WorldWideScience

Sample records for early hiv-1 infection

  1. HIV-1/HSV-2 co-infected adults in early HIV-1 infection have elevated CD4+ T cell counts.

    Directory of Open Access Journals (Sweden)

    Jason D Barbour

    Full Text Available INTRODUCTION: HIV-1 is often acquired in the presence of pre-existing co-infections, such as Herpes Simplex Virus 2 (HSV-2. We examined the impact of HSV-2 status at the time of HIV-1 acquisition for its impact on subsequent clinical course, and total CD4+ T cell phenotypes. METHODS: We assessed the relationship of HSV-1/HSV-2 co-infection status on CD4+ T cell counts and HIV-1 RNA levels over time prior in a cohort of 186 treatment naïve adults identified during early HIV-1 infection. We assessed the activation and differentiation state of total CD4+ T cells at study entry by HSV-2 status. RESULTS: Of 186 recently HIV-1 infected persons, 101 (54% were sero-positive for HSV-2. There was no difference in initial CD8+ T cell count, or differences between the groups for age, gender, or race based on HSV-2 status. Persons with HIV-1/HSV-2 co-infection sustained higher CD4+ T cell counts over time (+69 cells/ul greater (SD = 33.7, p = 0.04 than those with HIV-1 infection alone (Figure 1, after adjustment for HIV-1 RNA levels (-57 cells per 1 log(10 higher HIV-1 RNA, p<0.0001. We did not observe a relationship between HSV-2 infection status with plasma HIV-1 RNA levels over time. HSV-2 acquisition after HIV-1 acquisition had no impact on CD4+ count or viral load. We did not detect differences in CD4+ T cell activation or differentiation state by HSV-2+ status. DISCUSSION: We observed no effect of HSV-2 status on viral load. However, we did observe that treatment naïve, recently HIV-1 infected adults co-infected with HSV-2+ at the time of HIV-1 acquisition had higher CD4+ T cell counts over time. If verified in other cohorts, this result poses a striking paradox, and its public health implications are not immediately clear.

  2. HIV-1 infection of in vitro cultured human monocytes: early events and influence of anti HIV-1 antibodies

    DEFF Research Database (Denmark)

    Arendrup, M; Olofsson, S; Nielsen, Jens Ole;

    1994-01-01

    To characterize the role of the humoral immune response on HIV-1 infection of monocytes and macrophages (M phi s) we examined the susceptibility of in vitro cultured monocyte/M phi s to various HIV-1 isolates and the influence of heterologous and particularly autologous anti HIV-1 sera on this in...

  3. The development and utility of a clinical algorithm to predict early HIV-1 infection.

    Science.gov (United States)

    Sharghi, Neda; Bosch, Ronald J; Mayer, Kenneth; Essex, Max; Seage, George R

    2005-12-01

    The association between self-reported clinical factors and recent HIV-1 seroconversion was evaluated in a prospective cohort of 4652 high-risk participants in the HIV Network for Prevention Trials (HIVNET) Vaccine Preparedness Study. Eighty-six individuals seroconverted, with an overall annual seroconversion rate of 1.3 per 100 person-years. Four self-reported clinical factors were significantly associated with HIV-1 seroconversion in multivariate analyses: recent history of chlamydia infection or gonorrhea, recent fever or night sweats, belief of recent HIV exposure, and recent illness lasting > or =3 days. Two scoring systems, based on the presence of either 4 or 11 clinical factors, were developed. Sensitivity ranged from 2.3% (with a positive predictive value of 12.5%) to 72.1% (with a positive predictive value of 1%). Seroconversion rates were directly associated with the number of these clinical factors. The use of scoring systems comprised of clinical factors may aid in detecting early and acute HIV-1 infection in vaccine and microbicide trials. Organizers can educate high-risk trial participants to return for testing during interim visits if they develop these clinical factors. Studying individuals during early and acute HIV-1 infection would allow scientists to investigate the impact of the intervention being studied on early transmission or pathogenesis of HIV-1 infection.

  4. HIV-1 infection of in vitro cultured human monocytes: early events and influence of anti HIV-1 antibodies

    DEFF Research Database (Denmark)

    Arendrup, M; Olofsson, S; Nielsen, Jens Ole;

    1994-01-01

    on this infection. Depending on the period of in vitro cultivation and the virus isolate used different patterns of susceptibility were detected. One week old monocyte/M phi s were highly susceptible to HIV-1 infection, in contrast to monocyte/M phi s cultured 4 weeks. The infection by virus isolated immediately...... to CD4 and that post binding events may be common to the infection of lymphocytes. Anti HIV-1 sera showed neutralizing activity against heterologous and even autologous escape virus. This finding, together with the observation that monocytes and M phi s are infected in vivo, suggests that protection...

  5. Leukotrienes inhibit early stages of HIV-1 infection in monocyte-derived microglia-like cells

    Directory of Open Access Journals (Sweden)

    Bertin Jonathan

    2012-03-01

    Full Text Available Abstract Background Microglia are one of the main cell types to be productively infected by HIV-1 in the central nervous system (CNS. Leukotriene B4 (LTB4 and cysteinyl-leukotrienes such as LTC4 are some of the proinflammatory molecules produced in infected individuals that contribute to neuroinflammation. We therefore sought to investigate the role of leukotrienes (LTs in HIV-1 infection of microglial cells. Methods To evaluate the role of LTs on HIV-1 infection in the CNS, monocyte-derived microglial-like cells (MDMis were utilized in this study. Leukotriene-treated MDMis were infected with either fully replicative brain-derived HIV-1 isolates (YU2 or R5-tropic luciferase-encoding particles in order to assess viral production and expression. The efficacy of various steps of the replication cycle was evaluated by means of p24 quantification by ELISA, luciferase activity determination and quantitative real-time polymerase chain reaction (RT-PCR. Results We report in this study that virus replication is reduced upon treatment of MDMis with LTB4 and LTC4. Additional experiments indicate that these proinflammatory molecules alter the pH-independent entry and early post-fusion events of the viral life cycle. Indeed, LT treatment induced a diminution in integrated proviral DNA while reverse-transcribed viral products remained unaffected. Furthermore, decreased C-C chemokine receptor type 5 (CCR5 surface expression was observed in LT-treated MDMis. Finally, the effect of LTs on HIV-1 infection in MDMis appears to be mediated partly via a signal transduction pathway involving protein kinase C. Conclusions These data show for the first time that LTs influence microglial cell infection by HIV-1, and may be a factor in the control of viral load in the CNS.

  6. Leukotrienes inhibit early stages of HIV-1 infection in monocyte-derived microglia-like cells.

    Science.gov (United States)

    Bertin, Jonathan; Barat, Corinne; Bélanger, Dave; Tremblay, Michel J

    2012-03-16

    Microglia are one of the main cell types to be productively infected by HIV-1 in the central nervous system (CNS). Leukotriene B4 (LTB4) and cysteinyl-leukotrienes such as LTC4 are some of the proinflammatory molecules produced in infected individuals that contribute to neuroinflammation. We therefore sought to investigate the role of leukotrienes (LTs) in HIV-1 infection of microglial cells. To evaluate the role of LTs on HIV-1 infection in the CNS, monocyte-derived microglial-like cells (MDMis) were utilized in this study. Leukotriene-treated MDMis were infected with either fully replicative brain-derived HIV-1 isolates (YU2) or R5-tropic luciferase-encoding particles in order to assess viral production and expression. The efficacy of various steps of the replication cycle was evaluated by means of p24 quantification by ELISA, luciferase activity determination and quantitative real-time polymerase chain reaction (RT-PCR). We report in this study that virus replication is reduced upon treatment of MDMis with LTB4 and LTC4. Additional experiments indicate that these proinflammatory molecules alter the pH-independent entry and early post-fusion events of the viral life cycle. Indeed, LT treatment induced a diminution in integrated proviral DNA while reverse-transcribed viral products remained unaffected. Furthermore, decreased C-C chemokine receptor type 5 (CCR5) surface expression was observed in LT-treated MDMis. Finally, the effect of LTs on HIV-1 infection in MDMis appears to be mediated partly via a signal transduction pathway involving protein kinase C. These data show for the first time that LTs influence microglial cell infection by HIV-1, and may be a factor in the control of viral load in the CNS.

  7. Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection.

    Science.gov (United States)

    Plana, M; García, F; Gallart, T; Tortajada, C; Soriano, A; Palou, E; Maleno, M J; Barceló, J J; Vidal, C; Cruceta, A; Miró, J M; Gatell, J M

    2000-09-08

    To assess whether an almost complete restoration of immune system can be achieved when antiretroviral therapy is initiated at very early stages of asymptomatic chronic HIV-1 infection. T cell subsets and cell-mediated responses were analysed at baseline and after 12 months of either a double or a triple antiretroviral therapy in 26 asymptomatic HIV-1-infected patients with CD4 T cell counts > 500 x 10(6) cells/l and a baseline plasma viral load > 10000 copies/ml. Triple therapy was significantly more effective in reducing plasma HIV RNA to undetectable levels, in returning CD4:CD8 ratio to nearly normal levels, in reducing activated cells (CD38) and in increasing naive (CD45RA+CD45RO-) and memory (CD45RA-CD45RO+) CD4 cells. Both double and triple therapies caused a clear decrease in memory (CD45RA-CD45RO+) CD8 cells as well as a significant increase in the CD28 subset of CD8 cells. At baseline, there was an important increase in cells producing interferon-gamma (IFNgamma) with no significant abnormalities in T lymphocytes producing interleukin 2 (IL-2), tumour necrosis factor alpha and interleukin 4. Both types of therapy reduced IFNgamma- and IL2-producing CD4 T lymphocytes while IFNgamma-producing CD8 cells remained increased. Even before therapy, these HIV-1-positive patients lacked significant abnormalities in the T cell responsiveness to polyclonal stimuli as well as in the secretion of CCR5 chemokines by peripheral blood mononuclear cells. Initiating highly active antiretroviral therapy at very early stages of chronic HIV-1 infection allows rapid and almost complete normalization of T cell subsets and preservation of T cell functions. These early-treated patients could be excellent candidates for receiving additional HIV-specific immune-based therapies, which might be essential for the control of HIV infection.

  8. 急性期/早期HIV-1感染的临床研究进展%Clinical research progress of acute and early HIV-1 infection

    Institute of Scientific and Technical Information of China (English)

    吴焱; 徐克沂; 王玉光; 李兴旺

    2011-01-01

    Primary HIV-1 infection (PHI) includes acute HIV-1 infection (AHI)and early HIV-1 infection (EHI). AHI is often associated with an acute "retroviral syndrome" that usually includes fever with a variety of nonspecific clinical and laboratory abnormalities. Critical point of AHI and EHI is HIV-1 antibody seroconversion. Cut-off point of PHI and following chronic phage is whether HIV-1 RNA decrease to the set point. Early diagnosis depends on HIV RNA and P24 antigen tests. About 50% of new sexual transmission happens while a person is in this primary phase of infection. HIV pandemic could be slowed down by early diagnosis and immediate antiretroviral therapy intervention. Several studies have suggested that treatment of AHI allows long-term viral suppression and might lead to preservation and even increase of HIV-1 specific T helper cell responses. However, there are no sufficient data available to support the clinical benefit of early initiation of antiretroviral therapy and to address the risks of antiretroviral therapy and treatment interruptions.%原发Ⅰ型艾滋病病毒(HIV-1)感染(PHI)包括急性期感染(AHI)和早期感染(EHI).AHI通常与急性的"反转录病毒综合征"有关,包括一系列非特异的症状和实验室检测异常.AHI和EHI的分界点在于HIV抗体的阳转,而PHI和其后的慢性感染阶段的临界点在于体内何时达到HIV-1的调定点.早期诊断有赖于检测HIV-1RNA和P24抗原.大约50%经性传染HIV发生在急性期阶段,对急性期/早期感染者尽早诊断并给予抗病毒治疗,能明显减少HIV的传播.一些研究显示,早期抗病毒治疗能够使病毒得以长期抑制,并能保持甚至增加HIV-1特异性T细胞免疫应答,但早期治疗和治疗中断的临床益处还没有足够数据支持.

  9. Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection

    Science.gov (United States)

    Altfeld, Marcus; Rosenberg, Eric S.; Shankarappa, Raj; Mukherjee, Joia S.; Hecht, Frederick M.; Eldridge, Robert L.; Addo, Marylyn M.; Poon, Samuel H.; Phillips, Mary N.; Robbins, Gregory K.; Sax, Paul E.; Boswell, Steve; Kahn, James O.; Brander, Christian; Goulder, Philip J.R.; Levy, Jay A.; Mullins, James I.; Walker, Bruce D.

    2001-01-01

    Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection. PMID:11148221

  10. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Saurabh Mehandru

    2006-12-01

    Full Text Available BACKGROUND: During acute and early HIV-1 infection (AEI, up to 60% of CD4(+ T cells in the lamina propria of the lower gastrointestinal (GI tract are lost as early as 2-4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART is well established. However, the extent of immune reconstitution in the GI tract is unknown. METHODS AND FINDINGS: Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1-7 y of uninterrupted therapy. Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%-60% depletion of lamina propria lymphocytes despite 1-7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO+ HLA-DR+, returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4+ T cell depletion despite therapy. Rare HIV-1 RNA-expressing cells were detected by in situ hybridization. CONCLUSIONS: Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T

  11. Male reproduction and HIV-1 infection

    NARCIS (Netherlands)

    E. van Leeuwen

    2009-01-01

    From its initial presentation in the early nineteen eighties until 1996, HIV-1 infection almost inevitably led to AIDS, which was a death sentence. Because of the short life expectancy, patients were advised against pregnancy. The improved prognosis of patients with HIV-1 infection following the int

  12. Extensive complement-dependent enhancement of HIV-1 by autologous non-neutralising antibodies at early stages of infection

    Directory of Open Access Journals (Sweden)

    Williams Ian

    2011-03-01

    Full Text Available Abstract Background Non-neutralising antibodies to the envelope glycoprotein are elicited during acute HIV-1 infection and are abundant throughout the course of disease progression. Although these antibodies appear to have negligible effects on HIV-1 infection when assayed in standard neutralisation assays, they have the potential to exert either inhibitory or enhancing effects through interactions with complement and/or Fc receptors. Here we report that non-neutralising antibodies produced early in response to HIV-1 infection can enhance viral infectivity. Results We investigated this complement-mediated antibody-dependent enhancement (C'-ADE of early HIV infection by carrying out longitudinal studies with primary viruses and autologous sera derived sequentially from recently infected individuals, using a T cell line naturally expressing the complement receptor 2 (CR2; CD21. The C'-ADE was consistently observed and in some cases achieved infection-enhancing levels of greater than 350-fold, converting a low-level infection to a highly destructive one. C'-ADE activity declined as a neutralising response to the early virus emerged, but later virus isolates that had escaped the neutralising response demonstrated an increased capacity for enhanced infection by autologous antibodies. Moreover, sera with autologous enhancing activity were capable of C'ADE of heterologous viral isolates, suggesting the targeting of conserved epitopes on the envelope glycoprotein. Ectopic expression of CR2 on cell lines expressing HIV-1 receptors was sufficient to render them sensitive to C'ADE. Conclusions Taken together, these results suggest that non-neutralising antibodies to the HIV-1 envelope that arise during acute infection are not 'passive', but in concert with complement and complement receptors may have consequences for HIV-1 dissemination and pathogenesis.

  13. Extensive complement-dependent enhancement of HIV-1 by autologous non-neutralising antibodies at early stages of infection.

    Science.gov (United States)

    Willey, Suzanne; Aasa-Chapman, Marlén M I; O'Farrell, Stephen; Pellegrino, Pierre; Williams, Ian; Weiss, Robin A; Neil, Stuart J D

    2011-03-14

    Non-neutralising antibodies to the envelope glycoprotein are elicited during acute HIV-1 infection and are abundant throughout the course of disease progression. Although these antibodies appear to have negligible effects on HIV-1 infection when assayed in standard neutralisation assays, they have the potential to exert either inhibitory or enhancing effects through interactions with complement and/or Fc receptors. Here we report that non-neutralising antibodies produced early in response to HIV-1 infection can enhance viral infectivity. We investigated this complement-mediated antibody-dependent enhancement (C'-ADE) of early HIV infection by carrying out longitudinal studies with primary viruses and autologous sera derived sequentially from recently infected individuals, using a T cell line naturally expressing the complement receptor 2 (CR2; CD21). The C'-ADE was consistently observed and in some cases achieved infection-enhancing levels of greater than 350-fold, converting a low-level infection to a highly destructive one. C'-ADE activity declined as a neutralising response to the early virus emerged, but later virus isolates that had escaped the neutralising response demonstrated an increased capacity for enhanced infection by autologous antibodies. Moreover, sera with autologous enhancing activity were capable of C'ADE of heterologous viral isolates, suggesting the targeting of conserved epitopes on the envelope glycoprotein. Ectopic expression of CR2 on cell lines expressing HIV-1 receptors was sufficient to render them sensitive to C'ADE. Taken together, these results suggest that non-neutralising antibodies to the HIV-1 envelope that arise during acute infection are not 'passive', but in concert with complement and complement receptors may have consequences for HIV-1 dissemination and pathogenesis.

  14. Epigenetic modulations in activated cells early after HIV-1 infection and their possible functional consequences.

    Directory of Open Access Journals (Sweden)

    Juliana T Maricato

    Full Text Available Epigenetic modifications refer to a number of biological processes which alter the structure of chromatin and its transcriptional activity such as DNA methylation and histone post-translational processing. Studies have tried to elucidate how the viral genome and its products are affected by epigenetic modifications imposed by cell machinery and how it affects the ability of the virus to either, replicate and produce a viable progeny or be driven to latency. The purpose of this study was to evaluate epigenetic modifications in PBMCs and CD4+ cells after HIV-1 infection analyzing three approaches: (i global DNA- methylation; (ii qPCR array and (iii western blot. HIV-1 infection led to methylation increases in the cellular DNA regardless the activation status of PBMCs. The analysis of H3K9me3 and H3K27me3 suggested a trend towards transcriptional repression in activated cells after HIV-1 infection. Using a qPCR array, we detected genes related to epigenetic processes highly modulated in activated HIV-1 infected cells. SETDB2 and RSK2 transcripts showed highest up-regulation levels. SETDB2 signaling is related to transcriptional silencing while RSK2 is related to either silencing or activation of gene expression depending on the signaling pathway triggered down-stream. In addition, activated cells infected by HIV-1 showed lower CD69 expression and a decrease of IL-2, IFN-γ and metabolism-related factors transcripts indicating a possible functional consequence towards global transcriptional repression found in HIV-1 infected cells. Conversely, based on epigenetic markers studied here, non-stimulated cells infected by HIV-1, showed signs of global transcriptional activation. Our results suggest that HIV-1 infection exerts epigenetic modulations in activated cells that may lead these cells to transcriptional repression with important functional consequences. Moreover, non-stimulated cells seem to increase gene transcription after HIV-1 infection

  15. Identifying HIV-1 dual infections

    Directory of Open Access Journals (Sweden)

    Cornelissen Marion

    2007-09-01

    Full Text Available Abstract Transmission of human immunodeficiency virus (HIV is no exception to the phenomenon that a second, productive infection with another strain of the same virus is feasible. Experiments with RNA viruses have suggested that both coinfections (simultaneous infection with two strains of a virus and superinfections (second infection after a specific immune response to the first infecting strain has developed can result in increased fitness of the viral population. Concerns about dual infections with HIV are increasing. First, the frequent detection of superinfections seems to indicate that it will be difficult to develop a prophylactic vaccine. Second, HIV-1 superinfections have been associated with accelerated disease progression, although this is not true for all persons. In fact, superinfections have even been detected in persons controlling their HIV infections without antiretroviral therapy. Third, dual infections can give rise to recombinant viruses, which are increasingly found in the HIV-1 epidemic. Recombinants could have increased fitness over the parental strains, as in vitro models suggest, and could exhibit increased pathogenicity. Multiple drug resistant (MDR strains could recombine to produce a pan-resistant, transmittable virus. We will describe in this review what is presently known about super- and re-infection among ambient viral infections, as well as the first cases of HIV-1 superinfection, including HIV-1 triple infections. The clinical implications, the impact of the immune system, and the effect of anti-retroviral therapy will be covered, as will as the timing of HIV superinfection. The methods used to detect HIV-1 dual infections will be discussed in detail. To increase the likelihood of detecting a dual HIV-1 infection, pre-selection of patients can be done by serotyping, heteroduplex mobility assays (HMA, counting the degenerate base codes in the HIV-1 genotyping sequence, or surveying unexpected increases in the

  16. A Case of Seronegative HIV-1 Infection

    OpenAIRE

    Spivak, Adam M; Brennan, Tim; O'Connell, Karen; Sydnor, Emily; Thomas M Williams; Robert F. Siliciano; Gallant, Joel E.; Blankson, Joel N.

    2010-01-01

    Patients infected with HIV-1 typically seroconvert within weeks of primary infection. In rare cases, patients do not develop antibodies against HIV-1 despite demonstrable infection. We describe an HLA-B*5802 positive individual who presented with AIDS despite repeatedly negative HIV-1 antibody screening tests. Phylogenetic analysis of env clones revealed little sequence diversity, and weak HIV-1 specific CD8+ T cell responses were present to Gag epitopes. The patient seroconverted after immun...

  17. Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection.

    Directory of Open Access Journals (Sweden)

    Matthew R Henn

    Full Text Available Deep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more

  18. Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections.

    Directory of Open Access Journals (Sweden)

    S Gnanakaran

    2011-09-01

    Full Text Available Here we have identified HIV-1 B clade Envelope (Env amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413-415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.

  19. Dysfunctional phenotypes of CD4+ and CD8+ T cells are comparable in patients initiating ART during early or chronic HIV-1 infection.

    Science.gov (United States)

    Amu, Sylvie; Lantto Graham, Rebecka; Bekele, Yonas; Nasi, Aikaterini; Bengtsson, Carina; Rethi, Bence; Sorial, Sam; Meini, Genny; Zazzi, Maurizio; Hejdeman, Bo; Chiodi, Francesca

    2016-06-01

    Early initiation of antiretroviral therapy (ART) is becoming a common clinical practice according to current guidelines recommending treatment to all HIV-1-infected patients. However, it is not known whether ART initiated during the early phase of infection prevents the establishment of abnormal phenotypic features previously reported in CD4+ and CD8+T cells during chronic HIV-1 infection. In this cross-sectional study, blood specimens were obtained from 17 HIV-1-infected patients who began ART treatment shortly after infection (early ART [EA]), 17 age-matched HIV-1-infected patients who started ART during chronic phase of infection (late ART [LA]), and 25 age-matched non-HIV-1-infected controls. At collection of specimens, patients in EA and LA groups had received ART for comparable periods of time. Total HIV-1 DNA was measured in white blood cells by quantitative PCR. The concentration of 9 inflammatory parameters and 1 marker of fibrosis, including sCD14 and β-2 microglobulin, was measured in plasma. Furthermore, expression of markers of abnormal immune activation (human leukocyte antigen - antigen D related [HLA-DR] and CD38), exhaustion (programmed death 1, CD28, CD57) and terminal differentiation (CD127) was measured on CD4+ and CD8+T cells. T-cell proliferation was measured through Ki67 expression. The copies of total HIV-1 DNA in blood were significantly lower (P = 0.009) in EA compared with that in LA group. Only the expression of HLA-DR on naïve CD4+ T cells distinguished EA from LA, whereas expression of 3 surface markers distinguished T-cell populations of HIV-1-infected patients from controls. These included HLA-DR distinguishing CD4+ T cells from EA compared with controls, and also CD38 and CD127 on CD4+ and CD8+ T cells, respectively, distinguishing both groups of patients from controls. The sCD14 levels were significantly higher in EA patients, and β-2 microglobulin levels were higher in LA group compared with that in controls. Our results

  20. NKT cells in HIV-1 infection

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Natural killer T (NKT) cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-I infection and their recovery under highly active antiretrovirai treatment (HAART). Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV's disruption of NKT activation by downregulating CDId expression on antigen presentation cells (APC). HIV-1 protein Nefis found to play the major role by interrupting the intraceilular trafficking of nascent and recycling CDId molecules.

  1. Identification of low molecular weight nuclear complexes containing integrase during the early stages of HIV-1 infection.

    Science.gov (United States)

    Gérard, Annabelle; Soler, Nicolas; Ségéral, Emmanuel; Belshan, Michael; Emiliani, Stéphane

    2013-02-01

    HIV-1 replication requires integration of its reverse transcribed viral cDNA into a host cell chromosome. The DNA cutting and joining reactions associated to this key step are catalyzed by the viral protein integrase (IN). In infected cells, IN binds the viral cDNA, together with viral and cellular proteins, to form large nucleoprotein complexes. However, the dynamics of IN complexes formation is still poorly understood. Here, we characterized IN complexes during the early stages of T-lymphocyte infection. We found that following viral entry into the host cell, IN was rapidly targeted to proteasome-mediated degradation. Interactions between IN and cellular cofactors LEDGF/p75 and TNPO3 were detected as early as 6 h post-infection. Size exclusion chromatography of infected cell extracts revealed distinct IN complexes in vivo. While at 2 h post-infection the majority of IN eluted within a high molecular weight complex competent for integration (IN complex I), IN was also detected in a low molecular weight complex devoid of full-length viral cDNA (IN complex II, ~440 KDa). At 6 h post-infection the relative proportion of IN complex II increased. Inhibition of reverse transcription or integration did not alter the elution profile of IN complex II in infected cells. However, in cells depleted for LEDGF/p75 IN complex II shifted to a lower molecular weight complex (IN complex III, ~150 KDa) containing multimers of IN. Notably, cell fractionation experiments indicated that both IN complex II and III were exclusively nuclear. Finally, IN complex II was not detected in cells infected with a virus harboring a mutated IN defective for LEDGF/p75 interaction and tetramerization. Our findings indicate that, shortly after viral entry, a significant portion of DNA-free IN that is distinct from active pre-integration complexes accumulates in the nucleus.

  2. Identification of low molecular weight nuclear complexes containing integrase during the early stages of HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Gérard Annabelle

    2013-02-01

    Full Text Available Abstract Background HIV-1 replication requires integration of its reverse transcribed viral cDNA into a host cell chromosome. The DNA cutting and joining reactions associated to this key step are catalyzed by the viral protein integrase (IN. In infected cells, IN binds the viral cDNA, together with viral and cellular proteins, to form large nucleoprotein complexes. However, the dynamics of IN complexes formation is still poorly understood. Results Here, we characterized IN complexes during the early stages of T-lymphocyte infection. We found that following viral entry into the host cell, IN was rapidly targeted to proteasome-mediated degradation. Interactions between IN and cellular cofactors LEDGF/p75 and TNPO3 were detected as early as 6 h post-infection. Size exclusion chromatography of infected cell extracts revealed distinct IN complexes in vivo. While at 2 h post-infection the majority of IN eluted within a high molecular weight complex competent for integration (IN complex I, IN was also detected in a low molecular weight complex devoid of full-length viral cDNA (IN complex II, ~440 KDa. At 6 h post-infection the relative proportion of IN complex II increased. Inhibition of reverse transcription or integration did not alter the elution profile of IN complex II in infected cells. However, in cells depleted for LEDGF/p75 IN complex II shifted to a lower molecular weight complex (IN complex III, ~150 KDa containing multimers of IN. Notably, cell fractionation experiments indicated that both IN complex II and III were exclusively nuclear. Finally, IN complex II was not detected in cells infected with a virus harboring a mutated IN defective for LEDGF/p75 interaction and tetramerization. Conclusions Our findings indicate that, shortly after viral entry, a significant portion of DNA–free IN that is distinct from active pre-integration complexes accumulates in the nucleus.

  3. Gene Knockout Shows That PML (TRIM19) Does Not Restrict the Early Stages of HIV-1 Infection in Human Cell Lines.

    Science.gov (United States)

    Masroori, Nasser; Cherry, Pearl; Merindol, Natacha; Li, Jia-Xin; Dufour, Caroline; Poulain, Lina; Plourde, Mélodie B; Berthoux, Lionel

    2017-01-01

    The PML (promyelocytic leukemia) protein is a member of the TRIM family, a large group of proteins that show high diversity in functions but possess a common tripartite motif giving the family its name. We and others recently reported that both murine PML (mPML) and human PML (hPML) strongly restrict the early stages of infection by HIV-1 and other lentiviruses when expressed in mouse embryonic fibroblasts (MEFs). This restriction activity was found to contribute to the type I interferon (IFN-I)-mediated inhibition of HIV-1 in MEFs. Additionally, PML caused transcriptional repression of the HIV-1 promoter in MEFs. In contrast, the modulation of the early stages of HIV-1 infection of human cells by PML has been investigated by RNA interference, with unclear results. In order to conclusively determine whether PML restricts HIV-1 or not in human cells, we used the clustered regularly interspaced short palindromic repeat with Cas9 (CRISPR-Cas9) system to knock out its gene in epithelial, lymphoid, and monocytic human cell lines. Infection challenges showed that PML knockout had no effect on the permissiveness of these cells to HIV-1 infection. IFN-I treatments inhibited HIV-1 equally whether PML was expressed or not. Overexpression of individual hPML isoforms, or of mPML, in a human T cell line did not restrict HIV-1. The presence of PML was not required for the restriction of nonhuman retroviruses by TRIM5α (another human TRIM protein), and TRIM5α was inhibited by arsenic trioxide through a PML-independent mechanism. We conclude that PML is not a restriction factor for HIV-1 in human cell lines representing diverse lineages. IMPORTANCE PML is involved in innate immune mechanisms against both DNA and RNA viruses. Although the mechanism by which PML inhibits highly divergent viruses is unclear, it was recently found that it can increase the transcription of interferon-stimulated genes (ISGs). However, whether human PML inhibits HIV-1 has been debated. Here we provide

  4. Early preservation of CXCR5+ PD-1+ helper T cells and B cell activation predict the breadth of neutralizing antibody responses in chronic HIV-1 infection.

    Science.gov (United States)

    Cohen, Kristen; Altfeld, Marcus; Alter, Galit; Stamatatos, Leonidas

    2014-11-01

    Much is known about the characteristics of broadly neutralizing antibodies (bNAbs) generated during HIV-1 infection, but little is known about immunological mechanisms responsible for their development in only a minority of those infected by HIV-1. By monitoring longitudinally a cohort of HIV-1-infected subjects, we observed that the preservation of CXCR5(+) CD4(+) T helper cell frequencies and activation status of B cells during the first year of infection correlates with the maximum breadth of plasma neutralizing antibody responses during chronic infection independently of viral load. Although, during the first year of infection, no differences were observed in the abilities of peripheral CXCR5(+) CD4(+) T helper cells to induce antibody secretion by autologous naive B cells, higher frequencies of class-switched antibodies were detected in cocultures of CXCR5(+) CD4(+) T and B cells from the subjects who later developed broadly neutralizing antibody responses than those who did not. Furthermore, B cells from the former subjects had higher expression of AICDA than B cells from the latter subjects, and transcript levels correlated with the frequency of CXCR5(+) CD4(+) T cells. Thus, the early preservation of CXCR5(+) CD4(+) T cells and B cell function are central to the development of bNAbs. Our study provides a possible explanation for their infrequent generation during HIV-1 infection. Broadly neutralizing antibodies are developed by HIV-1-infected subjects, but so far (and despite intensive efforts over the past 3 decades) they have not been elicited by immunization. Understanding how bNAbs are generated during natural HIV-1 infection and why only some HIV-1-infected subjects generate such antibodies will assist our efforts to elicit bNAbs by immunization. CXCR5(+) PD-1(+) CD4(+) T cells are critical for the development of high-affinity antigen-specific antibody responses. In our study, we found that the HIV-1-infected subjects who develop bNAbs have a higher

  5. Specific Elimination of Latently HIV-1 Infected Cells Using HIV-1 Protease-Sensitive Toxin Nanocapsules.

    Science.gov (United States)

    Wen, Jing; Yan, Ming; Liu, Yang; Li, Jie; Xie, Yiming; Lu, Yunfeng; Kamata, Masakazu; Chen, Irvin S Y

    2016-01-01

    Anti-retroviral drugs suppress HIV-1 plasma viremia to undetectable levels; however, latent HIV-1 persists in reservoirs within HIV-1-infected patients. The silent provirus can be activated through the use of drugs, including protein kinase C activators and histone deacetylase inhibitors. This "shock" approach is then followed by "kill" of the producing cells either through direct HIV-1-induced cell death or natural immune mechanisms. However, these mechanisms are relatively slow and effectiveness is unclear. Here, we develop an approach to specifically target and kill cells that are activated early in the process of virus production. We utilize a novel nanocapsule technology whereby the ricin A chain is encapsulated in an inactive form within a polymer shell. Specificity for release of the ricin A toxin is conferred by peptide crosslinkers that are sensitive to cleavage by HIV-1 protease. By using well-established latent infection models, J-Lat and U1 cells, we demonstrate that only within an HIV-1-producing cell expressing functional HIV-1 protease will the nanocapsule release its ricin A cargo, shutting down viral and cellular protein synthesis, and ultimately leading to rapid death of the producer cell. Thus, we provide proof of principle for a novel technology to kill HIV-1-producing cells without effects on non-target cells.

