

  14. Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy

    DEFF Research Database (Denmark)

    Rodger, Alison J; Cambiano, Valentina; Bruun, Tina

    2016-01-01

    IMPORTANCE: A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex with suppressed HIV-1 RNA viral load for both anal and vaginal sex. OBJECTIVE: To evaluate the ra...

  15. In Search of a Trans-national Climate Change Law

    International Nuclear Information System (INIS)

    Lassus Saint-Genies, Geraud de

    2016-01-01

    Private entities engagement in the battle against climate change is a well-established fact, and a source of intense and diversified normative activity. A certain type of climate rules has thus arisen, with a private origin and an international scope, as they transcend the borders of existing territories. In this context, one could wonder about the possible existence of a trans-national climate change law, as a relatively autonomous body of law, which would exist at the margins of international and national climate change law. Building on the discussions that have been conducted about the trans-national law in other areas of regulations, this study intends to provide answers about the possible existence of a trans-national climate change law

  16. HIV antibodies for treatment of HIV infection.

    Science.gov (United States)

    Margolis, David M; Koup, Richard A; Ferrari, Guido

    2017-01-01

    The bar is high to improve on current combination antiretroviral therapy (ART), now highly effective, safe, and simple. However, antibodies that bind the HIV envelope are able to uniquely target the virus as it seeks to enter new target cells, or as it is expressed from previously infected cells. Furthermore, the use of antibodies against HIV as a therapeutic may offer advantages. Antibodies can have long half-lives, and are being considered as partners for long-acting antiretrovirals for use in therapy or prevention of HIV infection. Early studies in animal models and in clinical trials suggest that such antibodies can have antiviral activity but, as with small-molecule antiretrovirals, the issues of viral escape and resistance will have to be addressed. Most promising, however, are the unique properties of anti-HIV antibodies: the potential ability to opsonize viral particles, to direct antibody-dependent cellular cytotoxicity (ADCC) against actively infected cells, and ultimately the ability to direct the clearance of HIV-infected cells by effector cells of the immune system. These distinctive activities suggest that HIV antibodies and their derivatives may play an important role in the next frontier of HIV therapeutics, the effort to develop treatments that could lead to an HIV cure. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  17. Cellular Profile and Expression of Immunologic Markers in Chronic Apical Periodontitis from HIV-infected Patients Undergoing Highly Active Antiretroviral Therapy.

    Science.gov (United States)

    Gama, Túlio Gustavo Veiga; Pires, Fabio Ramoa; Armada, Luciana; Gonçalves, Lucio Souza

    2016-06-01

    This study tested the hypothesis that the inflammatory cell profile (CD3-, CD4-, CD8-, CD20-, and CD68-positive cells) and the expression of immunologic markers (tumor necrosis factor α, interferon-γ, interleukin-6, and interleukin-18) in chronic apical periodontitis are the same between non-HIV-infected patients and HIV-infected patients undergoing highly active antiretroviral therapy (HAART). Thirty-four surgically excised chronic apical periodontitis lesions were sampled from 34 patients (17 HIV-infected and 17 non-HIV-infected). The lesions were extracted from teeth with no previous endodontic treatment. All HIV-infected patients were undergoing HAART. The specimens were submitted to histopathologic and immunohistochemical analyses by using an optical microscope. Immunoexpression was graded into 2 levels, focal to weak and moderate to strong. The χ(2), Fisher exact, and Mann-Whitney tests were used to analyze all significant differences between groups. Periapical cysts represented 70.6% and 52.9% of the lesions in the HIV-infected and non-HIV-infected groups, respectively; however, no statistically significant difference was observed (P = .481). There were no statistically significant differences between groups for the inflammatory cell profile and for any of the immunologic markers (P > .05). There are no statistically significant differences of the cellular profile and expression of immunologic markers in chronic apical periodontitis between non-HIV-infected patients and HIV-infected patients undergoing HAART. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  18. Structural Basis for the Inhibition of RNase H Activity of HIV-1 Reverse Transcriptase by RNase H Active Site-Directed Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Su, Hua-Poo; Yan, Youwei; Prasad, G. Sridhar; Smith, Robert F.; Daniels, Christopher L.; Abeywickrema, Pravien D.; Reid, John C.; Loughran, H. Marie; Kornienko, Maria; Sharma, Sujata; Grobler, Jay A.; Xu, Bei; Sardana, Vinod; Allison, Timothy J.; Williams, Peter D.; Darke, Paul L.; Hazuda, Daria J.; Munshi, Sanjeev (Merck)

    2010-09-02

    HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.

  19. Mutation in cyclophilin B that causes hyperelastosis cutis in American Quarter Horse does not affect peptidylprolyl cis-trans isomerase activity but shows altered cyclophilin B-protein interactions and affects collagen folding.