  6. Hiv-1 genetic diversity in Argentina and early diagnosis of perinatal infection La diversidad genética del HIV-1 en la Argentina y el diagnóstico temprano de la infección perinatal

    Directory of Open Access Journals (Sweden)

    Paula C. Aulicino

    2006-08-01

    Full Text Available HIV-1 diagnosis of perinatally exposed children is usually performed by molecular biology-based methods, allowing the direct detection of the virus. Thus, HIV-1 genomic variability within and across strains plays a major role in relation to the sensitivity of these tests, often leading to misdiagnosis. We describe the performance of an in-house multiplex nested PCR (nPCR for early detection of HIV-1 infection in perinatally exposed children born in Argentina, where the percentage of diverse BF recombinants is as high as 80%. After evaluation of 1316 HIV-1 perinatally exposed children collected over a 7-year period, the specificity and sensitivity of the diagnostic nPCR was of 100% and 99.2% respectively, with only two false negative cases indicating a good performance of the diagnostic nPCR in the Argentine pediatric cohort. In search of unusual HIV-1 subtypes among 22 HIV-1 infected cases presenting partial or complete HIV-1 gene amplification failure, we performed phylogenetic and recombination analysis of a vpu-env fragment in addition to gag and env Heteroduplex Mobility Assay screening. The most unusual findings included two subtypes A and a novel BC recombinant, while the majority of the strains were a variety of different BF recombinants. These results indicate the presence of novel and heterogeneous genotypes in our country and the need of continuous viral surveillance not only for diagnostic test optimization but also for the eventual implementation of a successful vaccine.El diagnóstico temprano de infección por HIV-1 en niños expuestos perinatalmente al virus se realiza con técnicas de biología molecular, detectando el virus en sangre. Por ello, la variabilidad genómica intra e inter subtipo del HIV-1 juega un rol importante en relación a la sensibilidad de estos tests. Describimos aquí la performance de una PCR multiplex anidada artesanal (nPCR, rutinariamente usada para el diagnóstico temprano de la infección por HIV-1 en

  7. Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication

    Energy Technology Data Exchange (ETDEWEB)

    Di Nunzio, Francesca, E-mail: francesca.di-nunzio@pasteur.fr [Molecular Virology and Vaccinology unit, CNRS URA 3015, Department of Virology, Institut Pasteur, 25-28 rue du Dr. Roux, 75015 Paris (France); Fricke, Thomas [Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461 (United States); Miccio, Annarita [University of Modena e Reggio Emilia, Centro di Medicina Rigenerativa, Modena (Italy); Valle-Casuso, Jose Carlos; Perez, Patricio [Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461 (United States); Souque, Philippe [Molecular Virology and Vaccinology unit, CNRS URA 3015, Department of Virology, Institut Pasteur, 25-28 rue du Dr. Roux, 75015 Paris (France); Rizzi, Ermanno; Severgnini, Marco [Institute of Biomedical Technologies, CNR, Milano (Italy); Mavilio, Fulvio [University of Modena e Reggio Emilia, Centro di Medicina Rigenerativa, Modena (Italy); Genethon, Evry (France); Charneau, Pierre [Molecular Virology and Vaccinology unit, CNRS URA 3015, Department of Virology, Institut Pasteur, 25-28 rue du Dr. Roux, 75015 Paris (France); Diaz-Griffero, Felipe, E-mail: felipe.diaz-griffero@einstein.yu.edu [Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY 10461 (United States)

    2013-05-25

    The early steps of HIV-1 replication involve the entry of HIV-1 into the nucleus, which is characterized by viral interactions with nuclear pore components. HIV-1 developed an evolutionary strategy to usurp the nuclear pore machinery and chromatin in order to integrate and efficiently express viral genes. In the current work, we studied the role of nucleoporins 153 and 98 (Nup153 and Nup98) in infection of human Jurkat lymphocytes by HIV-1. We showed that Nup153-depleted cells exhibited a defect in nuclear import, while depletion of Nup 98 caused a slight defect in HIV integration. To explore the biochemical viral determinants for the requirement of Nup153 and Nup98 during HIV-1 infection, we tested the ability of these nucleoporins to interact with HIV-1 cores. Our findings showed that both nucleoporins bind HIV-1 cores suggesting that this interaction is important for HIV-1 nuclear import and/or integration. Distribution analysis of integration sites in Nup153-depleted cells revealed a reduced tendency of HIV-1 to integrate in intragenic sites, which in part could account for the large infectivity defect observed in Nup153-depleted cells. Our work strongly supports a role for Nup153 in HIV-1 nuclear import and integration. - Highlights: ► We studied the role of Nup98 and Nup153 in HIV-1 infection. ► Nup98 binds the HIV-1 core and is involved in HIV-1 integration. ► Nup153 binds the HIV-1 core and is involved in HIV-1 nuclear import. ► Depletion of Nup153 decreased the integration of HIV-1 in transcriptionally active sites.

  8. Prevention of HIV-1 Infection with Early Antiretroviral Therapy: Treatment as -

    Science.gov (United States)

    Gilada, Ishwar; Gilada, T.

    2014-07-01

    There are 34.2 million living with HIV/AIDS globally according to the UNAIDS. The incidence is 2.5 million new infections every year. Out of the 24.8 million patients eligible for antiretroviral treatment, only 8 million are actually receiving it. Nearly 1.7 million people (4658 per day) die of the disease every year i.e., 4658/day, making HIV/AIDS a planetary emergency. The most disturbing fact is that more than 50% of the infected people do not reveal their HIV status to their sexual partners. The UN Sec-Gen Ban Ki-moon suggested "3 Zeros"--Zero Infection, Zero Stigma, Zero AIDS-deaths in 2008...

  9. Early Combination Antiretroviral Therapy Limits HIV-1 Persistence in Children.

    Science.gov (United States)

    Luzuriaga, Katherine

    2016-01-01

    Globally, 240,000 infants are newly infected with HIV-1 each year and 3.2 million children are living with the infection. Combination antiretroviral therapy (cART) has reduced HIV-1-related disease and mortality in children but is not curative owing to the early generation of a latent reservoir of long-lived memory CD4(+) T cells bearing replication-competent HIV-1 provirus integrated into cellular DNA. This review focuses on recent advances in our understanding of the establishment of HIV-1 persistence in children and how early initiation of cART in the setting of the developing infant immune system limits the formation of the long-lived latent CD4(+) cell reservoir that remains a barrier to remission or cure.

  10. Impairment of B-cell functions during HIV-1 infection.

    Science.gov (United States)

    Amu, Sylvie; Ruffin, Nicolas; Rethi, Bence; Chiodi, Francesca

    2013-09-24

    A variety of B-cell dysfunctions are manifested during HIV-1 infection, as reported early during the HIV-1 epidemic. It is not unusual that the pathogenic mechanisms presented to elucidate impairment of B-cell responses during HIV-1 infection focus on the impact of reduced T-cell numbers and functions, and lack of germinal center formation in lymphoid tissues. To our understanding, however, perturbation of B-cell phenotype and function during HIV-1 infection may begin at several different B-cell developmental stages. These impairments can be mediated by intrinsic B-cell defects as well as by the lack of proper T-cell help. In this review, we will highlight some of the pathways and molecular interactions leading to B-cell impairment prior to germinal center formation and B-cell activation mediated through the B-cell receptor in response to HIV-1 antigens. Recent studies indicate a regulatory role for B cells on T-cell biology and immune responses. We will discuss some of these novel findings and how these regulatory mechanisms could potentially be affected by the intrinsic defects of B cells taking place during HIV-1 infection.

  11. Quasispecies tropism and compartmentalization in gut and peripheral blood during early and chronic phases of HIV-1 infection: possible correlation with immune activation markers.

    Science.gov (United States)

    Rozera, G; Abbate, I; Vlassi, C; Giombini, E; Lionetti, R; Selleri, M; Zaccaro, P; Bartolini, B; Corpolongo, A; D'Offizi, G; Baiocchini, A; Del Nonno, F; Ippolito, G; Capobianchi, M R

    2014-03-01

    HIV quasispecies was analysed in plasma and proviral genomes hosted by duodenal mucosa and peripheral blood cells (PBMC) from patients with early or chronic infection, with respect to viral heterogeneity, tropism compartmentalization and extent of immune activation. Seventeen HIV-1-infected combined antiretroviral therapy naive patients were enrolled (11 early infection and six chronic infection). V3 and nef genomic regions were analysed by ultra-deep pyrosequencing. Sequences were used to infer co-receptor usage and to construct phylogenetic trees. As markers of immune activation, plasma sCD14 and soluble tumour necrosis factor receptor II (sTNFRII) levels were measured. Median diversity of HIV RNA was lower in patients with early infection versus chronic infection patients. Overall, direct correlation was observed between V3 diversity and X4 frequency; V3 diversity of HIV RNA was inversely correlated with CD4 T-cell count; median sCD14 and sTNFRII values were similar in early and chronic patients, but X4 frequency of HIV RNA was directly correlated with plasma sCD14. The proportion of patients harbouring X4 variants and median intra-patient X4 frequency of proviral genomes tended to be higher in chronic infection than early infection patients. More pronounced compartmentalization of proviral quasispecies in gut compared with PBMC samples was observed in patients with early infection compared with chronic patients. The loss of gut/PBMC compartmentalization in more advanced stages of HIV infection was confirmed by longitudinal observation. More studies are needed to understand the pathogenetic significance of early HIV quasispecies compartmentalization and progressive intermixing of viral variants in subsequent phases of the infection, as well as the role of immune activation in tropism switch.

  12. Intestinal microbiota and HIV-1 infection

    Directory of Open Access Journals (Sweden)

    E. B. S. M. Trindade

    2007-01-01

    Full Text Available The intestinal microbiota consists of a qualitatively and quantitatively diverse range of microorganisms dynamically interacting with the host. It is remarkably stable with regard to the presence of microorganisms and their roles which, however, can be altered due to pathological conditions, diet composition, gastrointestinal disturbances and/or drug ingestion. The present review aimed at contributing to the discussion about changes in the intestinal microbiota due to HIV-1 infection, focusing on the triad infection-microbiota-nutrition as factors that promote intestinal bacterial imbalance. Intestinal microbiota alterations can be due to the HIV-1 infection as a primary factor or the pharmacotherapy employed, or they can be one of the consequences of the disease.

  13. A single HIV-1 cluster and a skewed immune homeostasis drive the early spread of HIV among resting CD4+ cell subsets within one month post-infection.

    Science.gov (United States)

    Bacchus, Charline; Cheret, Antoine; Avettand-Fenoël, Véronique; Nembot, Georges; Mélard, Adeline; Blanc, Catherine; Lascoux-Combe, Caroline; Slama, Laurence; Allegre, Thierry; Allavena, Clotilde; Yazdanpanah, Yazdan; Duvivier, Claudine; Katlama, Christine; Goujard, Cécile; Seksik, Bao Chau Phung; Leplatois, Anne; Molina, Jean-Michel; Meyer, Laurence; Autran, Brigitte; Rouzioux, Christine

    2013-01-01

    Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that

  14. A single HIV-1 cluster and a skewed immune homeostasis drive the early spread of HIV among resting CD4+ cell subsets within one month post-infection.

    Directory of Open Access Journals (Sweden)

    Charline Bacchus

    Full Text Available Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI. We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM] and short-lived (transitional-memory [TTM] and effector-memory cells [TEM] resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells, although 10-fold less (p = 0.0005 than in equally infected TCM (4.5, TTM (4.7 and TEM (4.6 cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells, unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells. The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility

  15. Cyclophilin B enhances HIV-1 infection

    Energy Technology Data Exchange (ETDEWEB)

    DeBoer, Jason; Madson, Christian J. [Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE (United States); Belshan, Michael, E-mail: michaelbelshan@creighton.edu [Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE (United States); The Nebraska Center for Virology, University of Nebraska, Lincoln, NE (United States)

    2016-02-15

    Cyclophilin B (CypB) is a member of the immunophilin family and intracellular chaperone. It predominantly localizes to the ER, but also contains a nuclear localization signal and is secreted from cells. CypB has been shown to interact with the Gag protein of human immunodeficiency type 1 (HIV-1). Several proteomic and genetic studies identified it as a potential factor involved in HIV replication. Herein, we show that over-expression of CypB enhances HIV infection by increasing nuclear import of viral DNA. This enhancement was unaffected by cyclosporine treatment and requires the N-terminus of the protein. The N-terminus contains an ER leader sequence, putative nuclear localization signal, and is required for secretion. Deletion of the N-terminus resulted in mislocalization from the ER and suppression of HIV infection. Passive transfer experiments showed that secreted CypB did not impact HIV infection. Combined, these experiments show that intracellular CypB modulates a pathway of HIV nuclear import. - Highlights: • CypB has been identified in several proteomic studies of HIV-1 infection. • CypB expression is upregulated in activated and infected T-cells. • Over-expression of CypB enhances HIV nuclear import and infection. • The N-terminus of CypB is necessary for these effects.

  16. Positron emission tomography in patients suffering from HIV-1 infection

    Energy Technology Data Exchange (ETDEWEB)

    Sathekge, Mike [University Hospital of Pretoria, Department of Nuclear Medicine, Pretoria (South Africa); Goethals, Ingeborg; Wiele, Christophe van de [University Hospital Ghent, Department of Nuclear Medicine, Ghent (Belgium); Maes, Alex [AZ Groening, Department of Nuclear Medicine, Kortrijk (Belgium)

    2009-07-15

    This paper reviews currently available PET studies performed either to improve our understanding of the pathogenesis of HIV-1 infection or to assess the value of PET imaging in the clinical decision making of patients infected with HIV-1 presenting with AIDS-related opportunistic infections and malignancies. FDG PET has shown that HIV-1 infection progresses by distinct anatomical steps, with involvement of the upper torso preceding involvement of the lower part of the torso, and that the degree of FDG uptake relates to viral load. The former finding suggests that lymphoid tissues are engaged in a predictable sequence and that diffusible mediators of activation might be important targets for vaccine or therapeutic intervention strategies. In lipodystrophic HIV-infected patients, limited available data support the hypothesis that stavudine-related lipodystrophy is associated with increased glucose uptake by adipose tissue as a result of the metabolic stress of adipose tissue in response to highly active antiretroviral treatment (HAART). Finally, in early AIDS-related dementia complex (ADC), striatal hypermetabolism is observed, whereas progressive ADC is characterized by a decrease in subcortical and cortical metabolism. In the clinical setting, PET has been shown to allow the differentiation of AIDS-related opportunistic infections and malignancies, and to allow monitoring of side effects of HAART. However, in patients suffering from HIV infection and presenting with extracerebral lymphoma or other human malignancies, knowledge of viraemia is essential when interpreting FDG PET imaging. (orig.)

  17. Suppression of HIV-1 Infectivity by Human Glioma Cells.

    Science.gov (United States)

    Hoque, Sheikh Ariful; Tanaka, Atsushi; Islam, Salequl; Ahsan, Gias Uddin; Jinno-Oue, Atsushi; Hoshino, Hiroo

    2016-05-01

    HIV-1 infection to the central nervous system (CNS) is very common in AIDS patients. The predominant cell types infected in the brain are monocytes and macrophages, which are surrounded by several HIV-1-resistant cell types, such as astrocytes, oligodendrocytes, neurons, and microvascular cells. The effect of these HIV-1-resistant cells on HIV-1 infection is largely unknown. In this study, we examined the stability of HIV-1 cultured with several human glioblastoma cell lines, for example, NP-2, U87MG, T98G, and A172, to determine whether these HIV-1-resistant brain cells could enhance or suppress HIV-1 infection and thus modulate HIV-1 infection in the CNS. The HIV-1 titer was determined using the MAGIC-5A indicator cell line as well as naturally occurring CD4(+) T cells. We found that the stability of HIV-1 incubated with NP-2 or U87MG cells at 37°C was significantly shorter (half-life, 2.5-4 h) compared to that of HIV-1 incubated with T98G or A172 cells or in culture medium without cells (half-life, 8-18 h). The spent culture media (SCM) of NP-2 and U87MG cells had the ability to suppress both R5- and X4-HIV-1 infection by inhibiting HIV-1 attachment to target cells. This inhibitory effect was eliminated by the treatment of the SCM with chondroitinase ABC but not heparinase, suggesting that the inhibitory factor(s) secreted by NP-2 and U87MG cells was chiefly mediated by chondroitin sulfate (CS) or CS-like moiety. Thus, this study reveals that some but not all glioma cells secrete inhibitory molecules to HIV-1 infection that may contribute in lowering HIV-1 infection in the CNS in vivo.

  18. Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo.

    Science.gov (United States)

    Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos; Schoofs, Till; Sarkar, Debolina; Halper-Stromberg, Ariel; Horwitz, Joshua A; Nogueira, Lilian; Golijanin, Jovana; Gazumyan, Anna; Ravetch, Jeffrey V; Caskey, Marina; Chakraborty, Arup K; Nussenzweig, Michel C

    2016-05-20

    Antiretroviral drugs and antibodies limit HIV-1 infection by interfering with the viral life cycle. In addition, antibodies also have the potential to guide host immune effector cells to kill HIV-1-infected cells. Examination of the kinetics of HIV-1 suppression in infected individuals by passively administered 3BNC117, a broadly neutralizing antibody, suggested that the effects of the antibody are not limited to free viral clearance and blocking new infection but also include acceleration of infected cell clearance. Consistent with these observations, we find that broadly neutralizing antibodies can target CD4(+) T cells infected with patient viruses and can decrease their in vivo half-lives by a mechanism that requires Fcγ receptor engagement in a humanized mouse model. The results indicate that passive immunotherapy can accelerate elimination of HIV-1-infected cells.

  19. Can HIV-1 infection be cured?%HIV-1感染能治愈吗?

    Institute of Scientific and Technical Information of China (English)

    张兴权

    2013-01-01

    A functional HIV-1 cure has been possible now.The ideal functional HIV-1 cure should get HIV-1 infected patients to the point where drugs are not needed after combination therapy and HIV-1 RNA cannot be detected in some patients.However,a functional HIV-1 cure is not equal to a cure for HIV-1,because HIV-1 RNA can still be detected in patients' latent infected cells and related symptoms have not been resolved completely.An era of eradication cure for HIV infection will be coming with further basic and clinical studies,especially when cleaning virus reservoirs by gene modifications successfully.%目前,HIV-1感染治疗已发展到“功能性治愈”阶段,即采用联合化疗一段时间后停止用药几年内,可以使部分患者体内的病毒达到检测不出的水平.然而,这还不是治愈,因为患者的静止淋巴细胞内仍可查到病毒痕迹,患者临床症状也并未完全消失.真正的治愈还须进行更深入的基础和临床研究,特别是通过基因修饰清除病毒的藏身之地.

  20. Thymic plasmacytoid dendritic cells are susceptible to productive HIV-1 infection and efficiently transfer R5 HIV-1 to thymocytes in vitro

    Directory of Open Access Journals (Sweden)

    Wright Edwina

    2011-06-01

    Full Text Available Abstract Background HIV-1 infection of the thymus contributes to the defective regeneration and loss of CD4+ T cells in HIV-1-infected individuals. As thymic dendritic cells (DC are permissive to infection by HIV-1, we examined the ability of thymic DC to enhance infection of thymocytes which may contribute to the overall depletion of CD4+ T cells. We compared productive infection in isolated human thymic and blood CD11c+ myeloid DC (mDC and CD123+ plasmacytoid DC (pDC using enhanced green fluorescent protein (EGFP CCR5 (R5-tropic NL(AD8 and CXCR4 (X4-tropic NL4-3 HIV-1 reporter viruses. Transfer of productive HIV-1 infection from thymic mDC and pDC was determined by culturing these DC subsets either alone or with sorted thymocytes. Results Productive infection was observed in both thymic pDC and mDC following exposure to R5 HIV-1 and X4 HIV-1. Thymic pDC were more frequently productively infected by both R5 and X4 HIV-1 than thymic mDC (p = 0.03; n = 6. Thymic pDC efficiently transferred productive R5 HIV-1 infection to both CD3hi (p = 0.01; mean fold increase of 6.5; n = 6 and CD3lo thymocytes (mean fold increase of 1.6; n = 2. In comparison, transfer of productive infection by thymic mDC was not observed for either X4 or R5 HIV-1. Conclusions The capacity of thymic pDC to efficiently transfer R5 HIV-1 to both mature and immature thymocytes that are otherwise refractory to R5 virus may represent a pathway to early infection and impaired production of thymocytes and CD4+ T cells in HIV-1-infected individuals.

  1. Methamphetamine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells

    OpenAIRE

    2008-01-01

    The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. We report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection ...

  2. Wound infection rates after invasive procedures in HIV-1 seropositive versus HIV-1 seronegative hemophiliacs.

    Science.gov (United States)

    Buehrer, J L; Weber, D J; Meyer, A A; Becherer, P R; Rutala, W A; Wilson, B; Smiley, M L; White, G C

    1990-01-01

    One-hundred and two patients with hemophilia A, hemophilia B, or acquired antibody to factor VIII who had undergone invasive procedures were cross referenced with patients participating in an ongoing prospective natural history study of HIV-1 infection in hemophiliacs. Matching revealed that HIV-1 status was known for 83 patients (83%) who had undergone 169 procedures between July 1979 and April 1988. Invasive procedures were classified as clean in 108 patients (63.9%), clean-contaminated in 45 (26.6%), contaminated in 2 (1.2%), and infected in 14 (8.3%). Wound infection rates by HIV-1 status were as follows (95% confidence intervals): HIV+ 1.4% (0% to 5%), HIV- 0% (0% to 9%), and procedure before testing HIV+ 1.5% (0% to 6%). There were no significant differences between the wound infection rates of HIV-positive and HIV-negative hemophiliacs nor in the wound infection rate among all three subgroups of patients (p greater than 0.5, Fisher's Exact Test). We conclude that surgery in HIV-1-infected patients who have not progressed to AIDS does not entail an increased risk of postoperative wound infections. PMID:2322041

  3. HIV-1 infected monozygotic twins: a tale of two outcomes

    Directory of Open Access Journals (Sweden)

    Pérez-Losada Marcos

    2011-03-01

    Full Text Available Abstract Background Replicate experiments are often difficult to find in evolutionary biology, as this field is inherently an historical science. However, viruses, bacteria and phages provide opportunities to study evolution in both natural and experimental contexts, due to their accelerated rates of evolution and short generation times. Here we investigate HIV-1 evolution by using a natural model represented by monozygotic twins infected synchronically at birth with an HIV-1 population from a shared blood transfusion source. We explore the evolutionary processes and population dynamics that shape viral diversity of HIV in these monozygotic twins. Results Despite the identical host genetic backdrop of monozygotic twins and the identical source and timing of the HIV-1 inoculation, the resulting HIV populations differed in genetic diversity, growth rate, recombination rate, and selection pressure between the two infected twins. Conclusions Our study shows that the outcome of evolution is strikingly different between these two "replicates" of viral evolution. Given the identical starting points at infection, our results support the impact of random epigenetic selection in early infection dynamics. Our data also emphasize the need for a better understanding of the impact of host-virus interactions in viral evolution.

  4. Astrocytes Resist HIV-1 Fusion but Engulf Infected Macrophage Material

    Directory of Open Access Journals (Sweden)

    Rebecca A. Russell

    2017-02-01

    Full Text Available HIV-1 disseminates to diverse tissues and establishes long-lived viral reservoirs. These reservoirs include the CNS, in which macrophage-lineage cells, and as suggested by many studies, astrocytes, may be infected. Here, we have investigated astrocyte infection by HIV-1. We confirm that astrocytes trap and internalize HIV-1 particles for subsequent release but find no evidence that these particles infect the cell. Astrocyte infection was not observed by cell-free or cell-to-cell routes using diverse approaches, including luciferase and GFP reporter viruses, fixed and live-cell fusion assays, multispectral flow cytometry, and super-resolution imaging. By contrast, we observed intimate interactions between HIV-1-infected macrophages and astrocytes leading to signals that might be mistaken for astrocyte infection using less stringent approaches. These results have implications for HIV-1 infection of the CNS, viral reservoir formation, and antiretroviral therapy.

  5. Detection of Acute HIV-1 Infection by RT-LAMP.

    Directory of Open Access Journals (Sweden)

    Donna L Rudolph

    Full Text Available A rapid, cost-effective diagnostic test for the detection of acute HIV-1 infection is highly desired. Isothermal amplification techniques, such as reverse-transcription loop-mediated isothermal amplification (RT-LAMP, exhibit characteristics that are ideal for the development of a rapid nucleic acid amplification test (NAAT because they are quick, easy to perform and do not require complex, dedicated equipment and laboratory space. In this study, we assessed the ability of the HIV-1 RT-LAMP assay to detect acute HIV infection as compared to a representative rapid antibody test and several FDA-approved laboratory-based assays. The HIV-1 RT-LAMP assay detected seroconverting individuals one to three weeks earlier than a rapid HIV antibody test and up to two weeks earlier than a lab-based antigen/antibody (Ag/Ab combo enzyme immunoassay (EIA. RT-LAMP was not as sensitive as a lab-based qualitative RNA assay, which could be attributed to the significantly smaller nucleic acid input volume. To our knowledge, this is the first demonstration of detecting acute HIV infection using the RT-LAMP assay. The availability of a rapid NAAT, such as the HIV-1 RT-LAMP assay, at the point of care (POC or in laboratories that do not have access to large platform NAAT could increase the percentage of individuals who receive an acute HIV infection status or confirmation of their HIV status, while immediately linking them to counseling and medical care. In addition, early knowledge of HIV status could lead to reduced high-risk behavior at a time when individuals are at a higher risk for transmitting the virus.

  6. Platelets and HIV-1 infection: old and new aspects.

    Science.gov (United States)

    Torre, Donato; Pugliese, Agostino

    2008-09-01

    In this review we summarize the data on interaction of platelets with HIV-1 infection. Thrombocytopenia is a common finding among HIV-1 infected patients; several combined factors contribute to low peripheral platelet counts, which are present during all the stages of the disease. In addition, a relationship between platelet count, plasma viral load and disease progression has been reported, and this shows the potential influence platelets may have on the natural history of HIV-1 disease. Several lines of evidence have shown that platelets are an integral part of inflammation, and can be also potent effector cells of innate immune response as well as of adaptive immunity. Thus, we rewieved the role of inflammatory cytokines, and chemokines as activators of platelets during HIV-1 infection. Moreover, platelets show a direct interaction with HIV-1 itself, through different pathogenic mechanisms as binding, engulfment, internalisation of HIV-1, playing a role in host defence during HIV-1 infection, by limiting viral spread and probably by inactivating viral particles. Platelets may also play an intriguing role on endothelial dysfunction present in HIV-1 infection, and this topic begins to receive systematic study, inasmuch as interaction between platelets and endothelial cells is important in the pathogenesis of atherosclerosis in HIV-1 infected patients, especially in those patients treated with antiretroviral drugs. Finally, this review attempts to better define the state of this emerging issue, to focus areas of potential clinical relevance, and to suggest several directions for future research.

  7. Broadly neutralizing antibodies: An approach to control HIV-1 infection.

    Science.gov (United States)

    Yaseen, Mahmoud Mohammad; Yaseen, Mohammad Mahmoud; Alqudah, Mohammad Ali

    2017-01-02

    Although available antiretroviral therapy (ART) has changed human immunodeficiency virus (HIV)-1 infection to a non-fatal chronic disease, the economic burden of lifelong therapy, severe adverse ART effects, daily ART adherence, and emergence of ART-resistant HIV-1 mutants require prospecting for alternative therapeutic modalities. Indeed, a growing body of evidence suggests that broadly neutralizing anti-HIV-1 antibodies (BNAbs) may offer one such feasible alternative. To evaluate their therapeutic potential in established HIV-1 infection, we sought to address recent advances in pre-clinical and clinical investigations in this area of HIV-1 research. In addition, we addressed the obstacles that may impede the success of such immunotherapeutic approach, suggested strategic solutions, and briefly compared this approach with the currently used ART to open new insights for potential future passive immunotherapy for HIV-1 infection.

  8. Innate immunity and chronic immune activation in HCV/HIV-1 co-infection.

    Science.gov (United States)

    Gonzalez, Veronica D; Landay, Alan L; Sandberg, Johan K

    2010-04-01

    Innate immune responses are critical in the defense against viral infections. NK cells, myeloid and plasmacytoid dendritic cells, and invariant CD1d-restricted NKT cells mediate both effector and regulatory functions in this early immune response. In chronic uncontrolled viral infections such as HCV and HIV-1, these essential immune functions are compromised and can become a double edged sword contributing to the immunopathogenesis of viral disease. In particular, recent findings indicate that innate immune responses play a central role in the chronic immune activation which is a primary driver of HIV-1 disease progression. HCV/HIV-1 co-infection is affecting millions of people and is associated with faster viral disease progression. Here, we review the role of innate immunity and chronic immune activation in HCV and HIV-1 infection, and discuss how mechanisms of innate immunity may influence protection as well as immunopathogenesis in the HCV/HIV-1 co-infected human host.

  9. Short Communication: Neutralizing Antibodies in HIV-1-Infected Brazilian Individuals

    Science.gov (United States)

    Morgado, Mariza Gonçalvez; Côrtes, Fernanda Heloise; Guimarães, Monick Lindermeyer; Mendonça-Lima, Leila; Pilotto, Jose Henrique; Grinsztejn, Beatriz; Veloso, Valdiléa Gonçalves; Bongertz, Vera

    2013-01-01

    Abstract Tests for the detection of the humoral immune response to HIV-1 have to be standardized and established, demanding regional efforts. For this purpose the neutralizing antibody (NAb) assay for HIV-1 in TZM-bl cells was introduced in Brazil. Twenty plasma samples from HIV-1-infected individuals were assayed: 10 progressors and 10 long-term nonprogressors. These were tested against eight env-pseudotyped viruses (psVs) in the TZM-bl NAb assay and against HIV-1 strain HTLV/IIIB (HIV-1 IIIB) in primary lymphocytes. Forty-four percent of the samples showed neutralizing titers for psVs and 55% for HIV-1 IIIB. Plasma from progressors showed a broader neutralization and a higher potency. The introduction of these reference reagents encourages the participation of Brazil in future comparative assessments of anti-HIV-1 antibodies. PMID:23145941

  10. Varicella vaccination in HIV-1-infected children after immune reconstitution

    NARCIS (Netherlands)

    V. Bekker; G.H.A. Westerlaken; H. Scherpbier; S. Alders; H. Zaaijer; D. van Baarle; T. Kuijper

    2006-01-01

    Background: HIV-1-infected children have an increased risk of severe chickenpox. However, vaccination is not recommended in severely immunocompromised children. Objective: Can the live-attenuated varicella zoster virus (VZV) Oka strain be safely and effectively given to HIV-1-infected children despi

  11. In-depth characterization of viral isolates from plasma and cells compared with plasma circulating quasispecies in early HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Judith Dalmau

    Full Text Available BACKGROUND: The use of in vitro models to unravel the phenotypic characteristics of circulating viral variants is key to understanding HIV-1 pathogenesis but limited by the availability of primary viral isolates from biological samples. However, overall in vivo genetic variability of HIV-1 within a subject may not be reflected in the viable viral population obtained after isolation. Although several studies have tried to determine whether viral populations expanded in vitro are representative of in vivo findings, the answer remains unclear due to the reduced number of clonal sequences analyzed or samples compared. In order to overcome previous experimental limitations, here we applied Deep Pyrosequencing (DPS technology in combination with phenotypic experiments to analyze and compare with unprecedented detail the composition of viral isolates and in vivo quasispecies. METHODOLOGY/PRINCIPAL FINDINGS: We amplified by DPS HIV-1 genomic regions covering gag, protease, integrase and env-V3 to characterize paired isolates from plasma and peripheral blood mononuclear cells and compare them with total plasma viral RNA in four recently HIV-1 infected subjects. Our study demonstrated the presence of unique haplotypes scattered between sample types with conservation of major variants. In addition, no differences in intra- and inter-population encoded protein variability were found between the different types of isolates or when these were compared to plasma viral RNA within subjects. Additionally, in vitro experiments demonstrated phenotypic similarities in terms of replicative capacity and co-receptor usage between viral isolates and plasma viral RNA. CONCLUSION: This study is the first in-depth comparison and characterization of viral isolates from different sources and plasma circulating quasispecies using DPS in recently HIV-1 infected subjects. Our data supports the use of primary isolates regardless of their plasma or cellular origin to define

  12. Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.

    Science.gov (United States)

    Levesque, Marc C; Moody, M Anthony; Hwang, Kwan-Ki; Marshall, Dawn J; Whitesides, John F; Amos, Joshua D; Gurley, Thaddeus C; Allgood, Sallie; Haynes, Benjamin B; Vandergrift, Nathan A; Plonk, Steven; Parker, Daniel C; Cohen, Myron S; Tomaras, Georgia D; Goepfert, Paul A; Shaw, George M; Schmitz, Jörn E; Eron, Joseph J; Shaheen, Nicholas J; Hicks, Charles B; Liao, Hua-Xin; Markowitz, Martin; Kelsoe, Garnett; Margolis, David M; Haynes, Barton F

    2009-07-07

    The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+) T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells. In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis. Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors' Summary.

  13. Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Marc C Levesque

    2009-07-01

    Full Text Available The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+ T cells in acute HIV-1 infection is well described, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells.In human participants, we analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. We found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal center loss in terminal ileum Peyer's patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis.Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal center loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1. Please see later in the article for Editors' Summary.

  14. Global human genetics of HIV-1 infection and China

    Institute of Scientific and Technical Information of China (English)

    Tuo Fu ZHU; Tie Jian FENG; Xin XIAO; Hui WANG; Bo Ping ZHOU

    2005-01-01

    Genetic polymorphisms in human genes can influence the risk for HIV-1 infection and disease progression, although the reported effects of these alleles have been inconsistent. This review highlights the recent discoveries on global and Chinese genetic polymorphisms and their association with HIV-1 transmission and disease progression.

  15. Schistosomiasis and HIV-1 infection in rural Zimbabwe

    DEFF Research Database (Denmark)

    Kallestrup, Per; Zinyama, Rutendo; Gomo, Exnevia

    2005-01-01

    Stunted development and reduced fecundity of Schistosoma parasites in immunodeficient mice and the impaired ability of human immunodeficiency virus 1 (HIV-1)-infected humans to excrete schistosome eggs have been described. This study explores the effect that HIV-1-associated immunodeficiency has...... on the excretion of schistosome eggs in a large cohort of coinfected individuals....

  16. Sexually transmitted infections among HIV-1-discordant couples.

    Directory of Open Access Journals (Sweden)

    Brandon L Guthrie

    Full Text Available INTRODUCTION: More new HIV-1 infections occur within stable HIV-1-discordant couples than in any other group in Africa, and sexually transmitted infections (STIs may increase transmission risk among discordant couples, accounting for a large proportion of new HIV-1 infections. Understanding correlates of STIs among discordant couples will aid in optimizing interventions to prevent HIV-1 transmission in these couples. METHODS: HIV-1-discordant couples in which HIV-1-infected partners were HSV-2-seropositive were tested for syphilis, chlamydia, gonorrhea, and trichomoniasis, and HIV-1-uninfected partners were tested for HSV-2. We assessed sociodemographic, behavioral, and biological correlates of a current STI. RESULTS: Of 416 couples enrolled, 16% were affected by a treatable STI, and among these both partners were infected in 17% of couples. A treatable STI was found in 46 (11% females and 30 (7% males. The most prevalent infections were trichomoniasis (5.9% and syphilis (2.6%. Participants were 5.9-fold more likely to have an STI if their partner had an STI (P<0.01, and STIs were more common among those reporting any unprotected sex (OR = 2.43; P<0.01 and those with low education (OR = 3.00; P<0.01. Among HIV-1-uninfected participants with an HSV-2-seropositive partner, females were significantly more likely to be HSV-2-seropositive than males (78% versus 50%, P<0.01. CONCLUSIONS: Treatable STIs were common among HIV-1-discordant couples and the majority of couples affected by an STI were discordant for the STI, with relatively high HSV-2 discordance. Awareness of STI correlates and treatment of both partners may reduce HIV-1 transmission. TRIAL REGISTRATION: ClinicalTrials.gov NCT00194519.

  17. Purinergic Receptors: Key Mediators of HIV-1 infection and inflammation

    Directory of Open Access Journals (Sweden)

    Talia H Swartz

    2015-11-01

    Full Text Available Human immunodeficiency virus (HIV-1 causes a chronic infection that afflicts more than 38 million individuals worldwide. While the infection can be suppressed with potent anti-retroviral therapies, individuals infected with HIV have elevated levels of inflammation as indicated by increased T cell activation, soluble biomarkers, and associated morbidity and mortality. A single mechanism linking HIV pathogenesis to this inflammation has yet to be identified. Purinergic receptors are known to mediate inflammation and have been shown to be required for HIV-1 infection at the level of HIV-1 membrane fusion. Here we review the literature on the role of purinergic receptors in HIV-1 infection and associated inflammation and describe a role for these receptors as potential therapeutic targets.

  18. Innate Immune Activation in Primary HIV-1 Infection

    OpenAIRE

    Chang, J. Judy; Altfeld, Marcus

    2010-01-01

    There is growing evidence highlighting the role of the immune response during acute HIV-1 infection on the control or development of disease. The adaptive immune responses do not appear until after the HIV-1 infection is already well established and as such the role of the earlier and faster responding innate immunity needs to be more closely scrutinized. In particular, two aspects of the innate immunity with growing developments will be examined in this review; type I IFNs and NK cells. Both...

  19. Genomic architecture of HIV-1 infection: current status & challenges.

    Science.gov (United States)

    Kaur, Gurvinder; Sharma, Gaurav; Kumar, Neeraj; Kaul, Mrinali H; Bansal, Rhea A; Vajpayee, Madhu; Wig, Naveet; Sharma, Surender K; Mehra, Narinder K

    2013-11-01

    Studies on host genomics have revealed the existence of identifiable HIV-1 specific protective factors among infected individuals who remain naturally resistant viraemia controllers with little or no evidence of virus replication. These factors are broadly grouped into those that are immune associated (MHC, chemokines, cytokines, CTLs and others), linked to viral entry (chemokine co-receptors and ligands), act as post-entry restriction elements (TRIM5a, APOBEC3) and those associated with viral replication (cytokines and others). These features have been identified through multiple experimental approaches ranging from candidate gene approaches, genome wide association studies (GWAS), expression analysis in conjunction with functional assays in humans to primate based models. Several studies have highlighted the individual and population level gross differences both in the viral clade sequences as well as host determined genetic associations. This review collates current information on studies involving major histocompatibility complex (MHC) as well as non MHC genes in the context of HIV-1 infection and AIDS involving varied ethnic groups. Special focus of the review is on the genetic studies carried out on the Indian population. Further challenges with regard to therapeutic interventions based on current knowledge have been discussed along with discussion on documented cases of stem cell therapy and very early highly active antiretroviral therapy (HAART) interventions.

  20. Schistosomiasis and HIV-1 infection in rural Zimbabwe: effect of treatment of schistosomiasis on CD4 cell count and plasma HIV-1 RNA load

    DEFF Research Database (Denmark)

    Kallestrup, Per; Zinyama, Rutendo; Gomo, Exnevia;

    2005-01-01

    To determine whether treatment of schistosomiasis has an effect on the course of human immunodeficiency virus type 1 (HIV-1) infection, individuals with schistosomiasis and with or without HIV-1 infection were randomized to receive praziquantel treatment at inclusion or after a delay of 3 months......; 287 participants were included in the study, and 227 (79%) were followed up. Among the 130 participants who were coinfected, those who received early treatment (n=64) had a significantly lower increase in plasma HIV-1 RNA load than did those who received delayed treatment (n=66) (P...

  1. Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag

    Directory of Open Access Journals (Sweden)

    Woods Matthew W

    2011-11-01

    Full Text Available Abstract Background The identification and characterization of several interferon (IFN-induced cellular HIV-1 restriction factors, defined as host cellular proteins or factors that restrict or inhibit the HIV-1 life cycle, have provided insight into the IFN response towards HIV-1 infection and identified new therapeutic targets for HIV-1 infection. To further characterize the mechanism underlying restriction of the late stages of HIV-1 replication, we assessed the ability of IFNbeta-induced genes to restrict HIV-1 Gag particle production and have identified a potentially novel host factor called HECT domain and RCC1-like domain-containing protein 5 (HERC5 that blocks a unique late stage of the HIV-1 life cycle. Results HERC5 inhibited the replication of HIV-1 over multiple rounds of infection and was found to target a late stage of HIV-1 particle production. The E3 ligase activity of HERC5 was required for blocking HIV-1 Gag particle production and correlated with the post-translational modification of Gag with ISG15. HERC5 interacted with HIV-1 Gag and did not alter trafficking of HIV-1 Gag to the plasma membrane. Electron microscopy revealed that the assembly of HIV-1 Gag particles was arrested at the plasma membrane, at an early stage of assembly. The mechanism of HERC5-induced restriction of HIV-1 particle production is distinct from the mechanism underlying HIV-1 restriction by the expression of ISG15 alone, which acts at a later step in particle release. Moreover, HERC5 restricted murine leukemia virus (MLV Gag particle production, showing that HERC5 is effective in restricting Gag particle production of an evolutionarily divergent retrovirus. Conclusions HERC5 represents a potential new host factor that blocks an early stage of retroviral Gag particle assembly. With no apparent HIV-1 protein that directly counteracts it, HERC5 may represent a new candidate for HIV/AIDS therapy.

  2. Impaired production of cytokines is an independent predictor of mortality in HIV-1-infected patients

    DEFF Research Database (Denmark)

    Ostrowski, Sisse R; Gerstoft, Jan; Pedersen, Bente K;

    2003-01-01

    With regard to the natural history of HIV-1 infection this study investigated whether whole-blood culture cytokine production was associated with mortality in HIV-1-infected patients.......With regard to the natural history of HIV-1 infection this study investigated whether whole-blood culture cytokine production was associated with mortality in HIV-1-infected patients....

  3. Dendritic Cells and HIV-1 Trans-Infection

    Directory of Open Access Journals (Sweden)

    David McDonald

    2010-08-01

    Full Text Available Dendritic cells initiate and sustain immune responses by migrating to sites of pathogenic insult, transporting antigens to lymphoid tissues and signaling immune specific activation of T cells through the formation of the immunological synapse. Dendritic cells can also transfer intact, infectious HIV-1 to CD4 T cells through an analogous structure, the infectious synapse. This replication independent mode of HIV-1 transmission, known as trans-infection, greatly increases T cell infection in vitro and is thought to contribute to viral dissemination in vivo. This review outlines the recent data defining the mechanisms of trans-infection and provides a context for the potential contribution of trans-infection in HIV-1 disease.

  4. Lipid and acute-phase protein alterations in HIV-1 infected patients in the early stages of infection: correlation with CD4+ lymphocytes

    Directory of Open Access Journals (Sweden)

    Treitinger Arício

    2001-01-01

    Full Text Available Lipid and acute-phase protein alterations have been described in various infection diseases, and they have been recorded during the early stages of HIV infection. Lipid and acute-phase protein profiles also have been correlated with cellular immunological abnormalities. To document these correlations during HIV infection, we studied 75 HIV-infected patients and 26 HIV-negative controls. Patients were classified according to the criteria proposed by the Walter Reed Army Institute: as WR-1 (CD4 lymphocytes, 1154 ± 268/mm³, WR-2 (CD4, 793 ± 348/mm³ and WR3/4 (CD4, 287±75 mm³. Triglycerides, total cholesterol and HDL-cholesterol concentrations were measured by enzymatic methods. Immunoglobulins (IgA and IgG and acute-phase proteins (haptoglobin, a1-acid glycoprotein, C-reactive protein and transferrin were determined by immunonephelometry. Haptoglobin levels were significantly increased in HIV-positive patients and correlated with the progression of HIV-infection (control

  5. Lipid and acute-phase protein alterations in HIV-1 infected patients in the early stages of infection: correlation with CD4+ lymphocytes.

    Science.gov (United States)

    Treitinger, A; Spada, C; da Silva, L M; Hermes, E M; Amaral, J A; Abdalla, D S

    2001-08-01

    Lipid and acute-phase protein alterations have been described in various infection diseases, and they have been recorded during the early stages of HIV infection. Lipid and acute-phase protein profiles also have been correlated with cellular immunological abnormalities. To document these correlations during HIV infection, we studied 75 HIV-infected patients and 26 HIV-negative controls. Patients were classified according to the criteria proposed by the Walter Reed Army Institute: as WR-1 (CD4 lymphocytes, 1154 +/- 268/mm3), WR-2 (CD4, 793 +/- 348/mm3) and WR3/4 (CD4, 287+/-75 mm3). Triglycerides, total cholesterol and HDL-cholesterol concentrations were measured by enzymatic methods. Immunoglobulins (IgA and IgG) and acute-phase proteins (haptoglobin, alpha1-acid glycoprotein, C-reactive protein and transferrin) were determined by immunonephelometry. Haptoglobin levels were significantly increased in HIV-positive patients and correlated with the progression of HIV-infection (control

  6. Lipid and acute-phase protein alterations in HIV-1 infected patients in the early stages of infection: correlation with CD4+ lymphocytes

    Directory of Open Access Journals (Sweden)

    Arício Treitinger

    Full Text Available Lipid and acute-phase protein alterations have been described in various infection diseases, and they have been recorded during the early stages of HIV infection. Lipid and acute-phase protein profiles also have been correlated with cellular immunological abnormalities. To document these correlations during HIV infection, we studied 75 HIV-infected patients and 26 HIV-negative controls. Patients were classified according to the criteria proposed by the Walter Reed Army Institute: as WR-1 (CD4 lymphocytes, 1154 ± 268/mm³, WR-2 (CD4, 793 ± 348/mm³ and WR3/4 (CD4, 287±75 mm³. Triglycerides, total cholesterol and HDL-cholesterol concentrations were measured by enzymatic methods. Immunoglobulins (IgA and IgG and acute-phase proteins (haptoglobin, a1-acid glycoprotein, C-reactive protein and transferrin were determined by immunonephelometry. Haptoglobin levels were significantly increased in HIV-positive patients and correlated with the progression of HIV-infection (control

  7. New insights into complications and treatment of HIV-1 infection

    NARCIS (Netherlands)

    van Lelyveld, S.F.L.

    2013-01-01

    In this thesis the complications and treatment of HIV-1 infection in the current era was studied. Life expectancy of HIV-infected patients has increased enormously with the introduction of combination antiretroviral therapy (cART). In line with this observation, we found that the outcome of HIV-infe

  8. Diversity of HIV-1 RNA and DNA in breast milk from HIV-1-infected mothers.

    Science.gov (United States)

    Becquart, Pierre; Courgnaud, Valerie; Willumsen, Juana; Van de Perre, Philippe

    2007-07-05

    We compared human immunodeficiency virus type 1 (HIV-1) RNA and DNA populations in the different fractions of breast milk (lactoserum, lipid layer, cell pellet) and between right and left breasts in four HIV-1-infected mothers by analyzing the hypervariable env C2-V5 region. Phylogenetic analyses of the viral quasispecies revealed that RNA populations and DNA populations were clearly distinct and that viral RNA sequences were similar in lipid layer and lactoserum in the milk of 3 out of 4 mothers. Comparison of viral DNA between milk from right and left breast showed a differential distribution of variants in three mothers. In contrast, RNA variants detected from milk of the two breasts were mixed in 3 out of 4 mothers. This study suggests that each mammary gland is subjected to microenvironmental pressure that may differ from the contralateral breast.

  9. Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Aylin Yilmaz

    Full Text Available INTRODUCTION: Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF and plasma in subjects receiving antiretroviral treatment regimens containing this drug. METHODS: Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma. RESULTS: Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0. The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180. CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations. CONCLUSIONS: Approximately 50% of the CSF specimens exceeded the IC(95 levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

  10. The macrophage in HIV-1 infection: From activation to deactivation?

    Directory of Open Access Journals (Sweden)

    Varin Audrey

    2010-04-01

    Full Text Available Abstract Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1 induced in particular by IFN-γ display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2 induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM. Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease.

  11. The macrophage in HIV-1 infection: from activation to deactivation?

    Science.gov (United States)

    Herbein, Georges; Varin, Audrey

    2010-04-09

    Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-gamma display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease.

  12. Flail arm-like syndrome associated with HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Nalini A

    2009-01-01

    Full Text Available During the last 20 years at least 23 cases of motor neuron disease have been reported in HIV-1 seropositive patients. In this report we describe the clinical picture of a young man with HIV-1 clade C infection and flail arm-like syndrome, who we were able to follow-up for a long period. We investigated and prospectively monitored a 34-year-old man with features of flail arm syndrome, who developed the weakness and wasting 1 year after being diagnosed with HIV-1 infection after a routine blood test. He presented in 2003 with progressive, symmetrical wasting and weakness of the proximal muscles of the upper limb of 2 years′ duration. He had severe wasting and weakness of the shoulder and arm muscles. There were no pyramidal signs. He has been on HAART for the last 4 years and the weakness or wasting has not worsened. At the last follow-up in July 2007, the patient had the same neurological deficit and no other symptoms or signs of HIV-1 infection. MRI of the spinal cord in 2007 showed characteristic T2 hyperintense signals in the central part of the spinal cord, corresponding to the central gray matter. Thus, our patient had HIV-1 clade C infection associated with a ′flail arm-like syndrome.′ The causal relationship between HIV-1 infection and amyotrophic lateral sclerosis (ALS-like syndrome is still uncertain. The syndrome usually manifests as a lower motor neuron syndrome, as was seen in our young patient. It is known that treatment with antiretroviral therapy (ART stabilizes/improves the condition. In our patient the weakness and atrophy remained stable over a period of 3.5 years after commencing HAART regimen.

  13. Prevention of HIV-1 infection 2013: glimmers of hope

    Directory of Open Access Journals (Sweden)

    Cohen M

    2012-11-01

    Full Text Available The efficiency of transmission of HIV depends on the infectiousness of the index case and the susceptibility of those exposed. Infectiousness is dictated by the concentration of HIV-1 in relevant fluids (regardless of route of transmission and the viral genotype and phenotype. People newly infected with HIV-1 (i.e. acute infection and those with STI co-infections excrete such a large concentration of virus as to be “hyperinfectious.” The actual transmission of HIV likely occurs in the first few hours after exposure. The probability of transmission may be as low as 1/10,000 episodes of intercourse or 1/10 sexual exposures when anal intercourse is practiced. The transmission of HIV is generally limited to one or a small number of founder variants which themselves may be “hyperinfectious.” Synergistic behavioural and biologic HIV prevention strategies have been developed and implemented. Safer sex includes limiting the number of sexual partners, use of male latex condoms, and structural interventions to reduce exposure. These strategies appear to have contributed to reduced HIV incidence in many countries. Biological interventions have proved catalytic: these include treatment of inflammatory cofactors, voluntary male circumcision and use of antiviral agents either for infected people (who can be rendered remarkably less contagious or as pre- and post-exposure prophylaxis (PrEP and PEP. Ecologic evidence suggests that broader, earlier antiviral treatment of HIV may be reducing incidence in some (but not all populations. However, maximal benefit of HIV “treatment for prevention” and application of PrEP will likely require a program of universal “test and treat,” where many more infected patients are identified, linked to care, and treated very early in disease and for life. Community randomized trials designed to support this approach are under way in Africa. The “test and treat” prevention strategy is resource-intensive and

  14. Raltegravir with optimized background therapy for resistant HIV-1 infection

    DEFF Research Database (Denmark)

    Steigbigel, Roy T; Cooper, David A; Kumar, Princy N;

    2008-01-01

    for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS: In HIV-infected patients with limited treatment options, raltegravir plus......BACKGROUND: Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS: We conducted two identical trials in different geographic regions to evaluate the safety and efficacy...... of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS: In the combined studies...

  15. Quantitative proteomic analysis of HIV-1 infected CD4+ T cells reveals an early host response in important biological pathways: Protein synthesis, cell proliferation, and T-cell activation

    Energy Technology Data Exchange (ETDEWEB)

    Navare, Arti T.; Sova, Pavel; Purdy, David E.; Weiss, Jeffrey M. [Department of Microbiology, University of Washington, Seattle, WA (United States); Wolf-Yadlin, Alejandro [Department of Genome Sciences, University of Washington, Seattle, WA (United States); Korth, Marcus J.; Chang, Stewart T.; Proll, Sean C. [Department of Microbiology, University of Washington, Seattle, WA (United States); Jahan, Tahmina A. [Proteomics Resource, UW Medicine at South Lake Union, Seattle, WA (United States); Krasnoselsky, Alexei L.; Palermo, Robert E. [Department of Microbiology, University of Washington, Seattle, WA (United States); Katze, Michael G., E-mail: honey@uw.edu [Department of Microbiology, University of Washington, Seattle, WA (United States); Washington National Primate Research Center, University of Washington, Seattle, WA (United States)

    2012-07-20

    Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value{<=}0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time-matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before.

  16. Differentially-Expressed Pseudogenes in HIV-1 Infection

    Directory of Open Access Journals (Sweden)

    Aditi Gupta

    2015-09-01

    Full Text Available Not all pseudogenes are transcriptionally silent as previously thought. Pseudogene transcripts, although not translated, contribute to the non-coding RNA pool of the cell that regulates the expression of other genes. Pseudogene transcripts can also directly compete with the parent gene transcripts for mRNA stability and other cell factors, modulating their expression levels. Tissue-specific and cancer-specific differential expression of these “functional” pseudogenes has been reported. To ascertain potential pseudogene:gene interactions in HIV-1 infection, we analyzed transcriptomes from infected and uninfected T-cells and found that 21 pseudogenes are differentially expressed in HIV-1 infection. This is interesting because parent genes of one-third of these differentially-expressed pseudogenes are implicated in HIV-1 life cycle, and parent genes of half of these pseudogenes are involved in different viral infections. Our bioinformatics analysis identifies candidate pseudogene:gene interactions that may be of significance in HIV-1 infection. Experimental validation of these interactions would establish that retroviruses exploit this newly-discovered layer of host gene expression regulation for their own benefit.

  17. Drug-induced reactivation of apoptosis abrogates HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Hartmut M Hanauske-Abel

    Full Text Available HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of

  18. HIV-1 Continues To Replicate and Evolve in Patients with Natural Control of HIV Infection

    DEFF Research Database (Denmark)

    Mens, Helene; Kearney, Mary; Wiegand, Ann

    2010-01-01

    Elucidating mechanisms leading to the natural control of HIV-1 infection is of great importance for vaccine design and for understanding viral pathogenesis. Rare HIV-1-infected individuals, termed HIV-1 controllers, have plasma HIV-1 RNA levels below the limit of detection by standard clinical...

  19. Elevated risk for HIV-1 infection in adolescents and young adults in Sao Paulo, Brazil.

    Directory of Open Access Journals (Sweden)

    Katia Cristina Bassichetto

    Full Text Available BACKGROUND: Recent studies have sought to describe HIV infection and transmission characteristics around the world. Identification of early HIV-1 infection is essential to proper surveillance and description of regional transmission trends. In this study we compare people recently infected (RI with HIV-1, as defined by Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS, to those with chronic infection. METHODOLOGY/PRINCIPAL FINDINGS: Subjects were identified from 2002-2004 at four testing sites in São Paulo. Of 485 HIV-1-positive subjects, 57 (12% were defined as RI. Of the participants, 165 (34.0% were aware of their serostatus at the time of HIV-1 testing. This proportion was statistically larger (p59 years-old age strata (p<0.001. The majority of study participants were male (78.4%, 25 to 45 years-old (65.8%, white (63.2%, single (61.7%, with family income of four or more times the minimum wage (41.0%, but with an equally distributed educational level. Of those individuals infected with HIV-1, the predominant route of infection was sexual contact (89.4%, with both hetero (47.5% and homosexual (34.5% exposure. Regarding sexual activity in these individuals, 43.9% reported possible HIV-1 exposure through a seropositive partner, and 49.4% reported multiple partners, with 47% having 2 to 10 partners and 37.4% 11 or more; 53.4% of infected individuals reported condom use sometimes; 34.2% reported non-injecting, recreational drug use and 23.6% were reactive for syphilis by VDRL. Subjects younger than 25 years of age were most vulnerable according to the multivariate analysis. CONCLUSIONS/SIGNIFICANCE: In this study, we evaluated RI individuals and discovered that HIV-1 has been spreading among younger individuals in São Paulo and preventive approaches should, therefore, target this age stratum.

  20. Virion-incorporated alpha-enolase suppresses the early stage of HIV-1 reverse transcription.

    Science.gov (United States)

    Kishimoto, Naoki; Iga, Nozomi; Yamamoto, Kengo; Takamune, Nobutoki; Misumi, Shogo

    2017-03-04

    Human immunodeficiency virus type-1 (HIV-1) particles contain not only viral-encoded but also host-encoded proteins. Interestingly, several studies showed that host proteins play a critical role in viral infectivity, replication and/or immunoreactivity in the next target cells. Here, we show that alpha-enolase (ENO1) is incorporated into HIV-1 virions and the virion-incorporated ENO1 prevents the early stage of HIV-1 reverse transcription. We found that viral particles contain two isoforms of ENO1 with different isoelectric points by two-dimensional electrophoresis. Suppression of ENO1 expression by RNA interference in the HIV-1 producer cells decreased ENO1 incorporation into virions without altering the packaging of viral structural proteins and viral production but increased viral infectivity. Although the low-level-ENO1-packaging virus maintained comparable levels of reverse transcriptase activity, viral genomic RNA and tRNA(Lys3) packaging to the control virus, its levels of early cDNA products of reverse transcription were higher than those of the control virus. In contrast, the high-level-ENO1-packaging virus, which was produced from ENO1-overexpressing cells, showed decreased infectivity and the levels of early cDNA products. Taken together, these findings reveal a novel function of ENO1 as a negative regulation factor targeting HIV-1 reverse transcription.

  1. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy

    Science.gov (United States)

    Rizzardi, G. Paolo; Harari, Alexandre; Capiluppi, Brunella; Tambussi, Giuseppe; Ellefsen, Kim; Ciuffreda, Donatella; Champagne, Patrick; Bart, Pierre-Alexandre; Chave, Jean-Philippe; Lazzarin, Adriano; Pantaleo, Giuseppe

    2002-01-01

    Primary HIV-1 infection causes extensive immune activation, during which CD4+ T cell activation supports massive HIV-1 production. We tested the safety and the immune-modulating effects of combining cyclosporin A (CsA) treatment with highly active antiretroviral therapy (HAART) during primary HIV-1 infection. Nine adults with primary HIV-1 infection were treated with CsA along with HAART. At week 8, all patients discontinued CsA but maintained HAART. Viral replication was suppressed to a comparable extent in the CsA + HAART cohort and in 29 control patients whose primary infection was treated with HAART alone. CsA restored normal CD4+ T cell levels, both in terms of percentage and absolute numbers. The increase in CD4+ T cells was apparent within a week and persisted throughout the study period. CsA was not detrimental to virus-specific CD8+ or CD4+ T cell responses. At week 48, the proportion of IFN-γ–secreting CD4+ and CD4+CCR7– T cells was significantly higher in the CsA + HAART cohort than in the HAART-alone cohort. In conclusion, rapid shutdown of T cell activation in the early phases of primary HIV-1 infection can have long-term beneficial effects and establish a more favorable immunologic set-point. Appropriate, immune-based therapeutic interventions may represent a valuable complement to HAART for treating HIV infection. PMID:11877476

  2. Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection.

    Science.gov (United States)

    Séror, Claire; Melki, Marie-Thérèse; Subra, Frédéric; Raza, Syed Qasim; Bras, Marlène; Saïdi, Héla; Nardacci, Roberta; Voisin, Laurent; Paoletti, Audrey; Law, Frédéric; Martins, Isabelle; Amendola, Alessandra; Abdul-Sater, Ali A; Ciccosanti, Fabiola; Delelis, Olivier; Niedergang, Florence; Thierry, Sylvain; Said-Sadier, Najwane; Lamaze, Christophe; Métivier, Didier; Estaquier, Jérome; Fimia, Gian Maria; Falasca, Laura; Casetti, Rita; Modjtahedi, Nazanine; Kanellopoulos, Jean; Mouscadet, Jean-François; Ojcius, David M; Piacentini, Mauro; Gougeon, Marie-Lise; Kroemer, Guido; Perfettini, Jean-Luc

    2011-08-29

    Extracellular adenosine triphosphate (ATP) can activate purinergic receptors of the plasma membrane and modulate multiple cellular functions. We report that ATP is released from HIV-1 target cells through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with new therapeutic approaches. © 2011 Séror et al.

  3. Genotypic and functional properties of early infant HIV-1 envelopes

    Directory of Open Access Journals (Sweden)

    Sullivan John L

    2011-08-01

    Full Text Available Abstract Background Understanding the properties of HIV-1 variants that are transmitted from women to their infants is crucial to improving strategies to prevent transmission. In this study, 162 full-length envelope (env clones were generated from plasma RNA obtained from 5 HIV-1 Clade B infected mother-infant pairs. Following extensive genotypic and phylogenetic analyses, 35 representative clones were selected for functional studies. Results Infant quasispecies were highly homogeneous and generally represented minor maternal variants, consistent with transmission across a selective bottleneck. Infant clones did not differ from the maternal in env length, or glycosylation. All infant variants utilized the CCR5 co-receptor, but were not macrophage tropic. Relatively high levels (IC50 ≥ 100 μg/ml of autologous maternal plasma IgG were required to neutralize maternal and infant viruses; however, all infant viruses were neutralized by pooled sera from HIV-1 infected individuals, implying that they were not inherently neutralization-resistant. All infant viruses were sensitive to the HIV-1 entry inhibitors Enfuvirtide and soluble CD4; none were resistant to Maraviroc. Sensitivity to human monoclonal antibodies 4E10, 2F5, b12 and 2G12 varied. Conclusions This study provides extensive characterization of the genotypic and functional properties of HIV-1 env shortly after transmission. We present the first detailed comparisons of the macrophage tropism of infant and maternal env variants and their sensitivity to Maraviroc, the only CCR5 antagonist approved for therapeutic use. These findings may have implications for improving approaches to prevent mother-to-child HIV-1 transmission.