    Science.gov (United States)

    Ishikawa, Yoshihiro; Vranka, Janice A; Boudko, Sergei P; Pokidysheva, Elena; Mizuno, Kazunori; Zientek, Keith; Keene, Douglas R; Rashmir-Raven, Ann M; Nagata, Kazuhiro; Winand, Nena J; Bächinger, Hans Peter

    2012-06-22

    The rate-limiting step of folding of the collagen triple helix is catalyzed by cyclophilin B (CypB). The G6R mutation in cyclophilin B found in the American Quarter Horse leads to autosomal recessive hyperelastosis cutis, also known as hereditary equine regional dermal asthenia. The mutant protein shows small structural changes in the region of the mutation at the side opposite the catalytic domain of CypB. The peptidylprolyl cis-trans isomerase activity of the mutant CypB is normal when analyzed in vitro. However, the biosynthesis of type I collagen in affected horse fibroblasts shows a delay in folding and secretion and a decrease in hydroxylysine and glucosyl-galactosyl hydroxylysine. This leads to changes in the structure of collagen fibrils in tendon, similar to those observed in P3H1 null mice. In contrast to cyclophilin B null mice, where little 3-hydroxylation was found in type I collagen, 3-hydroxylation of type I collagen in affected horses is normal. The mutation disrupts the interaction of cyclophilin B with the P-domain of calreticulin, with lysyl hydroxylase 1, and probably other proteins, such as the formation of the P3H1·CypB·cartilage-associated protein complex, resulting in less effective catalysis of the rate-limiting step in collagen folding in the rough endoplasmic reticulum.

  20. Mutation in Cyclophilin B That Causes Hyperelastosis Cutis in American Quarter Horse Does Not Affect Peptidylprolyl cis-trans Isomerase Activity but Shows Altered Cyclophilin B-Protein Interactions and Affects Collagen Folding*

    Science.gov (United States)

    Ishikawa, Yoshihiro; Vranka, Janice A.; Boudko, Sergei P.; Pokidysheva, Elena; Mizuno, Kazunori; Zientek, Keith; Keene, Douglas R.; Rashmir-Raven, Ann M.; Nagata, Kazuhiro; Winand, Nena J.; Bächinger, Hans Peter

    2012-01-01

    The rate-limiting step of folding of the collagen triple helix is catalyzed by cyclophilin B (CypB). The G6R mutation in cyclophilin B found in the American Quarter Horse leads to autosomal recessive hyperelastosis cutis, also known as hereditary equine regional dermal asthenia. The mutant protein shows small structural changes in the region of the mutation at the side opposite the catalytic domain of CypB. The peptidylprolyl cis-trans isomerase activity of the mutant CypB is normal when analyzed in vitro. However, the biosynthesis of type I collagen in affected horse fibroblasts shows a delay in folding and secretion and a decrease in hydroxylysine and glucosyl-galactosyl hydroxylysine. This leads to changes in the structure of collagen fibrils in tendon, similar to those observed in P3H1 null mice. In contrast to cyclophilin B null mice, where little 3-hydroxylation was found in type I collagen, 3-hydroxylation of type I collagen in affected horses is normal. The mutation disrupts the interaction of cyclophilin B with the P-domain of calreticulin, with lysyl hydroxylase 1, and probably other proteins, such as the formation of the P3H1·CypB·cartilage-associated protein complex, resulting in less effective catalysis of the rate-limiting step in collagen folding in the rough endoplasmic reticulum. PMID:22556420

  1. A Clinical Algorithm to Identify HIV Patients at High Risk for Incident Active Tuberculosis: A Prospective 5-Year Cohort Study.

    Directory of Open Access Journals (Sweden)

    Susan Shin-Jung Lee

    Full Text Available Predicting the risk of tuberculosis (TB in people living with HIV (PLHIV using a single test is currently not possible. We aimed to develop and validate a clinical algorithm, using baseline CD4 cell counts, HIV viral load (pVL, and interferon-gamma release assay (IGRA, to identify PLHIV who are at high risk for incident active TB in low-to-moderate TB burden settings where highly active antiretroviral therapy (HAART is routinely provided.A prospective, 5-year, cohort study of adult PLHIV was conducted from 2006 to 2012 in two hospitals in Taiwan. HAART was initiated based on contemporary guidelines (CD4 count < = 350/μL. Cox regression was used to identify the predictors of active TB and to construct the algorithm. The validation cohorts included 1455 HIV-infected individuals from previous published studies. Area under the receiver operating characteristic (ROC curve was calculated.Seventeen of 772 participants developed active TB during a median follow-up period of 5.21 years. Baseline CD4 < 350/μL or pVL ≥ 100,000/mL was a predictor of active TB (adjusted HR 4.87, 95% CI 1.49-15.90, P = 0.009. A positive baseline IGRA predicted TB in patients with baseline CD4 ≥ 350/μL and pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52-24.40, P = 0.01. Compared with an IGRA-alone strategy, the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5% to 99.2%. Compared with an untargeted strategy, the algorithm spared 468 (60.6% from unnecessary TB preventive treatment. Area under the ROC curve was 0.692 (95% CI: 0.587-0.798 for the study cohort and 0.792 (95% CI: 0.776-0.808 and 0.766 in the 2 validation cohorts.A validated algorithm incorporating the baseline CD4 cell count, HIV viral load, and IGRA status can be used to guide targeted TB preventive treatment in PLHIV in low-to-moderate TB burden settings where HAART is routinely provided to all PLHIV. The implementation of this algorithm will avoid unnecessary

  2. TransForm: TransAlta 2000 annual report

    International Nuclear Information System (INIS)