  4. Combining epidemiological and genetic networks signifies the importance of early treatment in HIV-1 transmission.

    Science.gov (United States)

    Zarrabi, Narges; Prosperi, Mattia; Belleman, Robert G; Colafigli, Manuela; De Luca, Andrea; Sloot, Peter M A

    2012-01-01

    Inferring disease transmission networks is important in epidemiology in order to understand and prevent the spread of infectious diseases. Reconstruction of the infection transmission networks requires insight into viral genome data as well as social interactions. For the HIV-1 epidemic, current research either uses genetic information of patients' virus to infer the past infection events or uses statistics of sexual interactions to model the network structure of viral spreading. Methods for a reliable reconstruction of HIV-1 transmission dynamics, taking into account both molecular and societal data are still lacking. The aim of this study is to combine information from both genetic and epidemiological scales to characterize and analyse a transmission network of the HIV-1 epidemic in central Italy.We introduce a novel filter-reduction method to build a network of HIV infected patients based on their social and treatment information. The network is then combined with a genetic network, to infer a hypothetical infection transmission network. We apply this method to a cohort study of HIV-1 infected patients in central Italy and find that patients who are highly connected in the network have longer untreated infection periods. We also find that the network structures for homosexual males and heterosexual populations are heterogeneous, consisting of a majority of 'peripheral nodes' that have only a few sexual interactions and a minority of 'hub nodes' that have many sexual interactions. Inferring HIV-1 transmission networks using this novel combined approach reveals remarkable correlations between high out-degree individuals and longer untreated infection periods. These findings signify the importance of early treatment and support the potential benefit of wide population screening, management of early diagnoses and anticipated antiretroviral treatment to prevent viral transmission and spread. The approach presented here for reconstructing HIV-1 transmission networks

  5. [Use of dried blood spots in early diagnosis of HIV-1 infection in children born to HIV-infected mothers as part of the prevention of mother-to-child transmission in Benin].

    Science.gov (United States)

    Tchiakpe, E; Hounto-Ogouyemi, A; Diop Ndiaye, H; Diouara, A A M; Aïssi, A K; Keke, R K; Kpangon, A A; Lafia, B; Métadokou, D; Bouraïma, B; Anthony, D; Hounsinou, A; Alao, M J; Azondekon, A; Ahouidi, A D; Bei, A K; Mbengue, M A S; Touré Kane, C; Zannou, D M

    2016-08-01

    The goal of this study was to evaluate using the molecular diagnosis, infection transmission rate of HIV in children born to HIV-1 positive mothers as part of the prevention of mother-to-child transmission (PMTCT) in Benin. The sample consisted of 524 dried blood spots (DBS) of children born to HIV-1 positive mothers, from 30 sites (PMTCT) taken between October 2009 and June 2010. The diagnosis of HIV-1 was performed by the qualitative detection of viral nucleic acids (RNA and DNA) in DBS on filter paper using the Abbott RealTime(®) HIV-1 Qualitative assay. We found that 51 DBS were positive (9.7%) and 473 were negative (90.3%). The failure rate of PMTCT among 420 mothers who received antiretroviral prophylaxis was 6.7% (28/420). This failure rate was significantly higher among children born to infected mothers on antiretroviral monotherapy than on triple therapy (HAART). The results of our study enrich the data in the literature on highly active antiretroviral chemoprophylaxis to reduce the transmission of HIV-1 from mother to child.

  6. Efficient human immunodeficiency virus (HIV-1) infection of cells lacking PDZD8.

    Science.gov (United States)

    Zhang, Shijian; Sodroski, Joseph

    2015-07-01

    PDZD8 can bind the capsid proteins of different retroviruses, and transient knockdown of PDZD8 results in a decrease in the efficiency of an early, post-entry event in the retrovirus life cycle. Here we used the CRISPR-CAS9 system to create cell lines in which PDZD8 expression is stably eliminated. The PDZD8-knockout cell lines were infected by human immunodeficiency virus (HIV-1) and murine leukemia virus as efficiently as the parental PDZD8-expressing cells. These results indicate that PDZD8 is not absolutely necessary for HIV-1 infection and diminishes its attractiveness as a potential target for intervention.

  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. Humanized mice dually challenged with R5 and X4 HIV-1 show preferential R5 viremia and restricted X4 infection of CCR5(+)CD4(+) T cells.

    Science.gov (United States)

    Terahara, Kazutaka; Ishige, Masayuki; Ikeno, Shota; Okada, Seiji; Kobayashi-Ishihara, Mie; Ato, Manabu; Tsunetsugu-Yokota, Yasuko

    2015-05-01

    CCR5-tropic (R5) immunodeficiency virus type 1 (HIV-1) strains are highly transmissible during the early stage of infection in humans, whereas CXCR4-tropic (X4) strains are less transmissible. This study aimed to explore the basis for early phase R5 and X4 HIV-1 infection in vivo by using humanized mice dually challenged with R5 HIV-1NLAD8-D harboring DsRed and X4 HIV-1(NL-E) harboring EGFP. Whereas R5 HIV-1 replicated well, X4 HIV-1 caused only transient viremia with variable kinetics; however, this was distinct from the low level but persistent viremia observed in mice challenged with X4 HIV-1 alone. Flow cytometric analysis of HIV-1-infected cells revealed that X4 HIV-1 infection of CCR5(+)CD4(+) T cells was significantly suppressed in the presence of R5 HIV-1. X4 HIV-1 was more cytopathic than R5 HIV-1; however, this was not the cause of restricted X4 HIV-1 infection because there were no significant differences in the mortality rates of CCR5(+) and CCR5(-) cells within the X4 HIV-1-infected cell populations. Taken together, these results suggest that restricted infection of CCR5(+)CD4(+) T cells by X4 HIV-1 (occurring via a still-to-be-identified mechanism) might contribute to the preferential transmission of R5 HIV-1 during the early phase of infection.

  9. Laser irradiation reduces HIV-1 infection in TZM-bl cells

    CSIR Research Space (South Africa)

    Lugongolo, Masixole Y

    2016-10-01

    Full Text Available HIV-1 epidemic remains a major health challenge. This study explores the effects of low level laser therapy on HIV-1 infected cells. Infection is reduced by irradiation and the mechanism needs to be investigated further....

  10. Δ(9)-Tetrahydrocannabinol treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection.

    Science.gov (United States)

    Williams, Julie C; Appelberg, Sofia; Goldberger, Bruce A; Klein, Thomas W; Sleasman, John W; Goodenow, Maureen M

    2014-06-01

    The major psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), also acts to suppress inflammatory responses. Receptors for THC, CB1, CB2, and GPR55, are differentially expressed on multiple cell types including monocytes and macrophages, which are important modulators of inflammation in vivo and target cells for HIV-1 infection. Use of recreational and medicinal marijuana is increasing, but the consequences of marijuana exposure on HIV-1 infection are unclear. Ex vivo studies were designed to investigate effects on HIV-1 infection in macrophages exposed to THC during or following differentiation. THC treatment of primary human monocytes during differentiation reduced HIV-1 infection of subsequent macrophages by replication competent or single cycle CCR5 using viruses. In contrast, treatment of macrophages with THC immediately prior to or continuously following HIV-1 exposure failed to alter infection. Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2. THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell, while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle. Cells treated during differentiation with THC displayed reduced expression of CD14, CD16, and CD163 and donor dependent increases in mRNA expression of selected viral restriction factors, suggesting a fundamental alteration in phenotype. Ultimately, the mechanism of THC suppression of HIV-1 infection was traced to a reduction in cell surface HIV receptor (CD4, CCR5 and CXCR4) expression that diminished entry efficiency.

  11. Δ9-tetrahydrocannabinol treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection

    Science.gov (United States)

    Williams, Julie C.; Appelberg, Sofia; Goldberger, Bruce A.; Klein, Thomas W.; Sleasman, John W.; Goodenow, Maureen M.

    2014-01-01

    The major psychoactive component of marijuana, Δ9-tetrahydrocannabinol (THC), also acts to suppress inflammatory responses. Receptors for THC, CB1, CB2, and GPR55, are differentially expressed on multiple cell types including monocytes and macrophages, which are important modulators of inflammation in vivo and target cells for HIV-1 infection. Use of recreational and medicinal marijuana is increasing, but the consequences of marijuana exposure on HIV-1 infection are unclear. Ex vivo studies were designed to investigate effects on HIV-1 infection in macrophages exposed to THC during or following differentiation. THC treatment of primary human monocytes during differentiation reduced HIV-1 infection of subsequent macrophages by replication competent or single cycle CCR5 using viruses. In contrast, treatment of macrophages with THC immediately prior to or continuously following HIV-1 exposure failed to alter infection. Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2. THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell, while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle. Cells treated during differentiation with THC displayed reduced expression of CD14, CD16, and CD163 and donor dependent increases in mRNA expression of selected viral restriction factors, suggesting a fundamental alteration in phenotype. Ultimately, the mechanism of THC suppression of HIV-1 infection was traced to a reduction in cell surface HIV receptor (CD4, CCR5 and CXCR4) expression that diminished entry efficiency. PMID:24562630

  12. Innate immune activation in primary HIV-1 infection.

    Science.gov (United States)

    Chang, J Judy; Altfeld, Marcus

    2010-10-15

    There is growing evidence that highlights the role of the immune response during acute human immunodeficiency virus type 1 (HIV-1) infection in the control or development of disease. The adaptive immune responses do not appear until after HIV-1 infection is already well established, so the role of earlier and faster-responding innate immunity needs to be more closely scrutinized. In particular, 2 aspects of innate immunity for which there are growing research developments will be examined in this review: the actions of type I interferons and natural killer cells. These two components of the innate immune response contribute to viral control both by killing infected cells and by modulating other immune cells that develop. However, the role of interferon α in immune activation is a double-edged sword, causing recruitment of adaptive immune cells that can assist in viral control but concurrently contributing to immune activation-dependent disease progression. Understanding the complexity of how innate responses affect the outcome of HIV-1 infection will help in the development of vaccines that can use innate immunity to enhance viral control with minimal pathogenesis.

  13. Early detection of HIV infection with Dried Blood Spot testing among infants in Yunnan province%滤纸片干血斑HIV-1DNA检测技术在婴儿HIV早期诊断中的应用

    Institute of Scientific and Technical Information of China (English)

    杨朝军; 陈敏; 陈玲; 苏莹珍; 陈会超; 闫文云; 杨莉

    2012-01-01

    目的 探讨滤纸片干血斑技术在婴儿HIV早期诊断中的应用效果.方法 于2010-2011年在云南省昆明、大理、德宏和临沧市(州)的14个妇幼保健院中,对所有感染HIV的孕妇所生的6周至18个月的婴儿进行调查,共计286名.采用滤纸片干血斑采血与罗氏HIV-1 DNA检测技术对HIV感染产妇所生的婴儿进行HIV早期诊断研究,并与18个月时婴儿的HIV抗体结果进行比较.同时阶段性采集并检测滤纸片干血斑的HIV抗体,了解未感染HIV婴儿的抗体阴转时间.并对孕妇抗病毒治疗情况及婴儿母乳喂养情况进行调查.结果 在286名婴儿中,有148名男性、138名女性.对286名婴儿进行了HIV-1 DNA检测,有8名婴儿HIV-1 DNA检测结果为阳性,HIV感染率为2.8%(8/286),与18个月时婴儿的HIV抗体检测结果完全一致;其余278名DNA检测结果为阴性的婴儿,其抗体也均为阴性.对143名HIV-1 DNA阴性的婴儿进行随访,其在出生后6、9、12和18个月时的累计抗体阴转率分别是14.0%(20/143)、61.5%(88/143)、88.1% (126/143)和100.0%( 143/143).286例感染HIV的孕妇中,抗病毒治疗组孕妇所生婴儿的HIV感染率为2.14%(6/280),未抗病毒治疗孕妇组婴儿HIV感染率为33.33% (2/6),差异有统计学意义(P<0.01).人工喂养组婴儿的HIV感染率为2.55% (7/274),纯母乳喂养组婴儿HIV感染率为8.33%(1/12).结论 滤纸片干血斑HIV-1 DNA检测方法可以较好地应用于6周至18个月龄婴儿HIV感染的早期诊断.%Objective To explore the application od Dried Blood Spot (DBS) testing for early detection of HIV infection among infants.Methods All of the infants aged between 6 weeks and 18 months and born by HIV positive mothers from 14 Maternity and Child Health Care Hospitals in Kunming,Dali,Dehong,Lincang of Yunnan province were investigated from 2010 to 2011.By using DBS and Roche HIV-1 DNA test techniques,286 infants were tested for HIV early diagnosis and

  14. Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.

    Directory of Open Access Journals (Sweden)

    Katharine J Bar

    Full Text Available Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC(50 selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical

  15. Altered sialylation of alveolar macrophages in HIV-1-infected individuals.

    Science.gov (United States)

    Perrin, C; Giordanengo, V; Bannwarth, S; Blaive, B; Lefebvre, J C

    1997-10-01

    In previous studies, we have demonstrated that O-glycans at the surface of HIV-1-infected cell lines were hyposialylated. Moreover, we and others have shown that HIV+ individuals produced autoantibodies that react with hyposialylated CD43, on T cell lines. Since the autoantigen responsible for this abnormal immune response was not easily found in the peripheral blood cells of corresponding patients, we searched for its possible presence in other sites. Using fluorescence staining of alveolar macrophages with various lectins, we show that the binding of the PNA lectin specific for asialo O-glycans is much more efficient on cells from HIV-1-infected individuals. Moreover, the degree of reactivity of PNA is correlated with the clinical stage of the illness.

  16. HIV-1 clade B pol evolution following primary infection.

    Directory of Open Access Journals (Sweden)

    George K Hightower

    Full Text Available OBJECTIVE: Characterize intra-individual HIV-1 subtype B pol evolution in antiretroviral naive individuals. DESIGN: Longitudinal cohort study of individuals enrolled during primary infection. METHODS: Eligible individuals were antiretroviral naïve participants enrolled in the cohort from December 1997-December 2005 and having at least two blood samples available with the first one collected within a year of their estimated date of infection. Population-based pol sequences were generated from collected blood samples and analyzed for genetic divergence over time in respect to dual infection status, HLA, CD4 count and viral load. RESULTS: 93 participants were observed for a median of 1.8 years (Mean = 2.2 years, SD =1.9 years. All participants classified as mono-infected had less than 0.7% divergence between any two of their pol sequences using the Tamura-Nei model (TN93, while individuals with dual infection had up to 7.0% divergence. The global substitution rates (substitutions/nucleotide/year for mono and dually infected individuals were significantly different (p<0.001; however, substitution rates were not associated with HLA haplotype, CD4 or viral load. CONCLUSIONS: Even after a maximum of almost 9 years of follow-up, all mono-infected participants had less than 1% divergence between baseline and longitudinal sequences, while participants with dual infection had 10 times greater divergence. These data support the use of HIV-1 pol sequence data to evaluate transmission events, networks and HIV-1 dual infection.

  17. Phenotypic Knockout of HIV-1 Chemokine Coreceptor CXCR4 and CCR5 by Intrakines for Blocking HIV-1 Infection

    Institute of Scientific and Technical Information of China (English)

    张颖; 张岩; 王平忠; 王九平; 黄长形; 孙永涛; 白雪帆

    2004-01-01

    To investigate the phenotypic knockout of HIV-1 chemokine coreceptor CXCR4 and CCR5 by intrakines and its inhibitory effect on HIV-1 infection. Primary human PBLs were transduced with the recombinant vector pLNCX-R-K-S-K(△NGFR), followed by anti-NGFR/anti-IgG-magnetic bead method selection and FCM detection. The transduced PBLs were infected with DP1 HIV-1 virus thereafter envelope-mediated syncytium formation and p24 detection were carried out to study the blockage of HIV-1 infection by co-inactivation of CCR5 and CXCR4. pLNCX-R-K-S-K (△NGFR)-transduced PBILs were isolated with an anti-NGFR/anti-IgG-magnetic bead method. After isolation, about 70% of the PBLs were positive for the NGFR marker. When the transduced PBLs were infected with DP1 HIV-1 virus, envelop-mediated syncytium formation was almost completely inhibited by pLNCX-R-K-S-K(△NGFR) transfection. Also, p24 antigen was very low in the cultures of pLNCX-R-K-S-K (△NGFR) transduced PBLs. pLNCX-R-K-S-K(△NGFR) transduction inhibited the production of DP1 p24 antigen by 15%, 43% and 19% on days 4, 7 and 10 respectively. The lymphocytes with the phenotypic knockout of CCR5 and CXCR4 could protect primary human PBLs from DP1 HIV-1 virus infection.

  18. Proviral HIV-1 DNA in gingival crevicular fluid of HIV-1-infected patients in various stages of HIV disease.

    Science.gov (United States)

    Maticic, M; Poljak, M; Kramar, B; Tomazic, J; Vidmar, L; Zakotnik, B; Skaleric, U

    2000-07-01

    The oral cavity is rarely reported to be a site of human immunodeficiency virus (HIV) transmission, despite detectable virus in saliva and relatively frequent prevalence of periodontal disease in HIV-infected persons yielding increased excretion of mononuclear-cell-enriched gingival fluid. To search for possible sources of HIV in saliva, and using the polymerase chain-reaction technique, we sought the presence and shedding patterns of proviral HIV-1 DNA in gingival crevicular fluid in a group of patients previously determined as HIV-1-seropositive. Periodontal status at the collection sites was monitored by several clinical parameters, including Plaque Index, Gingival Index, probing depth, and clinical attachment loss. Gingival crevicular fluid samples were collected by means of paper points. Proviral HIV-1 DNA was detected in the gingival fluid of 17 out of 35 HIV-1-infected patients. Its detection correlated significantly with higher plasma HIV-1 RNA viral load (p = 0.03) and not with peripheral blood CD4+ cell count, the presence of blood in gingival fluid, or oral lesions. There was a significant correlation between clinical attachment loss at the sites of fluid collection and plasma HIV-1 RNA viral load (p = 0.002), and borderline correlation between the latter and probing depth (p = 0.54) in the group of patients harboring proviral HIV-1 DNA in gingival crevicular fluid. The results of our study suggest that mononuclear cells present in gingival crevicular fluid and harboring proviral HIV-1 DNA could represent a potential source of HIV-1 in the presence or absence of local bleeding, especially in persons with advanced HIV infection and increased loss of clinical attachment.

  19. Proteomic modeling for HIV-1 infected microglia-astrocyte crosstalk.

    Directory of Open Access Journals (Sweden)

    Tong Wang

    Full Text Available HIV-1-infected and immune competent brain mononuclear phagocytes (MP; macrophages and microglia secrete cellular and viral toxins that affect neuronal damage during advanced disease. In contrast, astrocytes can affect disease by modulating the nervous system's microenvironment. Interestingly, little is known how astrocytes communicate with MP to influence disease.MP-astrocyte crosstalk was investigated by a proteomic platform analysis using vesicular stomatitis virus pseudotyped HIV infected murine microglia. The microglial-astrocyte dialogue was significant and affected microglial cytoskeleton by modulation of cell death and migratory pathways. These were mediated, in part, through F-actin polymerization and filament formation. Astrocyte secretions attenuated HIV-1 infected microglia neurotoxicity and viral growth linked to the regulation of reactive oxygen species.These observations provide unique insights into glial crosstalk during disease by supporting astrocyte-mediated regulation of microglial function and its influence on the onset and progression of neuroAIDS. The results open new insights into previously undisclosed pathogenic mechanisms and open the potential for biomarker discovery and therapeutics that may influence the course of HIV-1-mediated neurodegeneration.

  20. Dendritic cells are less susceptible to human immunodeficiency virus type 2 (HIV-2) infection than to HIV-1 infection

    NARCIS (Netherlands)

    M.G. Duvall (Melody); K. Loré (Karin); H. Blaak (Hetty); D.A. Ambrozak (David); W.C. Adams (William); K. Santos (Kathlyn); C. Geldmacher (Christof); J.R. Mascola (John); A.J. McMichael (Andrew); A. Jaye (Assan); H. Whittle (Hilton); S.L. Rowland-Jones (Sarah); R.A. Koup (Richard)

    2007-01-01

    textabstractHuman immunodeficiency virus type 1 (HIV-1) infection of dendritic cells (DCs) has been documented in vivo and may be an important contributor to HIV-1 transmission and pathogenesis. HIV-1-specific CD4+T cells respond to HIV antigens presented by HIV-1-infected DCs and in this process

  1. Exercise and Human Immunodeficiency Virus (HIV-1) Infection

    Science.gov (United States)

    Lawless, DeSales; Jackson, Catherine G. R.; Greenleaf, John E.

    1995-01-01

    The human immune system is highly efficient and remarkably protective when functioning properly. Similar to other physiological systems, it functions best when the body is maintained with a balanced diet, sufficient rest and a moderately stress-free lifestyle. It can be disrupted by inappropriate drug use and extreme emotion or exertion. The functioning of normal or compromised immune systems can be enhanced by properly prescribed moderate exercise conditioning regimens in healthy people, and in some human immunodeficiency virus (HIV-1)-infected patients but not in others who unable to complete an interval training program. Regular exercise conditioning in healthy people reduces cardiovascular risk factors, increases stamina, facilitates bodyweight control, and reduces stress by engendering positive feelings of well-being. Certain types of cancer may also be suppressed by appropriate exercise conditioning. Various exercise regimens are being evaluated as adjunct treatments for medicated patients with the HIV-1 syndrome. Limited anecdotal evidence from patients suggests that moderate exercise conditioning is per se responsible for their survival well beyond expectancy. HIV-1-infected patients respond positively, both physiologically and psychologically, to moderate exercise conditioning. However, the effectiveness of any exercise treatment programme depends on its mode, frequency, intensity and duration when prescribed o complement the pathological condition of the patient. The effectiveness of exercise conditioning regimens in patients with HIV-1 infection is reviewed in this article. In addition, we discuss mechanisms and pathways, involving the interplay of psychological and physiological factors, through which the suppressed immune system can be enhanced. The immune modulators discussed are endogenous opioids, cytokines, neurotransmitters and other hormones. Exercise conditioning treatment appears to be more effective when combined with other stress management

  2. High prevalence of CXCR4-using viruses in vertically HIV-1-infected infants in Thailand

    Directory of Open Access Journals (Sweden)

    T Samleerat

    2012-11-01

    observations may have implications for clinical and therapeutic aspects, especially in the early stage of HIV-1 infection in infants and may benefits for using of CCR5-antagonists in this population.

  3. Quantitative image analysis of HIV-1 infection in lymphoid tissue

    Energy Technology Data Exchange (ETDEWEB)

    Haase, A.T.; Zupancic, M.; Cavert, W. [Univ. of Minnesota Medical School, Minneapolis, MN (United States)] [and others

    1996-11-08

    Tracking human immunodeficiency virus-type 1 (HIV-1) infection at the cellular level in tissue reservoirs provides opportunities to better understand the pathogenesis of infection and to rationally design and monitor therapy. A quantitative technique was developed to determine viral burden in two important cellular compartments in lymphoid developed to determine viral burden in two important cellular compartments in lymphoid tissues. Image analysis and in situ hybridization were combined to show that in the presymptomatic stages of infection there is a large, relatively stable pool of virions on the surfaces of follicular dendritic cells and a smaller pool of productivity infected cells. Despite evidence of constraints on HIV-1 replication in the infected cell population in lymphoid tissues, estimates of the numbers of these cells and the virus they could produce are consistent with the quantities of virus that have been detected in the bloodstream. The cellular sources of virus production and storage in lymphoid tissues can now be studied with this approach over the course of infection and treatment. 22 refs., 2 figs., 2 tabs.

  4. Neutralizing antibodies in slowly progressing HIV-1 infection

    DEFF Research Database (Denmark)

    Schønning, Kristian; Nielsen, C; Iversen, Johan

    1995-01-01

    Ten asymptomatic individuals who had experienced only limited CD4+ cell loss after prolonged infection with HIV-1 were studied. These individuals had a mean CD4+ cell count of 674 x 10(6) cells/L and a mean duration of infection of 8.5 years. Also included were 10 asymptomatic HIV-1-infected...... individuals who, over a similar period of infection (7.5 years), had experienced a profound loss of CD4+ cells (mean CD4+ cell count, 54 x 10(6) cells/L). Proviral load was determined using a semiquantitative polymerase chain reaction and was significantly lower in the subjects with slowly progressing...... infection (SPI) than in subjects with rapidly progressing infection (RPI) (4,000 vs. 40,000 proviral copies/10(6) peripheral blood mononuclear cells; p = 0.0089). Isolation of virus was attempted in all individuals but succeeded only in 6 of 10 individuals with SPI versus all 10 individuals with RPI. Four...

  5. Pandemic Influenza A (H1N1) Virus Infection Increases Apoptosis and HIV-1 Replication in HIV-1 Infected Jurkat Cells.

    Science.gov (United States)

    Wang, Xue; Tan, Jiying; Biswas, Santanu; Zhao, Jiangqin; Devadas, Krishnakumar; Ye, Zhiping; Hewlett, Indira

    2016-02-02

    Influenza virus infection has a significant impact on public health, since it is a major cause of morbidity and mortality. It is not well-known whether influenza virus infection affects cell death and human immunodeficiency virus (HIV)-1 replication in HIV-1-infected patients. Using a lymphoma cell line, Jurkat, we examined the in vitro effects of pandemic influenza A (H1N1) virus (pH1N1) infection on cell death and HIV-1 RNA production in infected cells. We found that pH1N1 infection increased apoptotic cell death through Fas and Bax-mediated pathways in HIV-1-infected Jurkat cells. Infection with pH1N1 virus could promote HIV-1 RNA production by activating host transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), nuclear factor of activated T-cells (NFAT) and activator protein 1 (AP-1) through mitogen-activated protein kinases (MAPK) pathways and T-cell antigen receptor (TCR)-related pathways. The replication of HIV-1 latent infection could be reactivated by pH1N1 infection through TCR and apoptotic pathways. These data indicate that HIV-1 replication can be activated by pH1N1 virus in HIV-1-infected cells resulting in induction of cell death through apoptotic pathways.

  6. Sentinel Surveillance of HIV-1 Transmitted Drug Resistance, Acute Infection and Recent Infection

    Science.gov (United States)

    Truong, Hong-Ha M.; Kellogg, Timothy A.; McFarland, Willi; Louie, Brian; Klausner, Jeffrey D.; Philip, Susan S.; Grant, Robert M.

    2011-01-01

    -line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug resistance, recent infection, and acute infection testing should be considered for existing HIV/STI surveillance and prevention activities, particularly in an era of enhanced efforts for early diagnosis and treatment. PMID:22046237

  7. Sentinel surveillance of HIV-1 transmitted drug resistance, acute infection and recent infection.

    Directory of Open Access Journals (Sweden)

    Hong-Ha M Truong

    Full Text Available HIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection.A consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI clinic from 2004 to 2006 (N = 9,868 were evaluated by standard enzyme-linked immunoassays (EIA. HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36. Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI was the most common pattern detected, present in 28 cases of resistance (59.6%. Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p<0.001, unprotected anal intercourse (AOR = 2.27; p<0.001, sex with a known HIV-infected partner (AOR = 1.64; p = 0.02, and history of gonorrhea (AOR = 1.62; p = 0.03.New HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first-line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug

  8. Cell-specific RNA aptamer against human CCR5 specifically targets HIV-1 susceptible cells and inhibits HIV-1 infectivity.

    Science.gov (United States)

    Zhou, Jiehua; Satheesan, Sangeetha; Li, Haitang; Weinberg, Marc S; Morris, Kevin V; Burnett, John C; Rossi, John J

    2015-03-19

    The C-C chemokine receptor type 5 (CCR5) is a receptor expressed by T cells and macrophages that serves as a coreceptor for macrophage-tropic HIV-1. Loss of CCR5 is associated with resistance to HIV-1. Here, we combine the live-cell-based SELEX with high-throughput sequencing technology to generate CCR5 RNA aptamers capable of specifically targeting HIV-1 susceptible cells (as small interfering RNA [siRNA] delivery agent) and inhibiting HIV-1 infectivity (as antiviral agent) via block of the CCR5 required for HIV-1 to enter cells. One of the best candidates, G-3, efficiently bound and was internalized into human CCR5-expressing cells. The G-3 specifically neutralized R5 virus infection in primary peripheral blood mononuclear cells, and in vivo generated human CD4(+) T cells with a nanomolar inhibitory concentration 50%. G-3 was also capable of transferring functional siRNAs to CCR5-expressing cells. Collectively, the cell-specific, internalizing, CCR5-targeted aptamers and aptamer-siRNA conjugates offer promise for overcoming some of the current challenges of drug resistance in HIV-1 by providing cell-type- or tissue-specific delivery of various therapeutic moieties.

  9. Prognostic value of a CCR5 defective allele in pediatric HIV-1 infection.

    OpenAIRE

    2000-01-01

    BACKGROUND: A deletion of 32 base pairs in the CCR5 gene (delta32 CCR5) has been linked to resistance to HIV-1 infection in exposed adults and to the delay of disease progression in infected adults. MATERIALS AND METHODS: To determine the role of delta32 CCR5 in disease progression of HIV-1 infected children born to seropositive mothers, we studied a polymerase chain reaction in 301 HIV-1 infected, 262 HIV-1 exposed-uninfected and 47 HIV-1 unexposed-uninfected children of Spanish and Italian ...

  10. HTLV-1/-2 and HIV-1 Co-infections: Retroviral Interference On Host Immune Status

    Directory of Open Access Journals (Sweden)

    Elisabetta ePilotti

    2013-12-01

    Full Text Available The human retroviruses HIV-1 and HTLV-1/HTLV-2 share similar routes of transmission but cause significantly different diseases. In this review we have outlined the immune mediated mechanisms by which HTLVs affect HIV-1 disease in co-infected hosts. During co-infection with HIV-1, HTLV-2 modulates the cellular microenvironment favoring its own viability and inhibiting HIV-1 progression. This is achieved when the HTLV-2 proviral load is higher than that of HIV-1, and thanks to the ability of HTLV-2 to: i up-regulate viral suppressive CCL3L1 chemokine expression; ii overcome HIV-1 capacity to activate the JAK/STAT pathway; iii reduce the activation of T and NK cells; iv modulate the host miRNA profiles. These alterations of immune functions have been mainly attributed to the effects of the HTLV-2 regulatory protein Tax and suggest that HTLV-2 exerts a protective role against HIV-1 infection. Contrary to HIV-1/HTLV-2, the effect of HIV-1/HTLV-1 co-infection on immunological and pathological conditions is still controversial. There is evidence that indicate a worsening of HIV-1 infection, while other evidence does not show clinically relevant effects in HIV-positive people. Possible differences on innate immune mechanisms and a particularly impact on NK cells are becoming evident. The differences between the two HIV-1/HTLV-1 and HIV-1/HTLV-2 co-infections are highlighted and further discussed.

  11. The effect of X4 and R5 HIV-1 on C, C-C, and C-X-C chemokines during the early stages of infection in human PBMCs.

    Science.gov (United States)

    Wetzel, Michele A; Steele, Amber D; Henderson, Earl E; Rogers, Thomas J

    2002-01-05

    To better define a mechanism underlying the increase in expression of certain proinflammatory chemokines during HIV-1 infection, we analyzed the effect of X4 HIV-1 infection on C, C-C, and C-X-C chemokine mRNA levels. We demonstrate that X4 HIV-1 infection augments the expression of RANTES, IP-10, MCP-1, and Ltn in peripheral blood mononuclear cells (PBMCs). R5 HIV-1 also induces an increase in both IP-10 and MCP-1 production. Binding of UV-inactivated HIV-1 elevates MCP-1, RANTES, MIP-1alpha, MIP-1beta, and IL-8 expression, but fails to alter the production of IP-10, suggesting that the induction of IP-10 is dependent on downstream events following viral internalization. Indeed, recombinant gp120 alone was able to stimulate an eightfold increase in MCP-1 expression, but was unable to induce any detectable increase in IP-10 protein. HIV-induced modulation of chemokine expression suggests a mechanism by which HIV-infected monocytes and T cells might recruit target cells to sites of active viral replication, thus potentially aiding in the spread of the virus.

  12. HIV-1 Nef sequesters MHC-I intracellularly by targeting early stages of endocytosis and recycling.

    Science.gov (United States)

    Dirk, Brennan S; Pawlak, Emily N; Johnson, Aaron L; Van Nynatten, Logan R; Jacob, Rajesh A; Heit, Bryan; Dikeakos, Jimmy D

    2016-11-14

    A defining characteristic of HIV-1 infection is the ability of the virus to persist within the host. Specifically, MHC-I downregulation by the HIV-1 accessory protein Nef is of critical importance in preventing infected cells from cytotoxic T-cell mediated killing. Nef downregulates MHC-I by modulating the host membrane trafficking machinery, resulting in the endocytosis and eventual sequestration of MHC-I within the cell. In the current report, we utilized the intracellular protein-protein interaction reporter system, bimolecular fluorescence complementation (BiFC), in combination with super-resolution microscopy, to track the Nef/MHC-I interaction and determine its subcellular localization in cells. We demonstrate that this interaction occurs upon Nef binding the MHC-I cytoplasmic tail early during endocytosis in a Rab5-positive endosome. Disruption of early endosome regulation inhibited Nef-dependent MHC-I downregulation, demonstrating that Nef hijacks the early endosome to sequester MHC-I within the cell. Furthermore, super-resolution imaging identified that the Nef:MHC-I BiFC complex transits through both early and late endosomes before ultimately residing at the trans-Golgi network. Together we demonstrate the importance of the early stages of the endocytic network in the removal of MHC-I from the cell surface and its re-localization within the cell, which allows HIV-1 to optimally evade host immune responses.

  13. 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

  14. Community-Based HIV-1 Early Diagnosis and Risk Behavior Analysis of Men Having Sex with Men in Hong Kong.

    Science.gov (United States)

    Liang, Jianguo; Liu, Li; Cheung, Mandy; Lee, Man-Po; Wang, Haibo; Li, Chun-Ho; Chan, Chun-Chung; Nishiura, Kenji; Tang, Xian; Tan, Zhiwu; Peng, Jie; Cheung, Ka-Wai; Yam, Wing-Cheong; Chen, Zhiwei

    2015-01-01

    The increasing prevalence of HIV-1 among men having sex with men (MSM) calls for an investigation of HIV-1 prevalence and incidence in MSM by early diagnosis to assist with early preventive interventions in Hong Kong. The participants were recruited randomly from MSM communities within a one-year period. Rapid HIV Test (RHT) and real-time dried blood spot (DBS)-based quantitative polymerase chain reaction (DBS-qPCR) were used for the early diagnosis of 474 participants. Risk behavior analysis was performed by studying information obtained from the participants during the study period. The HIV-1 prevalence and incident rates in the studied MSM population were 4.01% (19/474) and 1.47% (7/474), respectively. Three infected participants were found at the acute phase of infection by DBS-qPCR. Only 46.4% (220/474) MSM were using condoms regularly for anal sex. HIV infection significantly correlated with unprotected receptive anal sex and syphilis infection. An increased number of infections was found among foreign MSM in Hong Kong. This study is the first to use DBS-qPCR to identify acutely infected individuals in a community setting and to provide both the prevalence and incident rates of HIV-1 infection among MSM in Hong Kong. The risk analysis provided evidence that behavior intervention strengthening is necessary to fight against the increasing HIV-1 epidemic among MSM in Hong Kong and surrounding regions in Asia.

  15. HIV-1 infection: no evidence of cognitive decline during the asymptomatic stages. The Multicenter AIDS Cohort Study.

    Science.gov (United States)

    Selnes, O A; Miller, E; McArthur, J; Gordon, B; Muñoz, A; Sheridan, K; Fox, R; Saah, A J

    1990-02-01

    Cross-sectional studies have not adequately resolved the question of whether subjects infected with HIV-1 may suffer cognitive decline during the early, asymptomatic stages of the infection. We studied longitudinally 238 asymptomatic healthy HIV-1-infected homosexual/bisexual men (CDC groups 2 and 3) and 170 uninfected controls in the Multicenter AIDS Cohort Study with neuropsychological testing at semiannual intervals. A comparison of change in scores between visits 1 and 4 as well as a multivariate autoregressive analysis revealed no evidence of decline in test performance over time in the HIV-1-infected group compared with the seronegative controls. These findings suggest that a gradual cognitive decline does not occur during the early, asymptomatic stages of HIV infection.

  16. Iron status in HIV-1 infection: implications in disease pathology

    Directory of Open Access Journals (Sweden)

    Banjoko S Olatunbosun

    2012-12-01

    Full Text Available Abstract Background There had been conflicting reports with levels of markers of iron metabolism in HIV infection. This study was therefore aimed at investigating iron status and its possible mediation of severity of HIV- 1 infection and pathogenesis. Method Eighty (80 anti-retroviral naive HIV-1 positive and 50 sero-negative controls were recruited for the study. Concentrations of serum total iron, transferrin, total iron binding capacity (TIBC, CD4+ T -lymphocytes, vitamin C, zinc, selenium and transferrin saturation were estimated. Results The mean CD4+ T-lymphocyte cell counts, serum iron, TIBC, transferrin saturation for the tests and controls were 319 ± 22, 952 ± 57 cells/μl (P 4+ T-lymphocyte cell count had a positive correlation with levels of vitamin C (r = 0.497, P Conclusion It could be inferred that derangement in iron metabolism, in addition to oxidative stress, might have contributed to the depletion of CD4+ T cell population in our subjects and this may result in poor prognosis of the disease.

  17. Changes in Natural Killer cell activation and function during primary HIV-1 Infection.

    Directory of Open Access Journals (Sweden)

    Vivek Naranbhai

    Full Text Available BACKGROUND: Recent reports suggest that Natural Killer (NK cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection. METHODOLOGY/PRINCIPAL FINDINGS: Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α(4β(7. Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p<0.0001, respectively, but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p<0.0001; post-infection, during primary infection r = 0.074;p = 0.09. Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32'p = 0.04 and r = 0.35;p = 0.02, respectively. The frequency of Killer Immunoglobulin-like Receptor-expressing (KIR(pos NK cells increased following HIV acquisition (p = 0.006, and KIR(pos NK cells were less activated than KIR(neg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p<0.0001 respectively. During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively. However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated

  18. Perinatal acquisition of drug-resistant HIV-1 infection: mechanisms and long-term outcome

    Directory of Open Access Journals (Sweden)

    Dollfus Catherine

    2009-09-01

    Full Text Available Abstract Background Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns. Patients and Methods We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing. Results Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%: drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available and in newborn lymphocytes (6/8 suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10 and neonatal lymphocytes (2/8 suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped. Conclusion This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%, drug

  19. Dynamics of a stochastic HIV-1 infection model with logistic growth

    Science.gov (United States)

    Jiang, Daqing; Liu, Qun; Shi, Ningzhong; Hayat, Tasawar; Alsaedi, Ahmed; Xia, Peiyan

    2017-03-01

    This paper is concerned with a stochastic HIV-1 infection model with logistic growth. Firstly, by constructing suitable stochastic Lyapunov functions, we establish sufficient conditions for the existence of ergodic stationary distribution of the solution to the HIV-1 infection model. Then we obtain sufficient conditions for extinction of the infection. The stationary distribution shows that the infection can become persistent in vivo.

  20. Rapid selection of escape mutants by the first CD8 T cell responses in acute HIV-1 infection

    Energy Technology Data Exchange (ETDEWEB)

    Korber, Bette Tina Marie [Los Alamos National Laboratory

    2008-01-01

    The recent failure of a vaccine that primes T cell responses to control primary HIV-1 infection has raised doubts about the role of CD8+ T cells in early HIV-1 infection. We studied four patients who were identified shortly after HIV-1 infection and before seroconversion. In each patient there was very rapid selection of multiple HIV-1 escape mutants in the transmitted virus by CD8 T cells, including examples of complete fixation of non-synonymous substitutions within 2 weeks. Sequencing by single genome amplification suggested that the high rate of virus replication in acute infection gave a selective advantage to virus molecules that contained simultaneous and gained sequential T cell escape mutations. These observations show that whilst early HIV-1 specific CD8 T cells can act against virus, rapid escape means that these T cell responses are unlikely to benefit the patient and may in part explain why current HIV-1 T cell vaccines may not be protective.

  1. An inhibition enzyme immunoassay, using a human monoclonal antibody (K14) reactive with gp41 of HIV-1, for the serology of HIV-1 infections.

    NARCIS (Netherlands)

    V.J.P. Teeuwsen; J.J. Schalken; G. van der Groen (Guido); R. van den Akker (Ruud); J. Goudsmit (Jaap); A.D.M.E. Osterhaus (Albert)

    1991-01-01

    textabstractAn inhibition enzyme immunoassay (IEIA), using a human monoclonal antibody (K14) reactive with gp41 of HIV-1, was evaluated for its applicability to the serology of HIV-1 infections. Using panels of serum samples from seronegative and confirmed HIV-1-seropositive individuals, it was show

  2. HIV-1 and GBV-C co-infection in Venezuela.

    Science.gov (United States)

    Rodríguez, Anny Karely; Garzaro, Domingo José; Loureiro, Carmen Luisa; Gutiérrez, Cristina R; Ameli, Gladys; Jaspe, Rossana Celeste; Porto, Leticia; Monsalve, Francisca; Pozada, Ángela; Vázquez, Luzmary; Quiñones-Mateu, Miguel E; Pujol, Flor Helene; Rangel, Héctor Rafael

    2014-07-14

    Co-infection with GB virus C (GBV-C) in patients infected with human immunodeficiency virus 1 (HIV-1) has been associated with prolonged survival. The aim of this study was to evaluate the prevalence of GBV-C infection among HIV-1-infected patients in Venezuela, and to determine the effects of the co-infection on the levels of relevant cytokines. Plasma samples were collected from 270 HIV-1-seronegative and 255 HIV-1-seropositive individuals. GBV-C infection was determined by RT-PCR of the NS5 region and genotyped by sequence analysis of the 5´UTR region. HIV-1 strains were characterized by sequence analysis of pol, vif, env, and nef genes. Selected cytokines were evaluated by ELISA. Ninety-seven of 525 (18.5%) plasma samples tested positive for GBV-C RNA. A significantly higher prevalence of GBV-C was found among HIV-1 patients compared to HIV-1-seronegative individuals (67/255, 26% versus 30/270, 11%; p HIV-1+GBV-C+ and HIV-1+GBV-C- (p = 0.014), although no differences in CD4+ cell counts were found between both groups. TNFα concentration was higher in HIV-1+GBV-C- than in HIV-1+GBV-C+ patients (25.9 pg/mL versus 17.3 pg/mL; p = 0.02); RANTES expression levels were more variable in GBV-C co-infected patients and more frequently elevated in HIV-1 mono-infected patients compared to patients co-infected with GBV-C. The previously observed beneficial effect of co-infection with HIV-1 and GBV-C on disease progression is complex and might be due in part to a change in the cytokine environment. More studies are required to understand the interaction between both viruses.

  3. Thiolated pyrimidine nucleotides may interfere thiol groups concentrated at lipid rafts of HIV-1 infected cells.

    Science.gov (United States)

    Kanizsai, Szilvia; Ongrádi, Joseph; Aradi, János; Nagy, Károly

    2014-12-01

    Upon HIV infection, cells become activated and cell surface thiols are present in increased number. Earlier we demonstrated in vitro anti-HIV effect of thiolated pyrimidine nucleotide UD29, which interferes thiol function. To further analyse the redox processes required for HIV-1 entry and infection, toxicity assays were performed using HIV-1 infected monolayer HeLaCD4-LTR/ β-gal cells and suspension H9 T cells treated with several thiolated nucleotide derivatives of UD29. Selective cytotoxicity of thiolated pyrimidines on HIV-1 infected cells were observed. Results indicate that thiolated pyrimidine derivates may interfere with -SH (thiol) groups concentrated in lipid rafts of cell membrane and interacts HIV-1 infected (activated) cells resulting in a selective cytotoxicity of HIV-1 infected cells, and reducing HIV-1 entry.

  4. Inhibition of HIV-1 infection by aqueous extracts of Prunella vulgaris L.

    Directory of Open Access Journals (Sweden)

    McCoy Joe-Ann

    2011-04-01

    Full Text Available Abstract Background The mint family (Lamiaceae produces a wide variety of constituents with medicinal properties. Several family members have been reported to have antiviral activity, including lemon balm (Melissa officinalis L., sage (Salvia spp., peppermint (Mentha × piperita L., hyssop (Hyssopus officinalis L., basil (Ocimum spp. and self-heal (Prunella vulgaris L.. To further characterize the anti-lentiviral activities of Prunella vulgaris, water and ethanol extracts were tested for their ability to inhibit HIV-1 infection. Results Aqueous extracts contained more anti-viral activity than did ethanol extracts, displaying potent antiviral activity against HIV-1 at sub μg/mL concentrations with little to no cellular cytotoxicity at concentrations more than 100-fold higher. Time-of-addition studies demonstrated that aqueous extracts were effective when added during the first five hours following initiation of infection, suggesting that the botanical constituents were targeting entry events. Further analysis revealed that extracts inhibited both virus/cell interactions and post-binding events. While only 40% inhibition was maximally achieved in our virus/cell interaction studies, extract effectively blocked post-binding events at concentrations similar to those that blocked infection, suggesting that it was targeting of these latter steps that was most important for mediating inhibition of virus infectivity. Conclusions We demonstrate that aqueous P. vulgaris extracts inhibited HIV-1 infectivity. Our studies suggest that inhibition occurs primarily by interference of early, post-virion binding events. The ability of aqueous extracts to inhibit early events within the HIV life cycle suggests that these extracts, or purified constituents responsible for the antiviral activity, are promising microbicides and/or antivirals against HIV-1.

  5. HIV-1 transmission during early antiretroviral therapy: evaluation of two HIV-1 transmission events in the HPTN 052 prevention study.

    Directory of Open Access Journals (Sweden)

    Li-Hua Ping

    Full Text Available In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART. We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention.

  6. Psychoneuroimmunology and HIV-1.

    Science.gov (United States)

    Antoni, Michael H.; And Others

    1990-01-01

    Presents evidence describing benefits of behavioral interventions such as aerobic exercise training on both psychological and immunological functioning among high risk human immunodeficiency virus-Type 1 (HIV-1) seronegative and very early stage seropositive homosexual men. HIV-1 infection is cast as chronic disease for which early…

  7. KI and WU polyomaviruses and CD4+ cell counts in HIV-1-infected patients, Italy.

    Science.gov (United States)

    Babakir-Mina, Muhammed; Ciccozzi, Massimo; Farchi, Francesca; Bergallo, Massimiliano; Cavallo, Rossana; Adorno, Gaspare; Perno, Carlo Federico; Ciotti, Marco

    2010-09-01

    To investigate an association between KI and WU polyomavirus (KIPyV and WUPyV) infections and CD4+ cell counts, we tested HIV-1-positive patients and blood donors. No association was found between cell counts and virus infections in HIV-1-positive patients. Frequency of KIPyV infection was similar for both groups. WUPyV was more frequent in HIV-1-positive patients.

  8. Early control of HIV-1 infection in long-term nonprogressors followed since diagnosis in the ANRS SEROCO/HEMOCO cohort.

    Science.gov (United States)

    Madec, Yoann; Boufassa, Faroudy; Avettand-Fenoel, Veronique; Hendou, Samia; Melard, Adeline; Boucherit, Soraya; Surzyn, Janina; Meyer, Laurence; Rouzioux, Christine

    2009-01-01

    To clarify early correlates and natural history of HIV long-term nonprogressors (LTNPs) since HIV diagnosis. Patients enrolled in the French ANRS SEROCO/HEMOCO cohort with CD4 count >500 cells/mm3 at HIV diagnosis. LTNP status was defined as being asymptomatic, antiretroviral free, and with CD4 cell count >500 cells/mm3 for >8 years after HIV diagnosis. In LTNPs, we modeled the biological markers' progression through a joint model. Factors associated with loss of LTNP status were identified through a Cox model. Sixty (9%) of 664 patients were identified as LTNPs during follow-up. At enrollment, HIV RNA was 1.85 log copies/10(6) PBMCs and high HIV DNA increase were associated with an increased risk of losing LTNP status [adjusted hazard ratio: 2.8 (1.2-6.8) and 2.2 (1.0-4.8), respectively]. LTNP status is established in the first years of HIV infection, low HIV DNA level at enrollment and slow increase of HIV DNA being associated with maintained LTNP status.

  9. Changes in plasma cytokines after treatment of ascaris lumbricoides infection in individuals with HIV-1 infection.

    Science.gov (United States)

    Blish, Catherine A; Sangaré, Laura; Herrin, Bradley R; Richardson, Barbra A; John-Stewart, Grace; Walson, Judd L

    2010-06-15

    Albendazole treatment of individuals with human immunodeficiency virus type 1 (HIV-1) and Ascaris lumbricoides co-infection has led to significantly improved CD4(+) cell counts and a trend for lower plasma HIV-1 RNA levels in a previous randomized placebo-controlled trial. To define mechanisms by which deworming contributed to changes in markers of HIV-1 disease progression, plasma cytokine levels were evaluated. Albendazole treatment, compared with placebo, was associated with significantly decreased plasma interleukin (IL) 10 levels (P = .01)ot associated with significant changes in levels of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12p70, IL-13, interferon gamma, tumor necrosis factor alpha, or thymic stromal lymphopoietin. Treatment of A. lumbricoides co-infection may delay HIV-1 disease progression by reducing helminth-induced, IL-10-mediated immunosuppression.

  10. Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1 infection.

    Science.gov (United States)

    Bruno, Christopher J; Jacobson, Jeffrey M

    2010-09-01

    The majority of currently available agents for the treatment of HIV-1 infection act by targeting one of several intracellular steps in the viral life cycle. Despite improvements in efficacy and tolerability, the development of viral resistance to these agents is common and significant toxicity and adherence issues still occur. For this reason the development of safe, well tolerated antiviral agents that target a novel step in the viral life cycle remains important. Viral entry into host cells affords several potential extracellular targets for antiretroviral therapy. Ibalizumab, a humanized monoclonal antibody to CD4, the primary host cellular receptor for HIV-1 entry, has been shown to block HIV-1 entry in vitro. Early clinical trials have demonstrated significant antiviral efficacy with a >1 log(10) reduction in viral load when given as monotherapy. Its long half-life, which allows weekly dosing, and its administration as an intravenous infusion differentiate it from other currently available antiretroviral agents. These properties may prove useful in allowing improved drug delivery to patients who have had difficulty adhering to daily oral regimens. Its unique mode of action reduces the risk of cross-resistance with currently available antiretroviral agents, with the potential to expand the choices available to treat drug-resistant HIV-1.

  11. High levels of divergent HIV-1 quasispecies in patients with neurological opportunistic infections in China.

    Science.gov (United States)

    Zhang, Yulin; Wei, Feili; Liang, Qi; Ding, Wei; Qiao, Luxin; Song, Fengli; Liu, Lifeng; Yang, Sufang; Jin, Ronghua; Gu, Jianhua; Li, Ning; Chen, Dexi

    2013-08-01

    Despite the fact that the survival of people infected with human immunodeficiency virus (HIV) has improved worldwide because of the increasingly powerful and highly active antiretroviral therapy, opportunistic infections (OIs) of the central nervous system (CNS) remain a serious burden. HIV-1 is capable of entering the CNS through infected peripheral monocytes, but its effect on OIs of CNS remains unclear. In this study, we investigated the characteristics of HIV-1 in acquired immunodeficiency syndrome (AIDS) patients with CNS OIs. A total of 24 patients with CNS OIs and 16 non-CNS OIs (control) cases were selected. These AIDS patients were infected with HIV-1 by paid blood donors in China. HIV-1 loads in plasma and cerebrospinal fluid (CSF) were detected using RT-PCR, and the C2-V5 region of HIV-1 envelope gene was amplified from viral quasispecies isolated from CSF using nested PCR. The CSF HIV-1 load of CNS OIs was higher than that of non-CNS OIs, but plasma HIV-1 load of CNS OIs was not higher than that of non-CNS OIs. The nucleotide sequence of C2-V5 region of the HIV-1 quasispecies isolated from the CSF of CNS OIs had a high diversity, and the HIV-1 quasispecies isolated from the CSF of CNS OIs revealed R5 tropism as 11/25 charge rule. These results suggest that high levels of divergent HIV-1 quasispecies in the CNS probably contribute to opportunistic infections.

  12. Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection.

    Science.gov (United States)

    Wagh, Kshitij; Bhattacharya, Tanmoy; Williamson, Carolyn; Robles, Alex; Bayne, Madeleine; Garrity, Jetta; Rist, Michael; Rademeyer, Cecilia; Yoon, Hyejin; Lapedes, Alan; Gao, Hongmei; Greene, Kelli; Louder, Mark K; Kong, Rui; Karim, Salim Abdool; Burton, Dennis R; Barouch, Dan H; Nussenzweig, Michel C; Mascola, John R; Morris, Lynn; Montefiori, David C; Korber, Bette; Seaman, Michael S

    2016-03-01

    The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.

  13. HIV-1自然感染中的中和抗体反应%Neutralizing antibodies responses during natural HIV-1 infection

    Institute of Scientific and Technical Information of China (English)

    任彩云; 李妍; 凌虹

    2012-01-01

    中和抗体(Nab)可以防止I型人类免疫缺陷病毒(HIV-1)侵入靶细胞.HIV-1感染数周后即可诱导产生Nab,这些早期抗体只能特异性地中和自体病毒但不能中和异源性病毒.在一些慢性感染者体内则可以检测到可同时中和同源性和异源性病毒的广谱中和抗体(BNab).BNab的靶点通常位于包膜蛋白的保守区域.HIV-1 BNab的产生还受到病毒变异及结构遮盖等因素的限制,同时Nab的中和广度与病毒载量具有相关性.%Neutralizing antibodies can protect a host against the infection by human immunodeficiency virus type 1 (HIV-1).Neutralizing antibodies can be induced several weeks after infection.However,the antibodies induced in the early stage can neutralize only the autologous but not heterologous viruses.Nevertheless,broad neutralizing antibodies,which can neutralize both autologous and heterologous viruses,have been found in some chronic patients.Inaddition,broad neutralizing antibodies usually target the conserved regions of HIV-1 envelope glycoprotein.However,the envelope glycoprotein mutation and its structure shielding limit the induction of these antibodies.

  14. Transmission of single and multiple viral variants in primary HIV-1 subtype C infection.

    Directory of Open Access Journals (Sweden)

    Vladimir Novitsky

    Full Text Available To address whether sequences of viral gag and env quasispecies collected during the early post-acute period can be utilized to determine multiplicity of transmitted HIV's, recently developed approaches for analysis of viral evolution in acute HIV-1 infection [1,2] were applied. Specifically, phylogenetic reconstruction, inter- and intra-patient distribution of maximum and mean genetic distances, analysis of Poisson fitness, shape of highlighter plots, recombination analysis, and estimation of time to the most recent common ancestor (tMRCA were utilized for resolving multiplicity of HIV-1 transmission in a set of viral quasispecies collected within 50 days post-seroconversion (p/s in 25 HIV-infected individuals with estimated time of seroconversion. The decision on multiplicity of HIV infection was made based on the model's fit with, or failure to explain, the observed extent of viral sequence heterogeneity. The initial analysis was based on phylogeny, inter-patient distribution of maximum and mean distances, and Poisson fitness, and was able to resolve multiplicity of HIV transmission in 20 of 25 (80% cases. Additional analysis involved distribution of individual viral distances, highlighter plots, recombination analysis, and estimation of tMRCA, and resolved 4 of the 5 remaining cases. Overall, transmission of a single viral variant was identified in 16 of 25 (64% cases, and transmission of multiple variants was evident in 8 of 25 (32% cases. In one case multiplicity of HIV-1 transmission could not be determined. In primary HIV-1 subtype C infection, samples collected within 50 days p/s and analyzed by a single-genome amplification/sequencing technique can provide reliable identification of transmission multiplicity in 24 of 25 (96% cases. Observed transmission frequency of a single viral variant and multiple viral variants were within the ranges of 64% to 68%, and 32% to 36%, respectively.

  15. Macrophages and lymphocytes differentially modulate the ability of RANTES to inhibit HIV-1 infection.

    Science.gov (United States)

    Gross, Eleanore; Amella, Carol A; Pompucci, Lorena; Franchin, Giovanni; Sherry, Barbara; Schmidtmayerova, Helena

    2003-11-01

    The beta-chemokines MIP-1alpha, MIP-1beta, and RANTES inhibit HIV-1 infection of CD4+ T cells by inhibiting interactions between the virus and CCR5 receptors. However, while beta-chemokine-mediated inhibition of HIV-1 infection of primary lymphocytes is well documented, conflicting results have been obtained using primary macrophages as the virus target. Here, we show that the beta-chemokine RANTES inhibits virus entry into both cellular targets of the virus, lymphocytes and macrophages. However, while virus entry is inhibited at the moment of infection in both cell types, the amount of virus progeny is lowered only in lymphocytes. In macrophages, early-entry restriction is lost during long-term cultivation, and the amount of virus produced by RANTES-treated macrophages is similar to the untreated cultures, suggesting an enhanced virus replication. We further show that at least two distinct cellular responses to RANTES treatment in primary lymphocytes and macrophages contribute to this phenomenon. In lymphocytes, exposure to RANTES significantly increases the pool of inhibitory beta-chemokines through intracellular signals that result in increased production of MIP-1alpha and MIP-1beta, thereby amplifying the antiviral effects of RANTES. In macrophages this amplification step does not occur. In fact, RANTES added to the macrophages is efficiently cleared from the culture, without inducing synthesis of beta-chemokines. Our results demonstrate dichotomous effects of RANTES on HIV-1 entry at the moment of infection, and on production and spread of virus progeny in primary macrophages. Since macrophages serve as a reservoir of HIV-1, this may contribute to the failure of endogenous chemokines to successfully eradicate the virus.

  16. Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease

    Science.gov (United States)

    Kumari, Namita; Ammosova, Tatiana; Diaz, Sharmin; Lin, Xionghao; Niu, Xiaomei; Ivanov, Andrey; Jerebtsova, Marina; Dhawan, Subhash; Oneal, Patricia; Nekhai, Sergei

    2017-01-01

    The low incidence of HIV-1 infection in patients with sickle cell disease (SCD) and inhibition of HIV-1 replication in vitro under the conditions of low intracellular iron or heme treatment suggests a potential restriction of HIV-1 infection in SCD. We investigated HIV-1 ex vivo infection of SCD peripheral blood mononuclear cells (PBMCs) and found that HIV-1 replication was inhibited at the level of reverse transcription (RT) and transcription. We observed increased expression of heme and iron-regulated genes, previously shown to inhibit HIV-1, including ferroportin, IKBα, HO-1, p21, and SAM domain and HD domain-containing protein 1 (SAMHD1). HIV-1 inhibition was less pronounced in hepcidin-treated SCD PBMCs and more pronounced in the iron or iron chelators treated, suggesting a key role of iron metabolism. In SCD PBMCs, labile iron levels were reduced and protein levels of ferroportin, HIF-1α, IKBα, and HO-1 were increased. Hemin treatment induced ferroportin expression and inhibited HIV-1 in THP-1 cells, mimicking the HIV-1 inhibition in SCD PBMCs, especially as hepcidin similarly prevented HIV-1 inhibition. In THP-1 cells with knocked down ferroportin, IKBα, or HO-1 genes but not HIF-1α or p21, HIV-1 was not inhibited by hemin. Activity of SAMHD1-regulatory CDK2 was decreased, and SAMHD1 phosphorylation was reduced in SCD PBMCs and hemin-treated THP-1 cells, suggesting SAMHD1-mediated HIV-1 restriction in SCD. Our findings point to ferroportin as a trigger of HIV-1 restriction in SCD settings, linking reduced intracellular iron levels to the inhibition of CDK2 activity, reduction of SAMHD1 phosphorylation, increased IKBα expression, and inhibition of HIV-1 RT and transcription.

  17. Targeted femtosecond laser driven drug delivery within HIV-1 infected cells: In-vitro studies [conference paper

    CSIR Research Space (South Africa)

    Maphanga, Charles P

    2017-01-01

    Full Text Available Human immunodeficiency virus (HIV-1) infection still remains one amongst the world’s most challenging infections since its discovery. Antiretroviral therapy is the recommended treatment of choice for HIV-1 infection taken by patients orally...

  18. Rapid Antiretroviral Therapy Initiation for Women in an HIV-1 Prevention Clinical Trial Experiencing Primary HIV-1 Infection during Pregnancy or Breastfeeding.

    Directory of Open Access Journals (Sweden)

    Susan Morrison

    Full Text Available During an HIV-1 prevention clinical trial in East Africa, we observed 16 cases of primary HIV-1 infection in women coincident with pregnancy or breastfeeding. Nine of eleven pregnant women initiated rapid combination antiretroviral therapy (ART, despite having CD4 counts exceeding national criteria for ART initiation; breastfeeding women initiated ART or replacement feeding. Rapid ART initiation during primary HIV-1 infection during pregnancy and breastfeeding is feasible in this setting.

  19. Effect of maraviroc intensification on HIV-1-specific T cell immunity in recently HIV-1-infected individuals.

    Directory of Open Access Journals (Sweden)

    Ai Kawana-Tachikawa

    Full Text Available BACKGROUND: The effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown. METHODS: Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation. RESULTS: Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8⁺ T cells were indistinguishable between the two arms and did not change over time between the groups. CONCLUSIONS: Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies.

  20. Parasitic helminths and HIV-1 infection: the effect of immunomodulatory antigens

    NARCIS (Netherlands)

    Mouser, E.E.I.M.

    2016-01-01

    In many regions of the world co-infection with parasitic helminths and HIV-1 is common. Both pathogens have major implications for the host immune system, helminths possess immunomodulatory properties whilst HIV-1 infects and kills immune cells. Currently very little is known regarding what effects

  1. Escherichia coli surface display of single-chain antibody VRC01 against HIV-1 infection

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Lin-Xu [Nebraska Center for Virology, Lincoln, NE (United States); School of Biological Sciences, University of Nebraska—Lincoln, Lincoln, NE 68583 (United States); Mellon, Michael [Nebraska Center for Virology, Lincoln, NE (United States); School of Veterinary Medicine and Biomedical Sciences, Lincoln, NE (United States); Bowder, Dane [Nebraska Center for Virology, Lincoln, NE (United States); School of Biological Sciences, University of Nebraska—Lincoln, Lincoln, NE 68583 (United States); Quinn, Meghan [Nebraska Center for Virology, Lincoln, NE (United States); School of Veterinary Medicine and Biomedical Sciences, Lincoln, NE (United States); Shea, Danielle; Wood, Charles [Nebraska Center for Virology, Lincoln, NE (United States); School of Biological Sciences, University of Nebraska—Lincoln, Lincoln, NE 68583 (United States); Xiang, Shi-Hua, E-mail: sxiang2@unl.edu [Nebraska Center for Virology, Lincoln, NE (United States); School of Veterinary Medicine and Biomedical Sciences, Lincoln, NE (United States)

    2015-01-15

    Human immunodeficiency virus type 1 (HIV-1) transmission and infection occur mainly via the mucosal surfaces. The commensal bacteria residing in these surfaces can potentially be employed as a vehicle for delivering inhibitors to prevent HIV-1 infection. In this study, we have employed a bacteria-based strategy to display a broadly neutralizing antibody VRC01, which could potentially be used to prevent HIV-1 infection. The VRC01 antibody mimics CD4-binding to gp120 and has broadly neutralization activities against HIV-1. We have designed a construct that can express the fusion peptide of the scFv-VRC01 antibody together with the autotransporter β-barrel domain of IgAP gene from Neisseria gonorrhoeae, which enabled surface display of the antibody molecule. Our results indicate that the scFv-VRC01 antibody molecule was displayed on the surface of the bacteria as demonstrated by flow cytometry and immunofluorescence microscopy. The engineered bacteria can capture HIV-1 particles via surface-binding and inhibit HIV-1 infection in cell culture. - Highlights: • Designed single-chain VRC01 antibody was demonstrated to bind HIV-1 envelope gp120. • Single-chain VRC01 antibody was successfully displayed on the surface of E. coli. • Engineered bacteria can absorb HIV-1 particles and prevent HIV-1 infection in cell culture.

  2. Mesenchymal stem cell derived hematopoietic cells are permissive to HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Mondal Debasis

    2011-01-01

    Full Text Available Abstract Background Tissue resident mesenchymal stem cells (MSCs are multipotent, self-renewing cells known for their differentiation potential into cells of mesenchymal lineage. The ability of single cell clones isolated from adipose tissue resident MSCs (ASCs to differentiate into cells of hematopoietic lineage has been previously demonstrated. In the present study, we investigated if the hematopoietic differentiated (HD cells derived from ASCs could productively be infected with HIV-1. Results HD cells were generated by differentiating clonally expanded cultures of adherent subsets of ASCs (CD90+, CD105+, CD45-, and CD34-. Transcriptome analysis revealed that HD cells acquire a number of elements that increase their susceptibility for HIV-1 infection, including HIV-1 receptor/co-receptor and other key cellular cofactors. HIV-1 infected HD cells (HD-HIV showed elevated p24 protein and gag and tat gene expression, implying a high and productive infection. HD-HIV cells showed decreased CD4, but significant increase in the expression of CCR5, CXCR4, Nef-associated factor HCK, and Vpu-associated factor BTRC. HIV-1 restricting factors like APOBEC3F and TRIM5 also showed up regulation. HIV-1 infection increased apoptosis and cell cycle regulatory genes in HD cells. Although undifferentiated ASCs failed to show productive infection, HIV-1 exposure increased the expression of several hematopoietic lineage associated genes such as c-Kit, MMD2, and IL-10. Conclusions Considering the presence of profuse amounts of ASCs in different tissues, these findings suggest the possible role that could be played by HD cells derived from ASCs in HIV-1 infection. The undifferentiated ASCs were non-permissive to HIV-1 infection; however, HIV-1 exposure increased the expression of some hematopoietic lineage related genes. The findings relate the importance of ASCs in HIV-1 research and facilitate the understanding of the disease process and management strategies.

  3. Necroptosis takes place in human immunodeficiency virus type-1 (HIV-1-infected CD4+ T lymphocytes.

    Directory of Open Access Journals (Sweden)

    Ting Pan

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 infection is characterized by progressive depletion of CD4+ T lymphocytes and dysfunction of the immune system. The numbers of CD4+ T lymphocytes in the human body are maintained constantly by homeostatic mechanisms that failed during HIV-1 infection, resulting in progressive loss of CD4+ T cells mainly via apoptosis. Recently, a non-apoptotic form of necrotic programmed cell death, named necroptosis, has been investigated in many biological and pathological processes. We then determine whether HIV-1-infected cells also undergo necroptosis. In this report, we demonstrate that HIV-1 not only induces apoptosis, but also mediates necroptosis in the infected primary CD4+ T lymphocytes and CD4+ T-cell lines. Necroptosis-dependent cytopathic effects are significantly increased in HIV-1-infected Jurkat cells that is lack of Fas-associated protein-containing death domain (FADD, indicating that necroptosis occurs as an alternative cell death mechanism in the absence of apoptosis. Unlike apoptosis, necroptosis mainly occurs in HIV-infected cells and spares bystander damage. Treatment with necrostatin-1(Nec-1, a RIP1 inhibitor that specifically blocks the necroptosis pathway, potently restrains HIV-1-induced cytopathic effect and interestingly, inhibits the formation of HIV-induced syncytia in CD4+ T-cell lines. This suggests that syncytia formation is mediated, at least partially, by necroptosis-related processes. Furthermore, we also found that the HIV-1 infection-augmented tumor necrosis factor-alpha (TNF-α plays a key role in inducing necroptosis and HIV-1 Envelope and Tat proteins function as its co-factors. Taken together,necroptosis can function as an alternative cell death pathway in lieu of apoptosis during HIV-1 infection, thereby also contributing to HIV-1-induced cytopathic effects. Our results reveal that in addition to apoptosis, necroptosis also plays an important role in HIV-1-induced pathogenesis.

  4. Down-regulation of HIV-1 Infection by Inhibition of the MAPK Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    Jian Gong; Xi-hui Shen; Chao Chen; Hui Qiu; Rong-ge Yang

    2011-01-01

    The human immunodeficiency virus type 1(HIV-1)can interact with and exploit the host cellular machinery to replicate and propagate itself.Numerous studies have shown that the Mitogen-activated protein kinase(MAPK)signal pathway can positively regulate the replication of HIV-1,but exactly how each MAPK pathway affects HIV-1 infection and replication is not understood.In this study,we used the Extracellular signal-regulated kinase(ERK)pathway inhibitor,PD98059,the Jun N-terminal kinase(JNK)pathway inhibitor,SP600125,and the p38 pathway inhibitor,SB203580,to investigate the roles of these pathways in HIV-1replication.We found that application of PD98059 results in a strong VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus and HIV-1NL4-3 virus inhibition activity.In addition,SB203580 and SP600125 also elicited marked VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus inhibition activity but no HIV-1NL4-3 virus inhibition activity.We also found that SB203580 and SP600125 can enhance the HIV-1 inhibition activity of PD98059when cells were treated with all three MAPK pathway inhibitors in combination.Finally,we show that HIV-1virus inhibition activity of the MAPK pathway inhibitors was the result of the negative regulation of HIV-1 LTR promoter activity.

  5. Longitudinal anthropometric assessment of infants born to HIV-1-infected mothers, Belo Horizonte, Southeastern Brazil

    Directory of Open Access Journals (Sweden)

    Maria Arlene Fausto

    2011-08-01

    Full Text Available OBJECTIVE: To evaluate the growth parameters in infants who were born to HIV-1-infected mothers. METHODS: The study was a longitudinal evaluation of the z-scores for the weight-for-age (WAZ, weight-for-length (WLZ and length-for-age (LAZ data collected from a cohort. A total of 97 non-infected and 33 HIV-infected infants born to HIV-1-infected mothers in Belo Horizonte, Southeastern Brazil, between 1995 and 2003 was studied. The average follow-up period for the infected and non-infected children was 15.8 months (variation: 6.8 to 18.0 months and 14.3 months (variation: 6.3 to 18.6 months, respectively. A mixed-effects linear regression model was used and was fitted using a restricted maximum likelihood. RESULTS: There was an observed decrease over time in the WAZ, LAZ and WLZ among the infected infants. At six months of age, the mean differences in the WAZ, LAZ and WLZ between the HIV-infected and non-infected infants were 1.02, 0.59, and 0.63 standard deviations, respectively. At 12 months, the mean differences in the WAZ, LAZ and WLZ between the HIV-infected and non-infected infants were 1.15, 1.01, and 0.87 standard deviations, respectively. CONCLUSIONS: The precocious and increasing deterioration of the HIV-infected infants' anthropometric indicators demonstrates the importance of the early identification of HIV-infected infants who are at nutritional risk and the importance of the continuous assessment of nutritional interventions for these infants.

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

    Science.gov (United States)

    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. PMID:26184775

  7. Factors Associated With the Control of Viral Replication and Virologic Breakthrough in a Recently Infected HIV-1 Controller.

    Science.gov (United States)

    Walker-Sperling, Victoria E; Pohlmeyer, Christopher W; Veenhuis, Rebecca T; May, Megan; Luna, Krystle A; Kirkpatrick, Allison R; Laeyendecker, Oliver; Cox, Andrea L; Carrington, Mary; Bailey, Justin R; Arduino, Roberto C; Blankson, Joel N

    2017-02-01

    HIV-1 controllers are patients who control HIV-1 viral replication without antiretroviral therapy. Control is achieved very early in the course of infection, but the mechanisms through which viral replication is restricted are not fully understood. We describe a patient who presented with acute HIV-1 infection and was found to have an HIV-1 RNA level of <100copies/mL. She did not have any known protective HLA alleles, but significant immune activation of CD8+ T cells and natural killer (NK) cells was present, and both cell types inhibited viral replication. Virus cultured from this patient replicated as well in vitro as virus isolated from her partner, a patient with AIDS who was the source of transmission. Virologic breakthrough occurred 9months after her initial presentation and was associated with an increase in CD4+ T cell activation levels and a significant decrease in NK cell inhibitory capacity. Remarkably, CD8+ T cell inhibitory capacity was preserved and there were no new escape mutations in targeted Gag epitopes. These findings suggest that fully replication-competent virus can be controlled in acute HIV-1 infection in some patients without protective HLA alleles and that NK cell responses may contribute to this early control of viral replication.

  8. Factors Associated With the Control of Viral Replication and Virologic Breakthrough in a Recently Infected HIV-1 Controller

    Directory of Open Access Journals (Sweden)

    Victoria E. Walker-Sperling

    2017-02-01

    Full Text Available HIV-1 controllers are patients who control HIV-1 viral replication without antiretroviral therapy. Control is achieved very early in the course of infection, but the mechanisms through which viral replication is restricted are not fully understood. We describe a patient who presented with acute HIV-1 infection and was found to have an HIV-1 RNA level of <100 copies/mL. She did not have any known protective HLA alleles, but significant immune activation of CD8+ T cells and natural killer (NK cells was present, and both cell types inhibited viral replication. Virus cultured from this patient replicated as well in vitro as virus isolated from her partner, a patient with AIDS who was the source of transmission. Virologic breakthrough occurred 9 months after her initial presentation and was associated with an increase in CD4+ T cell activation levels and a significant decrease in NK cell inhibitory capacity. Remarkably, CD8+ T cell inhibitory capacity was preserved and there were no new escape mutations in targeted Gag epitopes. These findings suggest that fully replication-competent virus can be controlled in acute HIV-1 infection in some patients without protective HLA alleles and that NK cell responses may contribute to this early control of viral replication.

  9. Oxidative Imbalance in HIV-1 Infected Patients Treated with Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    Antonella Mandas

    2009-01-01

    Full Text Available It is generally accepted that oxidative stress is involved in HIV infection. However, the role in oxidative balance of Highly Active Antiretroviral Therapy (HAART is still debated. In our study we assessed serum oxidant and antioxidant levels in an HIV-1-infected population treated with HAART, and compared them with those of untreated HIV-1 patients and HIV-1-negative subjects. The study included 116 HIV-1-infected patients (86 HAART-treated and 30 untreated, and 46 HIV-negative controls. Serum oxidant levels were significantly higher in the HIV-1 treated group as compared to untreated and control groups. In addition, a decrease of serum total antioxidant status was observed in the HIV-1 treated group. To be noted is that patients who rigorously follow antiretroviral therapy (optimal HAART adherence have significantly higher oxidative status than those who do not closely follow the therapy (poor HAART adherence. Analysis of variance revealed no significant further increase in oxidative status in HIV-1-infected patients taking antiretroviral and other drugs with the exception of psychiatric drugs (e.g. anxiolytics or antidepressants. Taken together, our results indicate that HAART may affect oxidative stress in HIV-1-infected patients and suggest that antiretroviral therapy plays an important role in the synergy of HIV infection and oxidative stress.

  10. Oral and vaginal epithelial cell lines bind and transfer cell-free infectious HIV-1 to permissive cells but are not productively infected.

    Directory of Open Access Journals (Sweden)

    Arinder Kohli

    Full Text Available The majority of HIV-1 infections worldwide are acquired via mucosal surfaces. However, unlike the vaginal mucosa, the issue of whether the oral mucosa can act as a portal of entry for HIV-1 infection remains controversial. To address potential differences with regard to the fate of HIV-1 after exposure to oral and vaginal epithelium, we utilized two epithelial cell lines representative of buccal (TR146 and pharyngeal (FaDu sites of the oral cavity and compared them with a cell line derived from vaginal epithelium (A431 in order to determine (i HIV-1 receptor gene and protein expression, (ii whether HIV-1 genome integration into epithelial cells occurs, (iii whether productive viral infection ensues, and (iv whether infectious virus can be transferred to permissive cells. Using flow cytometry to measure captured virus by HIV-1 gp120 protein detection and western blot to detect HIV-1 p24 gag protein, we demonstrate that buccal, pharyngeal and vaginal epithelial cells capture CXCR4- and CCR5-utilising virus, probably via non-canonical receptors. Both oral and vaginal epithelial cells are able to transfer infectious virus to permissive cells either directly through cell-cell attachment or via transcytosis of HIV-1 across epithelial cells. However, HIV-1 integration, as measured by real-time PCR and presence of early gene mRNA transcripts and de novo protein production were not detected in either epithelial cell type. Importantly, both oral and vaginal epithelial cells were able to support integration and productive infection if HIV-1 entered via the endocytic pathway driven by VSV-G. Our data demonstrate that under normal conditions productive HIV-1 infection of epithelial cells leading to progeny virion production is unlikely, but that epithelial cells can act as mediators of systemic viral dissemination through attachment and transfer of HIV-1 to permissive cells.

  11. Underestimated Amoebic Appendicitis among HIV-1-Infected Individuals in Japan

    Science.gov (United States)

    Kobayashi, Taiichiro; Yano, Hideaki; Murata, Yukinori; Igari, Toru; Nakada-Tsukui, Kumiko; Yagita, Kenji; Nozaki, Tomoyoshi; Kaku, Mitsuo; Tsukada, Kunihisa; Gatanaga, Hiroyuki; Kikuchi, Yoshimi; Oka, Shinichi

    2016-01-01

    ABSTRACT Entamoeba histolytica is not a common causative agent of acute appendicitis. However, amoebic appendicitis can sometimes be severe and life threatening, mainly due to a lack of awareness. Also, its frequency, clinical features, and pathogenesis remain unclear. The study subjects were HIV-1-infected individuals who presented with acute appendicitis and later underwent appendectomy at our hospital between 1996 and 2014. Formalin-fixed paraffin-embedded preserved appendix specimens were reexamined by periodic acid-Schiff (PAS) staining and PCR to identify undiagnosed amoebic appendicitis. Appendectomies were performed in 57 patients with acute appendicitis. The seroprevalence of E. histolytica was 33% (14/43) from the available stored sera. Based on the medical records, only 3 cases were clinically diagnosed as amoebic appendicitis, including 2 diagnosed at the time of appendectomy and 1 case diagnosed by rereview of the appendix after the development of postoperative complications. Retrospective analyses using PAS staining and PCR identified 3 and 3 more cases, respectively. Thus, E. histolytica infection was confirmed in 9 cases (15.8%) in the present study. Apart from a significantly higher leukocyte count in E. histolytica-positive patients than in negative patients (median, 13,760 versus 10,385 cells/μl, respectively, P = 0.02), there were no other differences in the clinical features of the PCR-positive and -negative groups. In conclusion, E. histolytica infection was confirmed in 9 (15.8%) of the appendicitis cases. However, only 3, including one diagnosed after intestinal perforation, were diagnosed before the present analyses. These results strongly suggest there is frequently a failure to detect trophozoites in routine examination, resulting in an underestimation of the incidence of amoebic appendicitis. PMID:27847377

  12. Underestimated Amoebic Appendicitis among HIV-1-Infected Individuals in Japan.

    Science.gov (United States)

    Kobayashi, Taiichiro; Watanabe, Koji; Yano, Hideaki; Murata, Yukinori; Igari, Toru; Nakada-Tsukui, Kumiko; Yagita, Kenji; Nozaki, Tomoyoshi; Kaku, Mitsuo; Tsukada, Kunihisa; Gatanaga, Hiroyuki; Kikuchi, Yoshimi; Oka, Shinichi

    2017-01-01

    Entamoeba histolytica is not a common causative agent of acute appendicitis. However, amoebic appendicitis can sometimes be severe and life threatening, mainly due to a lack of awareness. Also, its frequency, clinical features, and pathogenesis remain unclear. The study subjects were HIV-1-infected individuals who presented with acute appendicitis and later underwent appendectomy at our hospital between 1996 and 2014. Formalin-fixed paraffin-embedded preserved appendix specimens were reexamined by periodic acid-Schiff (PAS) staining and PCR to identify undiagnosed amoebic appendicitis. Appendectomies were performed in 57 patients with acute appendicitis. The seroprevalence of E. histolytica was 33% (14/43) from the available stored sera. Based on the medical records, only 3 cases were clinically diagnosed as amoebic appendicitis, including 2 diagnosed at the time of appendectomy and 1 case diagnosed by rereview of the appendix after the development of postoperative complications. Retrospective analyses using PAS staining and PCR identified 3 and 3 more cases, respectively. Thus, E. histolytica infection was confirmed in 9 cases (15.8%) in the present study. Apart from a significantly higher leukocyte count in E. histolytica-positive patients than in negative patients (median, 13,760 versus 10,385 cells/μl, respectively, P = 0.02), there were no other differences in the clinical features of the PCR-positive and -negative groups. In conclusion, E. histolytica infection was confirmed in 9 (15.8%) of the appendicitis cases. However, only 3, including one diagnosed after intestinal perforation, were diagnosed before the present analyses. These results strongly suggest there is frequently a failure to detect trophozoites in routine examination, resulting in an underestimation of the incidence of amoebic appendicitis. Copyright © 2016 Kobayashi et al.

  13. Antiretroviral treatment effect on immune activation reduces cerebrospinal fluid HIV-1 infection.

    Science.gov (United States)

    Sinclair, Elizabeth; Ronquillo, Rollie; Lollo, Nicole; Deeks, Steven G; Hunt, Peter; Yiannoutsos, Constantin T; Spudich, Serena; Price, Richard W

    2008-04-15

    To define the effect of antiretroviral therapy (ART) on activation of T cells in cerebrospinal fluid (CSF) and blood, and interactions of this activation with CSF HIV-1 RNA concentrations. Cross-sectional analysis of 14 HIV-negative subjects and 123 neuroasymptomatic HIV-1-infected subjects divided into 3 groups: not on ART (termed "offs"), on ART with plasma HIV-1 RNA >500 copies/mL ("failures"), and on ART with plasma HIV-1 RNA HIV-1, it maintained a coincident relation to CSF HIV-1 in both viremic groups. In addition to correlation with CSF HIV-1 concentrations, CD8 activation in blood and CSF correlated with CSF WBCs and CSF neopterin. Multivariate analysis confirmed the association of blood CD8 T-cell activation, along with plasma HIV-1 RNA and CSF neopterin, with CSF HIV-1 RNA levels. The similarity of CD8 T-cell activation in blood and CSF suggests these cells move from blood to CSF with only minor changes in CD38/HLA-DR expression. Differences in the relation of CD8 activation to HIV-1 concentrations in the blood and CSF in the 2 viremic groups suggest that changes in immune activation not only modulate CSF HIV-1 replication but also contribute to CSF treatment effects. The magnitude of systemic HIV-1 infection and intrathecal macrophage activation are also important determinants of CSF HIV-1 RNA levels.

  14. Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients.

    Science.gov (United States)

    Collins, Sean E; Grant, Philip M; Shafer, Robert W

    2016-01-01

    HIV-1-infected patients with suppressed plasma viral loads often require changes to their antiretroviral (ARV) therapy to manage drug toxicity and intolerance, to improve adherence, and to avoid drug interactions. In patients who have never experienced virologic failure while receiving ARV therapy and who have no evidence of drug resistance, switching to any of the acceptable US Department of Health and Human Services first-line therapies is expected to maintain virologic suppression. However, in virologically suppressed patients with a history of virologic failure or drug resistance, it can be more challenging to change therapy while still maintaining virologic suppression. In these patients, it may be difficult to know whether the discontinuation of one of the ARVs in a suppressive regimen constitutes the removal of a key regimen component that will not be adequately supplanted by one or more substituted ARVs. In this article, we review many of the clinical scenarios requiring ARV therapy modification in patients with stable virologic suppression and outline the strategies for modifying therapy while maintaining long-term virologic suppression.

  15. Efficient Human Immunodeficiency Virus (HIV-1) Infection of Cells Lacking PDZD8

    OpenAIRE

    Zhang, Shijian; Sodroski, Joseph

    2015-01-01

    PDZD8 can bind the capsid proteins of different retroviruses, and transient knockdown of PDZD8 results in a decrease in the efficiency of an early, post-entry event in the retrovirus life cycle. Here we used the CRISPR-CAS9 system to create cell lines in which PDZD8 expression is stably eliminated. The PDZD8-knockout cell lines were infected by human immunodeficiency virus (HIV-1) and murine leukemia virus as efficiently as the parental PDZD8-expressing cells. These results indicate that PDZD...

  16. Host genetic factors in susceptibility to HIV-1 infection and progression to AIDS

    Indian Academy of Sciences (India)

    Koushik Chatterjee

    2010-04-01

    HIV-1 infection has rapidly spread worldwide and has become the leading cause of mortality in infectious diseases. The duration for development of AIDS (AIDS progression) is highly variable among HIV–1 infected individuals, ranging from 2–3 years to no signs of AIDS development in the entire lifetime. Several factors regulate the rate at which HIV-1 infection progresses to AIDS. Host genetic factors play an important role in the outcome of such complex or multifactor diseases as AIDS and are also known to regulate the rate of disease progression. This review focuses on the major host genes reported to affect the progression to AIDS in HIV-1 infected individuals.

  17. Rates and Reasons for Early Change of First HAART in HIV-1-Infected Patients in 7 Sites throughout the Caribbean and Latin America

    Science.gov (United States)

    Cesar, Carina; Shepherd, Bryan E.; Krolewiecki, Alejandro J.; Fink, Valeria I.; Schechter, Mauro; Tuboi, Suely H.; Wolff, Marcelo; Pape, Jean W.; Leger, Paul; Padgett, Denis; Madero, Juan Sierra; Gotuzzo, Eduardo; Sued, Omar; McGowan, Catherine C.; Masys, Daniel R.; Cahn, Pedro E.

    2010-01-01

    Background HAART rollout in Latin America and the Caribbean has increased from approximately 210,000 in 2003 to 390,000 patients in 2007, covering 62% (51%–70%) of eligible patients, with considerable variation among countries. No multi-cohort study has examined rates of and reasons for change of initial HAART in this region. Methodology Antiretroviral-naïve patients > = 18 years who started HAART between 1996 and 2007 and had at least one follow-up visit from sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru were included. Time from HAART initiation to change (stopping or switching any antiretrovirals) was estimated using Kaplan-Meier techniques. Cox proportional hazards modeled the associations between change and demographics, initial regimen, baseline CD4 count, and clinical stage. Principal Findings Of 5026 HIV-infected patients, 35% were female, median age at HAART initiation was 37 years (interquartile range [IQR], 31–44), and median CD4 count was 105 cells/uL (IQR, 38–200). Estimated probabilities of changing within 3 months and one year of HAART initiation were 16% (95% confidence interval (CI) 15–17%) and 28% (95% CI 27–29%), respectively. Efavirenz-based regimens and no clinical AIDS at HAART initiation were associated with lower risk of change (hazard ratio (HR) = 1.7 (95% CI 1.1–2.6) and 2.1 (95% CI 1.7–2.5) comparing neverapine-based regimens and other regimens to efavirenz, respectively; HR = 1.3 (95% CI 1.1–1.5) for clinical AIDS at HAART initiation). The primary reason for change among HAART initiators were adverse events (14%), death (5.7%) and failure (1.3%) with specific toxicities varying among sites. After change, most patients remained in first line regimens. Conclusions Adverse events were the leading cause for changing initial HAART. Predictors for change due to any reason were AIDS at baseline and the use of a non-efavirenz containing regimen. Differences between participant sites were observed

  18. Prevalence of and risk factors for pulmonary tuberculosis among newly diagnosed HIV-1 infected Nigerian children

    Science.gov (United States)

    Ebonyi, Augustine O.; Oguche, Stephen; Ejeliogu, Emeka U.; Agbaji, Oche O.; Shehu, Nathan Y.; Abah, Isaac O.; Sagay, Atiene S.; Ugoagwu, Placid O.; Okonkwo, Prosper I.; Idoko, John A.; Kanki, Phyllis J.

    2016-01-01

    Introduction Studies on the prevalence of and risk factors for tuberculosis (TB) among newly diagnosed human immunodeficiency virus (HIV)-infected children in sub-Saharan Africa are scarce and in Nigeria there is paucity of reported data. We determined the prevalence of and risk factors for pulmonary TB (PTB) in newly diagnosed (treatment-naïve) HIV-1 infected children at the pediatric HIV clinic of the Jos University Teaching Hospital (JUTH) in Nigeria. Methods We performed a retrospective analysis of 876 children, aged 2 months – 13 years, diagnosed with HIV-1 infection between July 2005 and December 2012, of which 286 were diagnosed with PTB at presentation after TB screening. The study site was the AIDS Prevention Initiative in Nigeria (APIN)-supported Pediatric HIV clinic at JUTH, Jos. A multivariate forward logistic regression modelling was used to identify risk factors for PTB-HIV co-infection. Results The prevalence of PTB-HIV co-infection was 32% (286/876). Severe immunosuppression (SI) and World Health Organization (WHO) HIV clinical stage 3/4 were identified as independent risk factors for PTB-HIV co-infection in HIV infected children. The odds of PTB-HIV co-infection was increased two-fold in HIV-infected children with WHO clinical stage 3/4 compared to those with stage 1/2 (adjusted odds ratio (AOR) 1.76 [1.31-2.37], p<0.001) and 1.5-fold in children with SI compared to those without SI (AOR 1.52 [1.12-2.06], p=0.007). Conclusion In our setting, the burden of PTB was high among newly diagnosed HIV-infected children, and late WHO HIV clinical stage and severe immunosuppression were associated with PTB-HIV co-infection. Therefore there is a clear need to improve strategies for early diagnosis of both HIV and PTB to optimize clinical outcomes. PMID:27019829

  19. Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection.

    Directory of Open Access Journals (Sweden)

    Matthias Hoffmann

    2016-07-01

    Full Text Available The rate at which HIV-1 infected individuals progress to AIDS is highly variable and impacted by T cell immunity. CD8 T cell inhibitory molecules are up-regulated in HIV-1 infection and associate with immune dysfunction. We evaluated participants (n = 122 recruited to the SPARTAC randomised clinical trial to determine whether CD8 T cell exhaustion markers PD-1, Lag-3 and Tim-3 were associated with immune activation and disease progression. Expression of PD-1, Tim-3, Lag-3 and CD38 on CD8 T cells from the closest pre-therapy time-point to seroconversion was measured by flow cytometry, and correlated with surrogate markers of HIV-1 disease (HIV-1 plasma viral load (pVL and CD4 T cell count and the trial endpoint (time to CD4 count <350 cells/μl or initiation of antiretroviral therapy. To explore the functional significance of these markers, co-expression of Eomes, T-bet and CD39 was assessed. Expression of PD-1 on CD8 and CD38 CD8 T cells correlated with pVL and CD4 count at baseline, and predicted time to the trial endpoint. Lag-3 expression was associated with pVL but not CD4 count. For all exhaustion markers, expression of CD38 on CD8 T cells increased the strength of associations. In Cox models, progression to the trial endpoint was most marked for PD-1/CD38 co-expressing cells, with evidence for a stronger effect within 12 weeks from confirmed diagnosis of PHI. The effect of PD-1 and Lag-3 expression on CD8 T cells retained statistical significance in Cox proportional hazards models including antiretroviral therapy and CD4 count, but not pVL as co-variants. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. New markers to identify exhausted T cells and novel interventions to reverse exhaustion may inform the development of novel immunotherapeutic approaches.

  20. Identification of host proteins associated with HIV-1 preintegration complexes isolated from infected CD4+ cells.

    Science.gov (United States)

    Raghavendra, Nidhanapati K; Shkriabai, Nikolozi; Graham, Robert Lj; Hess, Sonja; Kvaratskhelia, Mamuka; Wu, Li

    2010-08-11

    An integrated HIV-1 genomic DNA leads to an infected cell becoming either an active or a latent virus-producing cell. Upon appropriate activation, a latently infected cell can result in production of progeny viruses that spread the infection to uninfected cells. The host proteins influence several steps of HIV-1 infection including formation of the preintegration complex (PIC), a key nucleoprotein intermediate essential for integration of reverse transcribed viral DNA into the chromosome. Much effort has gone into the identification of host proteins contributing to the assembly of functional PICs. Experimental approaches included the use of yeast two-hybrid system, co-immunoprecipitation, affinity tagged HIV-1 viral proteins and in vitro reconstitution of salt-stripped PIC activity. Several host proteins identified using these approaches have been shown to affect HIV-1 replication in cells and influence catalytic activities of recombinant IN in vitro. However, the comprehensive identification and characterization of host proteins associated with HIV-1 PICs of infected cells have been hindered in part by the technical limitation in acquiring sufficient amount of catalytically active PICs. To efficiently identify additional host factors associated with PICs in infected cells, we have developed the following novel approach. The catalytically active PICs from HIV-1-infected CD4+ cells were isolated using biotinylated target DNA, and the proteins selectively co-purifying with PICs have been analyzed by mass spectrometry. This technology enabled us to reveal at least 19 host proteins that are associated with HIV-1 PICs, of which 18 proteins have not been described previously with respect to HIV-1 integration. Physiological functions of the identified proteins range from chromatin organization to protein transport. A detailed characterization of these host proteins could provide new insights into the mechanism of HIV-1 integration and uncover new antiviral targets to

  1. Interaction between Tat and Drugs of Abuse during HIV-1 Infection and Central Nervous System Disease

    Directory of Open Access Journals (Sweden)

    Monique E Maubert

    2016-01-01

    Full Text Available In many individuals, drug abuse is intimately linked with HIV-1 infection. In addition to being associated with one-third of all HIV-1 infections in the United States, drug abuse also plays a role in disease progression and severity in HIV-1-infected patients, including adverse effects on the central nervous system (CNS. Specific systems within the brain are known to be damaged in HIV-1-infected individuals and this damage is similar to that observed in drug abuse. Even in the era of anti-retroviral therapy (ART, CNS pathogenesis occurs with HIV-1 infection, with a broad range of cognitive impairment observed, collectively referred to as HIV-1-associated neurocognitive disorders (HAND. A number of HIV-1 proteins (Tat, gp120, Nef, Vpr have been implicated in the etiology of pathogenesis and disease as a result of the biologic activity of the extracellular form of each of the proteins in a number of tissues, including the CNS, even in ART-suppressed patients. In this review, we have made Tat the center of attention for a number of reasons. First, it has been shown to be synthesized and secreted by HIV-1-infected cells in the CNS, despite the most effective suppression therapies available to date. Second, Tat has been shown to alter the functions of several host factors, disrupting the molecular and biochemical balance of numerous pathways contributing to cellular toxicity, dysfunction, and death. In addition, the advantages and disadvantages of ART suppression with regard to controlling the genesis and progression of neurocognitive impairment are currently under debate in the field and are yet to be fully determined. In this review, we discuss the individual and concerted contributions of HIV-1 Tat, drug abuse, and ART with respect to damage in the CNS, and how these factors contribute to the development of HAND in HIV-1-infected patients.

  2. Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1.

    Directory of Open Access Journals (Sweden)

    Richard E Haaland

    2009-01-01

    Full Text Available The HIV-1 epidemic in sub-Saharan Africa is driven largely by heterosexual transmission of non-subtype B viruses, of which subtypes C and A are predominant. Previous studies of subtype B and subtype C transmission pairs have suggested that a single variant from the chronically infected partner can establish infection in their newly infected partner. However, in subtype A infected individuals from a sex worker cohort and subtype B individuals from STD clinics, infection was frequently established by multiple variants. This study examined over 1750 single-genome amplified viral sequences derived from epidemiologically linked subtype C and subtype A transmission pairs very early after infection. In 90% (18/20 of the pairs, HIV-1 infection is initiated by a single viral variant that is derived from the quasispecies of the transmitting partner. In addition, the virus initiating infection in individuals who were infected by someone other than their spouse was characterized to determine if genital infections mitigated the severe genetic bottleneck observed in a majority of epidemiologically linked heterosexual HIV-1 transmission events. In nearly 50% (3/7 of individuals infected by someone other than their spouse, multiple genetic variants from a single individual established infection. A statistically significant association was observed between infection by multiple genetic variants and an inflammatory genital infection in the newly infected individual. Thus, in the vast majority of HIV-1 transmission events in cohabiting heterosexual couples, a single genetic variant establishes infection. Nevertheless, this severe genetic bottleneck can be mitigated by the presence of inflammatory genital infections in the at risk partner, suggesting that this restriction on genetic diversity is imposed in large part by the mucosal barrier.

  3. Change of positive selection pressure on HIV-1 envelope gene inferred by early and recent samples.

    Directory of Open Access Journals (Sweden)

    Izumi Yoshida

    Full Text Available HIV-1 infection has been on the rise in Japan recently, and the main transmission route has changed from blood transmission in the 1980s to homo- and/or hetero-sexual transmission in the 2000s. The lack of early viral samples with clinical information made it difficult to investigate the possible virological changes over time. In this study, we sequenced 142 full-length env genes collected from 16 Japanese subjects infected with HIV-1 in the 1980s and in the 2000s. We examined the diversity change in sequences and potential adaptive evolution of the virus to the host population. We used a codon-based likelihood method under the branch-site and clade models to detect positive selection operating on the virus. The clade model was extended to account for different positive selection pressures in different viral populations. The result showed that the selection pressure was weaker in the 2000s than in the 1980s, indicating that it might have become easier for the HIV to infect a new host and to develop into AIDS now than 20 years ago and that the HIV may be becoming more virulent in the Japanese population. The study provides useful information on the surveillance of HIV infection and highlights the utility of the extended clade models in analysis of virus populations which may be under different selection pressures.

  4. The prevalence of HSV-2 infection in HIV-1 discordant couples.

    Science.gov (United States)

    Duan, S; Ding, Y; Wu, Z; Rou, K; Yang, Y; Wang, J; Gao, M; Ye, R; Xiang, L; He, N

    2016-01-01

    We aimed to investigate the prevalence and associated factors of HSV-2 discordance and concordance in HIV-1-discordant couples. This study used the baseline data from a cohort study of HIV-1-discordant couples in Dehong prefecture of Yunnan province, China. Of 954 participating couples, 42·4% were affected by HSV-2, of which 20·4% were HSV-2-concordant positive, 7·6% were HSV-2-discordant where the male was HSV-2 positive, and 14·4% were HSV-2 discordant where the female was HSV-2 positive. Compared to HSV-2-negative concordance, HSV-2 discordance with an HSV-2-positive male spouse was significantly associated with characteristics of the male spouse, including Han ethnicity and being in a second marriage. HSV-2 discordance with an HSV-2-positive female spouse was significantly associated with characteristics of the female spouse, including Han ethnicity, having engaged in commercial sex, having a sexual relationship of HSV-2 discordance, HSV-2-positive concordance was significantly associated with an education level of middle school or higher for both spouses, a sexual relationship of ⩾3 years, more frequent sex and having an HIV-1-infected male spouse. The findings highlight the need for HSV-2 prevention and treatment efforts to reduce HSV-2 transmission in this population, and emphasize the importance of implementing prevention interventions early in couples' relationships.

  5. Assisted reproductive technologies to establish pregnancies in couples with an HIV-1-infected man

    NARCIS (Netherlands)

    E. van Leeuwen; S. Repping; J.M. Prins; P. Reiss; F. van der Veen

    2009-01-01

    For HIV -1-infected men and women the introduction of highly active antiretroviral therapy (HART) in 1996 led to a spectacular increase in life expectancy and quality of life. In Western society where HART is readily available, HIV -1 is now considered to be a chronic disease and as a consequence qu

  6. IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein

    Directory of Open Access Journals (Sweden)

    Jingyou Yu

    2015-10-01

    Full Text Available The interferon-induced transmembrane (IFITM proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env, thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection.

  7. 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.

  8. Impact of HIV-1 infection on the hematological recovery after clinical malaria.

    Science.gov (United States)

    Van Geertruyden, Jean-Pierre; Mulenga, Modest; Chalwe, Victor; Michael, Nambozi; Moerman, Filip; Mukwamataba, Doreen; Colebunders, Robert; D'alessandro, Umberto

    2009-02-01

    Anemia is the most frequent cytopenia in HIV-infected individuals and is often associated with malaria. To assess the impact of HIV-1 on the hematological recovery after a clinical malaria episode. In Ndola, Zambia, a region with high malaria and HIV prevalence, hemoglobin (Hb) was measured in 634 malaria patients 14 and 45 days after antimalarial treatment. Risk factors for hematological recovery were analyzed in a multivariate linear regression model. At enrollment, HIV-1-infected malaria patients had lower Hb compared with HIV-1 uninfected (122.7 vs 136.0 g/L; P < 0.001). In both groups, mean Hb was significantly lower at day 14 posttreatment than day 0 (P < 0.0001) and significantly higher at day 45 than at day 14 (HIV-1 negative: P = 0.0001; HIV-1 infected: P = 0.005). HIV-1 was a risk factor for a larger Hb decrease until day 14 (P < 0.001) and slower recovery until day 45 (P = 0.048). When considering the whole 45-day follow-up period, mean Hb increased in the HIV-1-negative group (+3.54 g/L; 95% confidence interval: 1.37 to 5.70; P = 0.001) but not in the HIV-1-infected group (-0.72 g/L; 95% confidence interval: -3.85 to +2.40; P = 0.64). HIV-1 infection as such (P < 0.0001), not CD4 cell count (P = 0.46), was an independent risk factor for a slower hematological recovery. HIV-1-infected malaria patients had a slower hematological recovery after successful parasite clearance. Malaria preventive measures should be targeted to this high-risk group.

  9. Exon level transcriptomic profiling of HIV-1-infected CD4(+ T cells reveals virus-induced genes and host environment favorable for viral replication.

    Directory of Open Access Journals (Sweden)

    Michaël Imbeault

    Full Text Available HIV-1 is extremely specialized since, even amongst CD4(+ T lymphocytes (its major natural reservoir in peripheral blood, the virus productively infects only a small proportion of cells under an activated state. As the percentage of HIV-1-infected cells is very low, most studies have so far failed to capture the precise transcriptomic profile at the whole-genome scale of cells highly susceptible to virus infection. Using Affymetrix Exon array technology and a reporter virus allowing the magnetic isolation of HIV-1-infected cells, we describe the host cell factors most favorable for virus establishment and replication along with an overview of virus-induced changes in host gene expression occurring exclusively in target cells productively infected with HIV-1. We also establish that within a population of activated CD4(+ T cells, HIV-1 has no detectable effect on the transcriptome of uninfected bystander cells at early time points following infection. The data gathered in this study provides unique insights into the biology of HIV-1-infected CD4(+ T cells and identifies genes thought to play a determinant role in the interplay between the virus and its host. Furthermore, it provides the first catalogue of alternative splicing events found in primary human CD4(+ T cells productively infected with HIV-1.

  10. Hepatitis C virus quasispecies and pseudotype analysis from acute infection to chronicity in HIV-1 co-infected individuals.

    Science.gov (United States)

    Ferns, R Bridget; Tarr, Alexander W; Hue, Stephane; Urbanowicz, Richard A; McClure, C Patrick; Gilson, Richard; Ball, Jonathan K; Nastouli, Eleni; Garson, Jeremy A; Pillay, Deenan

    2016-05-01

    HIV-1 infected patients who acquire HCV infection have higher rates of chronicity and liver disease progression than patients with HCV mono-infection. Understanding early events in this pathogenic process is important. We applied single genome sequencing of the E1 to NS3 regions and viral pseudotype neutralization assays to explore the consequences of viral quasispecies evolution from pre-seroconversion to chronicity in four co-infected individuals (mean follow up 566 days). We observed that one to three founder viruses were transmitted. Relatively low viral sequence diversity, possibly related to an impaired immune response, due to HIV infection was observed in three patients. However, the fourth patient, after an early purifying selection displayed increasing E2 sequence evolution, possibly related to being on suppressive antiretroviral therapy. Viral pseudotypes generated from HCV variants showed relative resistance to neutralization by autologous plasma but not to plasma collected from later time points, confirming ongoing virus escape from antibody neutralization.

  11. Apoptotic cell death, detected ex vivo in peripheral blood lymphocytes of HIV-1 infected persons

    Directory of Open Access Journals (Sweden)

    L. F. te Velde

    1996-01-01

    Full Text Available In HIV-1 infection the ongoing depletion of CD4+ T-lymphocytes is believed, to a large extent, to be due to apoptosis. Until now quantitative information about in vivo apoptosis of lymphocytes in HIV-patients is scarce because of the very nature of the apoptotic process. Successful detection of apoptosis ex vivo requires the recognition of the initial phase of this process, because at a later stage the cells may not remain any longer in the circulation. We measured quantitatively the amount of early apoptotic peripheral blood lymphocytes directly ex vivo in HIV-1 infected patients using a recently described flow cytometric assay. With this method we observed in an unselected heterogenous group of twelve HIV-infected individuals a median percentage of apoptotic lymphocytes to be significantly higher than in ten healthy controls. To the best of our knowledge this is the first report of ex vivo observed increased apoptosis of peripheral blood lymphocytes in HIV-infected persons.

  12. Dysregulation of beta-chemokines in the lungs of HIV-1-infected patients.

    Science.gov (United States)

    Aung, H; McKenna, S M; Ketoff, N R; Jones, L; Wu, M; Hejal, R; Rich, E A; Toossi, Z

    2001-04-01

    The beta-chemokines, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, monocyte chemotactic protein (MCP)-1 and regulated-on-activation normal T cell, expressed and secreted (RANTES) are not only chemotactic for mononuclear cells but may be important in suppression of HIV-1 replication through competitive binding to the chemokine receptor, CCR5, which is critical to viral entry. In this study, bronchoalveolar cells (BACs) and autologous peripheral blood mononuclear cells (PBMCs) were obtained from HIV-1-infected participants who did not manifest clinical signs of lung disease with peripheral CD4 T-cell count >200/mm(3) (n = 7, group with high CD4 count), or CD4 T-cell count CCR5 was assessed. Induction of MIP-1 alpha by lipopolysaccharide (LPS) in BAC of HIV-1-infected study subjects from the low CD4 group was less than BAC from healthy study subjects (p HIV-1-infected patients was significantly less than that from healthy study subjects (p CCR5 and MIP-1 alpha in BAC was significantly lower in HIV-1-infected patients compared with in healthy study subjects (p HIV-1-infected patients with high CD4 count was significantly higher than healthy study subjects (p HIV-1 infection in the lung.

  13. Mother-to-Child HIV-1 Transmission Events Are Differentially Impacted by Breast Milk and Its Components from HIV-1-Infected Women.

    Directory of Open Access Journals (Sweden)

    Ruizhong Shen

    Full Text Available Breast milk is a vehicle of infection and source of protection in post-natal mother-to-child HIV-1 transmission (MTCT. Understanding the mechanism by which breast milk limits vertical transmission will provide critical insight into the design of preventive and therapeutic approaches to interrupt HIV-1 mucosal transmission. However, characterization of the inhibitory activity of breast milk in human intestinal mucosa, the portal of entry in postnatal MTCT, has been constrained by the limited availability of primary mucosal target cells and tissues to recapitulate mucosal transmission ex vivo. Here, we characterized the impact of skimmed breast milk, breast milk antibodies (Igs and non-Ig components from HIV-1-infected Ugandan women on the major events of HIV-1 mucosal transmission using primary human intestinal cells and tissues. HIV-1-specific IgG antibodies and non-Ig components in breast milk inhibited the uptake of Ugandan HIV-1 isolates by primary human intestinal epithelial cells, viral replication in and transport of HIV-1- bearing dendritic cells through the human intestinal mucosa. Breast milk HIV-1-specific IgG and IgA, as well as innate factors, blocked the uptake and transport of HIV-1 through intestinal mucosa. Thus, breast milk components have distinct and complementary effects in reducing HIV-1 uptake, transport through and replication in the intestinal mucosa and, therefore, likely contribute to preventing postnatal HIV-1 transmission. Our data suggests that a successful preventive or therapeutic approach would require multiple immune factors acting at multiple steps in the HIV-1 mucosal transmission process.

  14. Stages of restricted HIV-1 infection in astrocyte cultures derived from human fetal brain tissue.

    Science.gov (United States)

    Messam, C A; Major, E O

    2000-05-01

    The predominant cell types infected by HIV-1 in AIDS associated encephalopathy are cells of the macrophage/microglial lineage. There has been consistent evidence, however, that astrocytes also become infected although not at the same frequency or level of multiplication as microglial cells. HIV-1 antigens and/or nucleic acid have been identified in astrocytes in brain autopsy tissue from both adult and pediatric AIDS cases. In cell cultures, HIV-1 infection of astrocytes results in an initial productive but non-cytopathogenic infection that diminishes to a viral persistence or latent state. Understanding the nature of HIV-1 infection of astrocytes, which represents the largest population of cells in the brain, will contribute to the understanding of AIDS encephalopathy and the dementia that occurs in nearly one-quarter of all AIDS patients.

  15. HIV-1 Entry and Trans-Infection of Astrocytes Involves CD81 Vesicles

    Science.gov (United States)

    Gray, Lachlan R.; Turville, Stuart G.; HItchen, Tina L.; Cheng, Wan-Jung; Ellett, Anne M.; Salimi, Hamid; Roche, Michael J.; Wesselingh, Steve L.; Gorry, Paul R.; Churchill, Melissa J.

    2014-01-01

    Astrocytes are extensively infected with HIV-1 in vivo and play a significant role in the development of HIV-1-associated neurocognitive disorders. Despite their extensive infection, little is known about how astrocytes become infected, since they lack cell surface CD4 expression. In the present study, we investigated the fate of HIV-1 upon infection of astrocytes. Astrocytes were found to bind and harbor virus followed by biphasic decay, with HIV-1 detectable out to 72 hours. HIV-1 was observed to associate with CD81-lined vesicle structures. shRNA silencing of CD81 resulted in less cell-associated virus but no loss of co-localization between HIV-1 and CD81. Astrocytes supported trans-infection of HIV-1 to T-cells without de novo virus production, and the virus-containing compartment required 37°C to form, and was trypsin-resistant. The CD81 compartment observed herein, has been shown in other cell types to be a relatively protective compartment. Within astrocytes, this compartment may be actively involved in virus entry and/or spread. The ability of astrocytes to transfer virus, without de novo viral synthesis suggests they are capable of sequestering and protecting virus and thus, they could potentially facilitate viral dissemination in the CNS. PMID:24587404

  16. Comparison of immunologic restoration and virologic response in plasma, tonsillar tissue, and cerebrospinal fluid in HIV-1-infected patients treated with double versus triple antiretroviral therapy in very early stages: The Spanish EARTH-2 Study. Early Anti-Retroviral Therapy Study.

    Science.gov (United States)

    García, F; Alonso, M M; Romeu, J; Knobel, H; Arrizabalaga, J; Ferrer, E; Dalmau, D; Ruiz, I; Vidal, F; Frances, A; Segura, F; Gomez-Sirvent, J L; Cruceta, A; Clotet, B; Pumarola, T; Gallart, T; O'Brien, W A; Miró, J M; Gatell, J M

    2000-09-01

    The objective of antiretroviral therapy is to obtain an almost complete and durable suppression of viral replication in all compartments to facilitate recovery of the immune system. We assessed the virologic effect in plasma, tonsillar tissue, and cerebrospinal fluid (CSF) in 94 HIV-1-infected patients with CD4 counts >500 x 106 cells per liter and viral load >5000 copies/ml randomly assigned to triple antiretroviral therapy (two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor) versus double therapy (two NRTIs). We also analyzed the immunologic recovery in this cohort of patients. Lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to HIV-1 specific antigens, and other immunophenotypic markers were analyzed. The proportion of patients who achieved a decrease in HIV RNA levels to <200 copies/ml was significantly greater in the triple therapy group than in the two drug groups (p =.0002 for each pair-wise difference). At week 52, tonsillar tissue HIV RNA from 5 patients treated with triple therapy was lower than the limit of detection, whereas the mean +/- standard error in patients with double therapy (n = 5) was 5.03 +/- 0.34 copies/mg/tissue. In all 10 patients, CSF viral load (VL) was <20 HIV-1 RNA copies/ml at week 52. CSF cell counts and protein levels tended to decrease after 52 weeks of antiretroviral therapy. After 1 year of therapy, 13 of 21 patients (62%) in the double-therapy groups (zidovudine plus lamivudine [n = 9] and stavudine plus lamivudine [n = 12]) had evidence of M184V mutation. None of the 10 samples of patients receiving triple therapy could be amplified because of low HIV RNA levels. The mean increase in CD4 cells at week 52 was greater in the stavudine and lamivudine and indinavir group than in the double-treatment arms (186 versus 67 and 102, respectively; p =.03). In patients treated with triple therapy, the increase in naive T cells (CD4 and CD8

  17. Association of Neutralization Sensitivity of HIV- 1 Primary Isolates With Biological Properties of Isolates From HIV-1 Infected Chinese Individuals

    Institute of Scientific and Technical Information of China (English)

    FA-XIN HEI; HAI-LI TANG; KUN-XUE HONG; JIAN-PING CHEN; HONG PENG; LIN YUAN; JIANG-QING XU; YI-MING SHAO

    2005-01-01

    Objective Although HIV-1 infection is prevalent in many regions in China, it remains largely unknown on the biological characteristics of dominant circulating isolates. This study was designed to isolate the circulating viral strains from different prevalent regions and to characterize their biological properties and neutralization sensitivity. Methods Primary viruses were isolated from fresh PBMCs using the traditional co-culture method and their capacity of inducing syncytium was tested in MT-2 cells. Meanwhile, their coreceptor usage was determined with two cell lines: Magi and GHOST (3) stably expressing CD4 and the chemokine receptor CCR5 or CXCR4. Furthermore, the sensitivity of these viruses to neutralization by HIV-1-infected patients' plasma which were highly active to neutralize SF33 strain, was quantified in GHOST cell-based neutralization assay. Results Six primary viral strains were isolated from 4 separated regions. Isolates LTG0213,LTG0214 and XVS032691 induced syncytia in MT-2 cells, and used CXCR4 as coreceptor. Isolates XJN0021, XJN0091, or SHXDC0041 did not induce syncytia, and used CCR5 as coreceptor. Overall neutralization sensitivity differed among four representative strains: HIV-1 XVS032691>LTG0214>XJN0091≈SHXDC0041. Conclusion The neutralization sensitivity of HIV isolates is linked with the phenotype of isolates, in which syncytium-inducing (SI) or CXCR4-tropic (X4) viruses are more easily neutralized than non-syncytium-inducing (NSI) or CCR5-tropic (R5) viruses. The genetic subtypes based on the phylogeny of env sequences are not classical neutralization serotypes.

  18. Platelets and erythrocyte-bound platelets bind infectious HIV-1 in plasma of chronically infected patients.

    Science.gov (United States)

    Beck, Zoltan; Jagodzinski, Linda L; Eller, Michael A; Thelian, Doris; Matyas, Gary R; Kunz, Anjali N; Alving, Carl R

    2013-01-01

    Chronic HIV-1 infection is associated with persistent viremia in most patients, but it remains unclear how free virus may survive the potential hostile effects of plasma. We investigated whether sites might exist on the surfaces of circulating blood cells for protection of infectious HIV-1 particles. Red blood cells (RBC) either from blood of uninfected normal individuals, or from blood obtained without EDTA from chronically infected HIV-1 patients, invariably contained a small number of RBC having attached platelets as determined by flow cytometry, light microscopy, and immunofluorescence microscopy. After mixing normal RBC with platelet-rich plasma, discrete populations of RBC, platelets, and complexes of platelets attached to RBC were purified by fluorescence-activated cell sorting. Upon incubation of purified cells or platelets with HIV-1 followed by washing and co-incubation with CD4-positive peripheral blood mononuclear cells (PBMC), platelets, and platelet-RBC complexes, but not platelet-free RBC, caused infection of PBMC. Infection was prevented by pre-treating the platelet-RBC complexes with EDTA. Plasma and RBC (comprising a RBC/platelet-RBC mixture) from chronically infected patients with low viral loads were also co-incubated with PBMC ex vivo to determine the presence of infectious HIV-1. All freshly isolated plasmas from the HIV-1-infected donors, obtained in the absence of anticoagulant, were noninfectious. Interestingly, the RBC from most of the patients caused cell-cell infection of PBMC that was prevented by stripping the RBC with EDTA. A monoclonal antibody to DC-SIGN partially inhibited cell-cell HIV-1 infection of PBMC by normal RBC pre-incubated with platelets and HIV-1. We conclude: (a) platelet-free EDTA-free plasma from chronically infected HIV-1 patients, although containing viral RNA, is an environment that lacks detectable infectious HIV-1; (b) platelets and platelet-RBC complexes, but not purified RBC, bind infectious HIV-1; (c) DC

  19. Platelets and erythrocyte-bound platelets bind infectious HIV-1 in plasma of chronically infected patients.

    Directory of Open Access Journals (Sweden)

    Zoltan Beck

    Full Text Available Chronic HIV-1 infection is associated with persistent viremia in most patients, but it remains unclear how free virus may survive the potential hostile effects of plasma. We investigated whether sites might exist on the surfaces of circulating blood cells for protection of infectious HIV-1 particles. Red blood cells (RBC either from blood of uninfected normal individuals, or from blood obtained without EDTA from chronically infected HIV-1 patients, invariably contained a small number of RBC having attached platelets as determined by flow cytometry, light microscopy, and immunofluorescence microscopy. After mixing normal RBC with platelet-rich plasma, discrete populations of RBC, platelets, and complexes of platelets attached to RBC were purified by fluorescence-activated cell sorting. Upon incubation of purified cells or platelets with HIV-1 followed by washing and co-incubation with CD4-positive peripheral blood mononuclear cells (PBMC, platelets, and platelet-RBC complexes, but not platelet-free RBC, caused infection of PBMC. Infection was prevented by pre-treating the platelet-RBC complexes with EDTA. Plasma and RBC (comprising a RBC/platelet-RBC mixture from chronically infected patients with low viral loads were also co-incubated with PBMC ex vivo to determine the presence of infectious HIV-1. All freshly isolated plasmas from the HIV-1-infected donors, obtained in the absence of anticoagulant, were noninfectious. Interestingly, the RBC from most of the patients caused cell-cell infection of PBMC that was prevented by stripping the RBC with EDTA. A monoclonal antibody to DC-SIGN partially inhibited cell-cell HIV-1 infection of PBMC by normal RBC pre-incubated with platelets and HIV-1. We conclude: (a platelet-free EDTA-free plasma from chronically infected HIV-1 patients, although containing viral RNA, is an environment that lacks detectable infectious HIV-1; (b platelets and platelet-RBC complexes, but not purified RBC, bind infectious HIV

  20. Sialoadhesin expressed on IFN-induced monocytes binds HIV-1 and enhances infectivity.

    Directory of Open Access Journals (Sweden)

    Hans Rempel

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  1. Uridine metabolism in HIV-1-infected patients: effect of infection, of antiretroviral therapy and of HIV-1/ART-associated lipodystrophy syndrome.

    Directory of Open Access Journals (Sweden)

    Pere Domingo

    Full Text Available BACKGROUND: Uridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS, although its metabolism in HIV-1-infected patients is poorly understood. METHODS: Plasma uridine concentrations were measured in 35 controls and 221 HIV-1-infected patients and fat uridine in 15 controls and 19 patients. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Uridine was measured by a binary gradient-elution HPLC method. Analysis of genes encoding uridine metabolizing enzymes in fat was performed with TaqMan RT-PCR. RESULTS: Median plasma uridine concentrations for HIV-1-infected patients were 3.80 µmol/l (interquartile range: 1.60, and for controls 4.60 µmol/l (IQR: 1.8 (P = 0.0009. In fat, they were of 6.0 (3.67, and 2.8 (4.65 nmol/mg of protein, respectively (P = 0.0118. Patients with a mixed HALS form had a median plasma uridine level of 4.0 (IC95%: 3.40-4.80 whereas in those with isolated lipoatrophy it was 3.25 (2.55-4.15 µmol/l/l (P = 0.0066. The expression of uridine cytidine kinase and uridine phosphorylase genes was significantly decreased in all groups of patients with respect to controls. A higher expression of the mRNAs for concentrative nucleoside transporters was found in HIV-1-infected patients with respect to healthy controls. CONCLUSIONS: HIV-1 infection is associated with a decrease in plasma uridine and a shift of uridine to the adipose tissue compartment. Antiretroviral therapy was not associated with plasma uridine concentrations, but pure lipoatrophic HALS was associated with significantly lower plasma uridine concentrations.

  2. Acute plasma biomarkers of T cell activation set-point levels and of disease progression in HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Anne-Sophie Liovat

    Full Text Available T cell activation levels, viral load and CD4(+ T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-β1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4(+ T cell counts at set-point and capable to predict 30% of the CD4(+ T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4(+ T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4(+ T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4(+ T cell counts or

  3. Elevated Levels of Microbial Translocation Markers and CCL2 Among Older HIV-1-Infected Men.

    Science.gov (United States)

    Scully, Eileen; Lockhart, Ainsley; Huang, Lisa; Robles, Yvonne; Becerril, Carlos; Romero-Tejeda, Marisol; Albrecht, Mary A; Palmer, Christine D; Bosch, Ronald J; Altfeld, Marcus; Kuritzkes, Daniel R; Lin, Nina H

    2016-03-01

    The aging of the human immunodeficiency virus type 1 (HIV-1)-infected population obligates a focus on the interaction between aging, comorbid conditions, and HIV-1. We recruited a cohort of HIV-1-infected men aged ≤ 35 years or ≥ 50 years who were receiving fully suppressive antiretroviral therapy (ART). We analyzed plasma markers of inflammation; T-cell activation, exhaustion, proliferation; and innate cellular subsets and functional capacity. Levels of lipopolysaccharide and the plasma marker of chemokine (C-C motif) ligand 2 were significantly elevated in older HIV-infected men despite comparable cellular phenotypes. Compared with similarly age-stratified uninfected subjects, older HIV-1-infected adults were also more frequently in the upper quartile of soluble CD14 expression.

  4. Potential of RNA aptamers in the prevention of HIV-1 subtype C infections

    CSIR Research Space (South Africa)

    London, GM

    2014-10-01

    Full Text Available Compounds that have been used to prevent human immunodeficiency virus type-I (HIV-1) infections include synthetic chemicals, plant extras and monoclonal antibodies. Although most of these compounds have potent antiviral activity, they often fail...

  5. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection.

    Science.gov (United States)

    Chen, Huabiao; Ndhlovu, Zaza M; Liu, Dongfang; Porter, Lindsay C; Fang, Justin W; Darko, Sam; Brockman, Mark A; Miura, Toshiyuki; Brumme, Zabrina L; Schneidewind, Arne; Piechocka-Trocha, Alicja; Cesa, Kevin T; Sela, Jennifer; Cung, Thai D; Toth, Ildiko; Pereyra, Florencia; Yu, Xu G; Douek, Daniel C; Kaufmann, Daniel E; Allen, Todd M; Walker, Bruce D

    2012-06-10

    The human leukocyte antigens HLA-B27 and HLA-B57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B27 and HLA-B57 are unable to control HIV-1. Here we found that HLA-B27-restricted CD8(+) T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B57-restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.

  6. Endometrial Histopathology in Patients with Laparoscopic Proven Salpingitis and HIV-1 Infection

    Directory of Open Access Journals (Sweden)

    Nelly R. Mugo

    2011-01-01

    Full Text Available Study Objective. To identify sensitive and specific histological criteria for endometritis in women with laparoscopically-confirmed acute salpingitis. Methods. Women, age 18–40 years of age presenting with complaints of lower abdominal pain ≤2 weeks and no antibiotics use in past two weeks, were enrolled. They underwent clinical examination, screening for HIV; other sexually transmitted infections plus endometrial biopsy sampling for histopathology. Diagnostic laparoscopy confirmed the diagnosis of acute salpingitis. Controls were women undergoing tubal ligation and HIV-1 infected women asymptomatic for genital tract infection. Results. Of 125 women with laparoscopically-confirmed salpingitis, 38% were HIV-1 seropositive. Nineteen HIV-1 negative controls were recruited. For the diagnosis of endometritis, ≥1 plasma cells (PC and ≥3 polymorphonuclear lymphocytes (PMN per HPF in the endometrium had a sensitivity of 74% for HIV-1-seropositive, 63% for HIV-1-seronegative women with a specificity of 75% and positive predictive value of 85% regardless of HIV-1-infection for predicting moderate to severe salpingitis. For HIV-1-seronegative women with mild salpingitis, ≥1 PC and ≥3 PMN had a sensitivity of 16% and a PPV of 57%. Conclusion. Endometrial histology, did not perform well as a surrogate marker for moderate to severe salpingitis, and failed as a surrogate marker for mild salpingitis.

  7. The Role of Cationic Polypeptides in Modulating HIV-1 Infection of the Cervicovaginal Mucosa

    Science.gov (United States)

    Cole, Amy Liese; Cole, Alexander M.

    2014-01-01

    The mucosa and overlying fluid of the female reproductive tract (FRT) are portals for the heterosexual transmission of HIV-1. Toward the ongoing development of topically applied microbicides and mucosal vaccines against HIV-1, it is evermore important to understand how the dynamic FRT mucosa is involved in controlling transmission and infection of HIV-1. Cationic peptides and proteins are the principal innate immune effector molecules of mucosal surfaces, and interact in a combinatorial fashion to modulate HIV-1 infection of the cervix and vagina. While cationic peptides and proteins have historically been categorized as antimicrobial or have other host-benefitting roles, an increasing number of these molecules have been found to augment HIV-1 infection and potentially antagonize host defense. Complex environmental factors such as hormonal fluctuations and/or bacterial and viral co-infections provide additional challenges to both experimentation and interpretation of results. In the context of heterosexual transmission of HIV-1, this review explores how various cationic peptides and proteins participate in modulating host defense against HIV-1 of the cervicovaginal mucosa. PMID:27025760

  8. The Role of Cationic Polypeptides in Modulating HIV-1 Infection of the Cervicovaginal Mucosa

    Directory of Open Access Journals (Sweden)

    Amy Liese Cole

    2014-11-01

    Full Text Available The mucosa and overlying fluid of the female reproductive tract (FRT are portals for the heterosexual transmission of HIV-1. Toward the ongoing development of topically applied microbicides and mucosal vaccines against HIV-1, it is evermore important to understand how the dynamic FRT mucosa is involved in controlling transmission and infection of HIV-1. Cationic peptides and proteins are the principal innate immune effector molecules of mucosal surfaces, and interact in a combinatorial fashion to modulate HIV-1 infection of the cervix and vagina. While cationic peptides and proteins have historically been categorized as antimicrobial or have other host-benefitting roles, an increasing number of these molecules have been found to augment HIV-1 infection and potentially antagonize host defense. Complex environmental factors such as hormonal fluctuations and/or bacterial and viral co-infections provide additional challenges to both experimentation and interpretation of results. In the context of heterosexual transmission of HIV-1, this review explores how various cationic peptides and proteins participate in modulating host defense against HIV-1 of the cervicovaginal mucosa.

  9. HIV-1-infection of T lymphocytes and macrophages affects their migration via Nef

    Directory of Open Access Journals (Sweden)

    Christel eVérollet

    2015-10-01

    Full Text Available The human immunodeficiency virus (HIV-1 disseminates in the body and is found in several organs and tissues. While HIV-1 mainly targets both CD4+ T lymphocytes and macrophages, it has contrasting effects between these cell populations. HIV-1 infection namely reduces the viability of CD4+ T cells, whereas infected macrophages are long-lived. In addition, the migration of T cells is reduced by the infection, while HIV-1 differentially modulates the migration modes of macrophages. In 2-dimensions (2D assays, infected macrophages are less motile compared to the control counterparts. In 3D environments, macrophages use two migration modes that are dependent on the matrix architecture: amoeboid and mesenchymal migration. HIV-1 infected macrophages exhibit a reduced amoeboid migration but an enhanced mesenchymal migration, via the viral protein Nef. Indeed, the mesenchymal migration involves podosomes, and Nef stabilizes these cell structures through the activation of the tyrosine kinase Hck, which in turn phosphorylates the Wiskott Aldrich Syndrome Protein (WASP. WASP is a key player in actin remodeling and cell migration. The reprogramed motility of infected macrophages observed in vitro correlates in vivo with enhanced macrophage infiltration in experimental tumors in Nef-transgenic mice compared to control mice.In conclusion, HIV infection of host target cells modifies their migration capacity; we infer that HIV-1 enhances virus spreading in confined environments by reducing T cells migration, and facilitates virus dissemination into different organs and tissues of the human body by enhancing macrophage mesenchymal migration.

  10. Diminished representation of HIV-1 variants containing select drug resistance-conferring mutations in primary HIV-1 infection.

    Science.gov (United States)

    Turner, Dan; Brenner, Bluma; Routy, Jean-Pierre; Moisi, Daniela; Rosberger, Zeev; Roger, Michel; Wainberg, Mark A

    2004-12-15

    This study compared the incidence of HIV-1 variants harboring mutations conferring resistance to thymidine analogues, ie, thymidine analogue mutations (TAMs), nonnucleoside reverse transcriptase (RT) inhibitors (NNMs), lamivudine (3TC) (ie, M184V), and protease inhibitors (PIs) acquired in primary HIV infection (PHI) (n = 59) to their observed prevalence in a corresponding potential transmitter (PT) population of persons harboring resistant infections (n = 380). Both of these populations in the context of this cohort analysis possessed similar demographics. Whereas the frequencies of observed TAMs, NNMs, M184V, and protease-associated mutations (PRAMs) were similar in the PT groups, the prevalence of M184V and major PI mutations were significantly lower in the PHI group (PHI/PT ratios of 0.14 and 0.39, respectively). There was a decreased prevalence in the PHI population of resistant viruses co-expressing NNMs or TAMs with M184V compared with viruses that harbored NNMs or TAMs in the absence of M184V (P < 0.0001). It was also observed that individuals in the PT subgroups who harbored RT mutations or PRAMs with M184V had lower levels of plasma viremia than individuals who lacked M184V (P < 0.05). These findings suggest that both decreased viremia and viral fitness in the case of M184V-containing HIV-1 variants may impact on viral transmissibility.

  11. Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates

    Science.gov (United States)

    Mikulak, Joanna; Di Vito, Clara; Zaghi, Elisa; Mavilio, Domenico

    2017-01-01

    A better understanding of the mechanisms employed by HIV-1 to escape immune responses still represents one of the major tasks required for the development of novel therapeutic approaches targeting a disease still lacking a definitive cure. Host innate immune responses against HIV-1 are key in the early phases of the infection as they could prevent the development and the establishment of two hallmarks of the infection: chronic inflammation and viral reservoirs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to a family of transmembrane proteins able to dampen host immune responses and set appropriate immune activation thresholds upon ligation with their natural ligands, the sialylated carbohydrates. This immune-modulatory function is also targeted by many pathogens that have evolved to express sialic acids on their surface in order to escape host immune responses. HIV-1 envelope glycoprotein 120 (gp120) is extensively covered by carbohydrates playing active roles in life cycle of the virus. Indeed, besides forming a protecting shield from antibody recognition, this coat of N-linked glycans interferes with the folding of viral glycoproteins and enhances virus infectivity. In particular, the sialic acid residues present on gp120 can bind Siglec-7 on natural killer and monocytes/macrophages and Siglec-1 on monocytes/macrophages and dendritic cells. The interactions between these two members of the Siglec family and the sialylated glycans present on HIV-1 envelope either induce or increase HIV-1 entry in conventional and unconventional target cells, thus contributing to viral dissemination and disease progression. In this review, we address the impact of Siglecs in the pathogenesis of HIV-1 infection and discuss how they could be employed as clinic and therapeutic targets.

  12. The Immune Interaction between HIV-1 Infection and Mycobacterium tuberculosis.

    Science.gov (United States)

    Du Bruyn, Elsa; Wilkinson, Robert John

    2016-12-01

    The modulation of tuberculosis (TB)-induced immunopathology caused by human immunodeficiency virus (HIV)-1 coinfection remains incompletely understood but underlies the change seen in the natural history, presentation, and prognosis of TB in such patients. The deleterious combination of these two pathogens has been dubbed a "deadly syndemic," with each favoring the replication of the other and thereby contributing to accelerated disease morbidity and mortality. HIV-1 is the best-recognized risk factor for the development of active TB and accounts for 13% of cases globally. The advent of combination antiretroviral therapy (ART) has considerably mitigated this risk. Rapid roll-out of ART globally and the recent recommendation by the World Health Organization (WHO) to initiate ART for everyone living with HIV at any CD4 cell count should lead to further reductions in HIV-1-associated TB incidence because susceptibility to TB is inversely proportional to CD4 count. However, it is important to note that even after successful ART, patients with HIV-1 are still at increased risk for TB. Indeed, in settings of high TB incidence, the occurrence of TB often remains the first presentation of, and thereby the entry into, HIV care. As advantageous as ART-induced immune recovery is, it may also give rise to immunopathology, especially in the lower-CD4-count strata in the form of the immune reconstitution inflammatory syndrome. TB-immune reconstitution inflammatory syndrome will continue to impact the HIV-TB syndemic.

  13. Pharmacokinetics of antiretroviral therapy in HIV-1-infected children

    NARCIS (Netherlands)

    P.L.A. Fraaij (Pieter); J.J.A. van Kampen (Jeroen); D.M. Burger (David); R. de Groot (Ronald)

    2005-01-01

    textabstractThe initiation of antiretroviral therapy has resulted in an impressive reduction in the rate of disease progression in AIDS and HIV-1-related deaths in children; however, there are still several major challenges to be faced in order to improve therapy. A major topic that needs to be deal

  14. IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection

    Science.gov (United States)

    Younes, Souheil-Antoine; Freeman, Michael L.; Mudd, Joseph C.; Shive, Carey L.; Reynaldi, Arnold; Estes, Jacob D.; Deleage, Claire; Lucero, Carissa; Anderson, Jodi; Schacker, Timothy W.; Davenport, Miles P.; McCune, Joseph M.; Hunt, Peter W.; Lee, Sulggi A.; Debernardo, Robert L.; Jacobson, Jeffrey M.; Canaday, David H.; Sekaly, Rafick-Pierre; Sieg, Scott F.; Lederman, Michael M.

    2016-01-01

    In HIV-1infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1infected patients. Compared with healthy controls, untreated HIV-1infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients. PMID:27322062

  15. The SCID-hu mouse as a model for HIV-1 infection.

    Science.gov (United States)

    Aldrovandi, G M; Feuer, G; Gao, L; Jamieson, B; Kristeva, M; Chen, I S; Zack, J A

    1993-06-24

    During normal fetal ontogeny, one of the first organs to harbour CD4-positive cells is the thymus. This organ could therefore be one of the earliest targets infected by human immunodeficiency virus type 1 (HIV-1) in utero. HIV-1-infected cells and pathological abnormalities of the thymus have been seen in HIV-1-infected adults and children, and in some fetuses aborted from infected women. Studies of HIV-1 pathogenesis have been hampered by lack of a suitable animal model system. Here we use the SCID-hu mouse as a model to investigate the effect of virus infection on human tissue. The mouse is homozygous for the severe combined immunodeficiency (SCID) defect. The model is constructed by implanting human fetal liver and thymus under the mouse kidney capsule. A conjoint human organ develops, which allows normal maturation of human thymocytes. After direct inoculation of HIV-1 into these implants, we observed severe depletion of human CD4-bearing cells within a few weeks of infection. This correlated with increasing virus load in the implants. Thus the SCID-hu mouse may be a useful in vivo system for the study of HIV-1-induced pathology.

  16. The Role of Sexually Transmitted Infections in HIV-1 Progression: A Comprehensive Review of the Literature

    Directory of Open Access Journals (Sweden)

    Helen M. Chun

    2013-01-01

    Full Text Available Due to shared routes of infection, HIV-infected persons are frequently coinfected with other sexually transmitted infections (STIs. Studies have demonstrated the bidirectional relationships between HIV and several STIs, including herpes simplex virus-2 (HSV-2, hepatitis B and C viruses, human papilloma virus, syphilis, gonorrhea, chlamydia, and trichomonas. HIV-1 may affect the clinical presentation, treatment outcome, and progression of STIs, such as syphilis, HSV-2, and hepatitis B and C viruses. Likewise, the presence of an STI may increase both genital and plasma HIV-1 RNA levels, enhancing the transmissibility of HIV-1, with important public health implications. Regarding the effect of STIs on HIV-1 progression, the most studied interrelationship has been with HIV-1/HSV-2 coinfection, with recent studies showing that antiherpetic medications slow the time to CD4 <200 cells/µL and antiretroviral therapy among coinfected patients. The impact of other chronic STIs (hepatitis B and C on HIV-1 progression requires further study, but some studies have shown increased mortality rates. Treatable, nonchronic STIs (i.e., syphilis, gonorrhea, chlamydia, and trichomonas typically have no or transient impacts on plasma HIV RNA levels that resolve with antimicrobial therapy; no long-term effects on outcomes have been shown. Future studies are advocated to continue investigating the complex interplay between HIV-1 and other STIs.

  17. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117.

    Science.gov (United States)

    Caskey, Marina; Klein, Florian; Lorenzi, Julio C C; Seaman, Michael S; West, Anthony P; Buckley, Noreen; Kremer, Gisela; Nogueira, Lilian; Braunschweig, Malte; Scheid, Johannes F; Horwitz, Joshua A; Shimeliovich, Irina; Ben-Avraham, Sivan; Witmer-Pack, Maggi; Platten, Martin; Lehmann, Clara; Burke, Leah A; Hawthorne, Thomas; Gorelick, Robert J; Walker, Bruce D; Keler, Tibor; Gulick, Roy M; Fätkenheuer, Gerd; Schlesinger, Sarah J; Nussenzweig, Michel C

    2015-06-25

    HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.

  18. In vitro anti-HIV-1 antibody production in subjects in different stages of HIV-1 infection.

    Science.gov (United States)

    Rusconi, S; Riva, A; Meroni, L; Zehender, G; Cocchi, F; Scapellato, L; Galli, M

    1995-01-01

    We evaluated the in vitro antibody production from peripheral blood mononuclear cells (PBMC) against HIV-1 proteins in infected adults. Fifty-four HIV-1 infected patients (four recent seroconverters, 15 asymptomatics with a CD4 count higher than 500/microliters, 27 asymptomatics with a CD4 count between 200 and 500/microliters and eight symptomatic patients) were tested. PBMC were incubated in the presence or absence of 1% pokeweed mitogen (PWM) at 37 degrees C for 8 days. Western blot assay, p24 antigen ELISA and anti-p24 antibody ELISA were performed on serum and culture supernatants. Spontaneous production of anti-env antibody in culture supernatants was evidenced in all subjects. All the positive supernatants for anti-core antibodies (18/54) were derived from asymptomatic patients. PBMC from recent seroconverters and from symptomatic patients did not produce any anti-core antibody. Antibody production decreased after stimulation with PWM. The concentration of p24 antigen did not significantly increase in p24 positive supernatants following acidification (P = 0.1), suggesting that the inability to detect p24 antibody was not due to the anti-p24 antibody complexed to p24 antigen in culture supernatants. In vitro production of anti-p24 antibodies was significantly more frequent in asymptomatic subjects with high CD4+ cell counts (P = 0.02) and was absent in recent seroconverters. This last finding suggests that during the initial phases of the infection, anti-p24 antibody production may be restricted to cells residing in lymphoid organs. In addition, the lower percentage of anti-core antibody in people with low CD4+ cell counts is not merely a consequence of the binding of the antibody to an increased amount of antigen, but probably reflects an impaired production or a sequestration of producing cells in lymphoid tissue during the late stages of the infection. PMID:7554395

  19. Humans with chimpanzee-like major histocompatibility complex-specificities control HIV-1 infection

    DEFF Research Database (Denmark)

    Hoof, Ilka; Kesmir, Can; Lund, Ole;

    2008-01-01

    Background: Major histocompatibility complex (MHC) class I molecules allow immune surveillance by presenting a snapshot of the intracellular state of a cell to circulating cytotoxic T lymphocytes. The MHC class I alleles of an HIV-1 infected individual strongly influence the level of viremia...... and the progression rate to AIDS. Chimpanzees control HIV-1 viral replication and develop a chronic infection without progressing to AIDS. A similar course of disease is observed in human long-term non-progressors. Objective: To investigate if long-term non-progressors and chimpanzees have functional similarities...... in their MHC class I repertoire. Methods: We compared the specificity of groups of human MHC molecules associated with different levels of viremia in HIV-1 infected individuals with those of chimpanzee. Results and conclusion: We demonstrate that human MHC with control of HIV-1 viral load share binding motifs...

  20. Evaluation of a single round polymerase chain reaction assay using dried blood spots for diagnosis of HIV-1 infection in infants in an African setting

    Directory of Open Access Journals (Sweden)

    Ng'ayo Musa

    2011-02-01

    Full Text Available Abstract Background The aim of this study was to develop an economical 'in-house' single round polymerase chain reaction (PCR assay using filter paper-dried blood spots (FP-DBS for early infant HIV-1 diagnosis and to evaluate its performance in an African setting. Methods An 'in-house' single round PCR assay that targets conserved regions in the HIV-1 polymerase (pol gene was validated for use with FP-DBS; first we validated this assay using FP-DBS spiked with cell standards of known HIV-1 copy numbers. Next, we validated the assay by testing the archived FP-DBS (N = 115 from infants of known HIV-1 infection status. Subsequently this 'in-house' HIV-1 pol PCR FP-DBS assay was then established in Nairobi, Kenya for further evaluation on freshly collected FP-DBS (N = 186 from infants, and compared with findings from a reference laboratory using the Roche Amplicor® HIV-1 DNA Test, version 1.5 assay. Results The HIV-1 pol PCR FP-DBS assay could detect one HIV-1 proviral copy in 38.7% of tests, 2 copies in 46.9% of tests, 5 copies in 72.5% of tests and 10 copies in 98.1% of tests performed with spiked samples. Using the archived FP-DBS samples from infants of known infection status, this assay was 92.8% sensitive and 98.3% specific for HIV-1 infant diagnosis. Using 186 FP-DBS collected from infants recently defined as HIV-1 positive using the commercially available Roche Amplicor v1.5 assay, 178 FP-DBS tested positive by this 'in-house' single-round HIV-1 pol PCR FP-DBS PCR assay. Upon subsequent retesting, the 8 infant FP-DBS samples that were discordant were confirmed as HIV-1 negative by both assays using a second blood sample. Conclusions HIV-1 was detected with high sensitivity and specificity using both archived and more recently collected samples. This suggests that this 'in-house' HIV-1 pol FP-DBS PCR assay can provide an alternative cost-effective, reliable and rapid method for early detection of HIV-1 infection in infants.

  1. Immune control of HIV-1 infection after therapy interruption: immediate versus deferred antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Bernaschi Massimo

    2009-10-01

    Full Text Available Abstract Background The optimal stage for initiating antiretroviral therapies in HIV-1 bearing patients is still a matter of debate. Methods We present computer simulations of HIV-1 infection aimed at identifying the pro et contra of immediate as compared to deferred Highly Active Antiretroviral Therapy (HAART. Results Our simulations highlight that a prompt specific CD8+ cytotoxic T lymphocytes response is detected when therapy is delayed. Compared to very early initiation of HAART, in deferred treated patients CD8+ T cells manage to mediate the decline of viremia in a shorter time and, at interruption of therapy, the virus experiences a stronger immune pressure. We also observe, however, that the immunological effects of the therapy fade with time in both therapeutic regimens. Thus, within one year from discontinuation, viral burden recovers to the value at which it would level off in the absence of therapy. In summary, simulations show that immediate therapy does not prolong the disease-free period and does not confer a survival benefit when compared to treatment started during the chronic infection phase. Conclusion Our conclusion is that, since there is no therapy to date that guarantees life-long protection, deferral of therapy should be preferred in order to minimize the risk of adverse effects, the occurrence of drug resistances and the costs of treatment.

  2. Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector

    Directory of Open Access Journals (Sweden)

    Bryan P Burke

    2015-01-01

    Full Text Available We described earlier a dual-combination anti-HIV type 1 (HIV-1 lentiviral vector (LVsh5/C46 that downregulates CCR5 expression of transduced cells via RNAi and inhibits HIV-1 fusion via cell surface expression of cell membrane-anchored C46 antiviral peptide. This combinatorial approach has two points of inhibition for R5-tropic HIV-1 and is also active against X4-tropic HIV-1. Here, we utilize the humanized bone marrow, liver, thymus (BLT mouse model to characterize the in vivo efficacy of LVsh5/C46 (Cal-1 vector to engineer cellular resistance to HIV-1 pathogenesis. Human CD34+ hematopoietic stem/progenitor cells (HSPC either nonmodified or transduced with LVsh5/C46 vector were transplanted to generate control and treatment groups, respectively. Control and experimental groups displayed similar engraftment and multilineage hematopoietic differentiation that included robust CD4+ T-cell development. Splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 during ex vivo challenge experiments. Treatment group animals challenged with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks postinfection. Gene-marking and transgene expression were confirmed stable at 26 weeks post-transplantation. These data strongly support the use of LVsh5/C46 lentiviral vector in gene and cell therapeutic applications for inhibition of HIV-1 infection.

  3. Predictors of mortality in HIV-1 infected children on antiretroviral therapy in Kenya: a prospective cohort

    Directory of Open Access Journals (Sweden)

    Mbori-Ngacha Dorothy A

    2010-05-01

    Full Text Available Abstract Background Among children, early mortality following highly active antiretroviral therapy (HAART remains high. It is important to define correlates of mortality in order to improve outcome. Methods HIV-1-infected children aged 18 months-12 years were followed up at Kenyatta National Hospital, Nairobi after initiating NNRTI-based HAART. Cofactors for mortality were determined using multivariate Cox regression models. Results Between August 2004 and November 2008, 149 children were initiated on HAART of whom 135 were followed for a total of 238 child-years (median 21 months after HAART initiation. Baseline median CD4% was 6.8% and median HIV-1-RNA was 5.98-log10 copies/ml. Twenty children (13.4% died at a median of 35 days post-HAART initiation. Mortality during the entire follow-up period was 8.4 deaths per 100 child-years (46 deaths/100 child-years in first 4 months and 1.0 deaths/100 child-years after 4 months post-HAART initiation. On univariate Cox regression, baseline hemoglobin (Hb Conclusion High early mortality was observed in this cohort of Kenyan children receiving HAART, and low baseline hemoglobin was an independent risk factor for death.

  4. New tools to expand regulatory T cells from HIV-1-infected individuals.

    Science.gov (United States)

    Angin, Mathieu; King, Melanie; Addo, Marylyn Martina

    2013-05-30

    CD4+ Regulatory T cells (Tregs) are potent immune modulators and serve an important function in human immune homeostasis. Depletion of Tregs has led to measurable increases in antigen-specific T cell responses in vaccine settings for cancer and infectious pathogens. However, their role in HIV-1 immuno-pathogenesis remains controversial, as they could either serve to suppress deleterious HIV-1-associated immune activation and thus slow HIV-1 disease progression or alternatively suppress HIV-1-specific immunity and thereby promote virus spread. Understanding and modulating Treg function in the context of HIV-1 could lead to potential new strategies for immunotherapy or HIV vaccines. However, important open questions remain on their role in the context of HIV-1 infection, which needs to be carefully studied. Representing roughly 5% of human CD4+ T cells in the peripheral blood, studying the Treg population has proven to be difficult, especially in HIV-1 infected individuals where HIV-1-associated CD4 T cell and with that Treg depletion occurs. The characterization of regulatory T cells in individuals with advanced HIV-1 disease or tissue samples, for which only very small biological samples can be obtained, is therefore extremely challenging. We propose a technical solution to overcome these limitations using isolation and expansion of Tregs from HIV-1-positive individuals. Here we describe an easy and robust method to successfully expand Tregs isolated from HIV-1-infected individuals in vitro. Flow-sorted CD3(+)CD4(+)CD25(+)CD127(low) Tregs were stimulated with anti-CD3/anti-CD28 coated beads and cultured in the presence of IL-2. The expanded Tregs expressed high levels of FOXP3, CTLA4 and HELIOS compared to conventional T cells and were shown to be highly suppressive. Easier access to large numbers of Tregs will allow researchers to address important questions concerning their role in HIV-1 immunopathogenesis. We believe answering these questions may provide useful

  5. TRIM5 and the Regulation of HIV-1 Infectivity

    Directory of Open Access Journals (Sweden)

    Jeremy Luban

    2012-01-01

    Full Text Available The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.

  6. Sulfatide--a new candidate for ART treatment in HIV-1 infection.

    Science.gov (United States)

    Sundell, I Birgitta; Cortado, Ruth V; Koka, Prasad S

    2012-01-01

    New combination drug treatment(s) now available to patients with HIV-1 infection allows them to live longer lives with good quality of life although they suffer from the incurable HIV-1 infection. In a previous study we found that sulfatide was efficient in lowering HIV-1 viral loads in SCID mice engrafted with human fetal liver/thymus tissues (SCID-hu). Current antiviral treatments carry an increased risk of other complications like cardiovascular disease and diabetes after long-term use. There is a need for new potent safe pharmaceutical agents. Endogenous sulfatide is a mixture of -isoforms, i.e. sulfatide molecules with different long-chain bases and fatty acid chain lengths and saturation. Sulfatide isoforms may have different physicochemical properties i.e, they are of different potency at different target cells. Other investigators have shown that incubation of cultured cells with sulfatide incorporated into the plasma membrane inhibited HIV-1 entry into the cells thereby inhibiting intracellular HIV-1 replication. We have shown that CD1d dependent stimulation by sulfatide may activate pDC antigen expressing cells that produce type I inteferons. Type I inteferons are known to reduce HIV-1 replication. This could provide a second likely explanation (after the inhibition of virus entry) for the more efficient lowering of HIV-1 viral loads in sulfatide versus AZT treated mice. This review aims to show the efficiency of sulfatide in reducing HIV-1 viral loads as compared to conventional HAART treatment. We also discuss the risks of HAART treatment and propose a clinical alternative of sulfatide in HIV-1 infection.

  7. Vpr14-88-Apobec3G fusion protein is efficiently incorporated into Vif-positive HIV-1 particles and inhibits viral infection.

    Directory of Open Access Journals (Sweden)

    Zhujun Ao

    Full Text Available BACKGROUND: APOBEC3G (A3G, a deoxycytidine deaminase, is a potent host antiviral factor that can restrict HIV-1 infection. During Vif-negative HIV-1 replication, A3G is incorporated into HIV-1 particles, induces mutations in reverse transcribed viral DNA and inhibits reverse transcription. However, HIV-1 Vif counteracts A3G's activities by inducing its degradation and by blocking its incorporation into HIV-1 particles. Thus, it is interesting to elucidate a mechanism that would allow A3G to escape the effects of Vif in order to rescue its potent antiviral activity and to provide a possible novel therapeutic strategy for treating HIV-1 infection. METHODS AND FINDINGS: In this study, we generated an R88-A3G fusion protein by fusing A3G to a virion-targeting polypeptide (R14-88 derived from HIV-1 Vpr protein and compared its antiviral effects relative to those of HA-tagged native A3G (HA-A3G. Our study showed that transient expression of the R88-A3G fusion protein in both Vif(- and Vif(+ HIV-1 producing cells drastically inhibited viral infection in HeLa-CD4-CCR5-cells, CD4(+ C8166 T cells and human primary PBMCs. Moreover, we established CD4(+ C8166 T cell lines that stably express either R88-A3G or HA-A3G by transduction with VSV-G-pseudotyped lentiviral vector that harbor expression cassettes for R88-A3G or HA-A3G, respectively, and tested their susceptibility to Vif(+ HIV-1 infection. Our results clearly reveal that expression of R88-A3G in transduced CD4(+ C8166 cells significantly blocked Vif(+ HIV-1 infection. In an attempt to understand the mechanism underlying the antiviral activity of R88-A3G, we demonstrated that R88-A3G was efficiently incorporated into viral particles in the presence of Vif. Moreover, PCR analysis revealed that R88-A3G significantly inhibited viral cDNA synthesis during the early stage of Vif(+ virus infection. CONCLUSIONS: Our results clearly indicate that R88 delivers A3G into Vif(+ HIV-1 particles and inhibits

  8. HIV-1 infection initiates an inflammatory cascade in human renal tubular epithelial cells.

    Science.gov (United States)

    Ross, Michael J; Fan, Cheng; Ross, Michael D; Chu, Te-Huatearina; Shi, Yueyue; Kaufman, Lewis; Zhang, Weijia; Klotman, Mary E; Klotman, Paul E

    2006-05-01

    HIV-associated nephropathy (HIVAN) is the most common cause of chronic renal failure in HIV-infected patients. Tubulointerstitial inflammation is a prominent component of the histopathology of HIVAN. The pathogenesis of HIVAN is a result of infection of renal epithelial cells, but the cellular response to this infection remains poorly defined. In these studies, we used oligonucleotide microarrays to identify differentially expressed genes in renal tubular epithelial cells from a patient with HIVAN at three time points after infection with vesicular stomatitis virus-pseudotyped gag/pol-deleted HIV-1. Very few genes were differentially expressed 12 and 24 hours after infection. Three days after infection, however, 47 genes were upregulated by at least 1.8-fold. The most prominent response of these cells to HIV-1 expression was production of proinflammatory mediators, including chemokines, cytokines, and adhesion molecules. Many of the upregulated genes are targets of interleukin 6 and nuclear factor kappa B regulation, suggesting a central role for these proteins in the response of tubular epithelial cells to HIV-1 infection. Analysis of kidneys from HIV-1 transgenic mice revealed upregulation of many of the proinflammatory genes identified in the microarray studies. These studies provide novel insights into the mechanisms by which HIV-1 infection of tubular epithelial cells leads to tubulointerstitial inflammation and progressive renal injury.

  9. Effects of HIV-1 infection on malaria parasitemia in milo sub-location, western Kenya.

    Science.gov (United States)

    Rutto, Erick Kipkoech; Nyagol, Joshua; Oyugi, Julius; Ndege, Samson; Onyango, Noel; Obala, Andrew; Simiyu, Chrispinus J; Boor, Gye; Cheriro, Winfrida Chelangat; Otsyula, Barasa; Estambale, Ben

    2015-07-15

    Malaria and HIV infections are both highly prevalent in sub-Saharan Africa, with HIV-infected patients being at higher risk of acquiring malaria. HIV-1 infection is known to impair the immune response and may increase the incidence of clinical malaria. However, a positive association between HIV-1 and malaria parasitaemia is still evolving. Equally, the effect of malaria on HIV-1 disease stage has not been well established, but when fever and parasitemia are high, malaria may be associated with transient increases in HIV-1 viral load, and progression of HIV-1 asymptomatic disease phase to AIDS. To determine the effects of HIV-1 infection on malaria parasitaemia among consented residents of Milo sub-location, Bungoma County in western Kenya. Census study evaluating malaria parasitaemia in asymptomatic individuals with unknown HIV-1 status. After ethical approvals from both Moi University and MTRH research ethics committees, data of 3,258 participants were retrieved from both Webuye health demographic surveillance system (WHDSS), and Academic Model Providing Access to Healthcare (AMPATH) in the year 2010. The current study was identifying only un-diagnosed HIV-1 individuals at the time the primary data was collected. The data was then analysed for significant statistical association for malaria parasitemia and HIV-1 infection, using SPSS version 19. Demographic characteristics such as age and sex were summarized as means and percentages, while relationship between malaria parasitaemia and HIV-1 (serostatus) was analyzed using Chi square. Age distribution for the 3,258 individuals ranged between 2 and 94 years, with a mean age of 26 years old. Females constituted 54.3%, while males were 45.8%. In terms of age distribution, 2-4 years old formed 15.1% of the study population, 5-9 years old were 8.8%, 10-14 years old were 8.6% while 15 years old and above were 67.5%. Of the 3,258 individuals whose data was eligible for analysis, 1.4% was newly diagnosed HIV-1 positive

  10. Diphtheria Antibodies and T lymphocyte Counts in Patients Infected with HIV-1

    Directory of Open Access Journals (Sweden)

    Francisco A. B. Speranza

    2012-09-01

    Full Text Available We assessed the IgG levels anti-diphtheria (D-Ab and T cell counts (CD4+ and CD8+ in HIV-1 infected subjects undergoing or not highly active antiretroviral therapy (HAART. Approximately 70% of all HIV-1 patients were unprotected against diphtheria. There were no differences in D-Ab according to CD4 counts. Untreated patients had higher D-Ab (geometric mean of 0.62 IU/ml than HAART-patients (geometric mean of 0.39 IU/ml. The data indicated the necessity of keeping all HIV-1 patients up-to-date with their vaccination.

  11. LINE-1 retrotransposable element DNA accumulates in HIV-1-infected cells.

    Science.gov (United States)

    Jones, R Brad; Song, Haihan; Xu, Yang; Garrison, Keith E; Buzdin, Anton A; Anwar, Naveed; Hunter, Diana V; Mujib, Shariq; Mihajlovic, Vesna; Martin, Eric; Lee, Erika; Kuciak, Monika; Raposo, Rui André Saraiva; Bozorgzad, Ardalan; Meiklejohn, Duncan A; Ndhlovu, Lishomwa C; Nixon, Douglas F; Ostrowski, Mario A

    2013-12-01

    Type 1 long-interspersed nuclear elements (L1s) are autonomous retrotransposable elements that retain the potential for activity in the human genome but are suppressed by host factors. Retrotransposition of L1s into chromosomal DNA can lead to genomic instability, whereas reverse transcription of L1 in the cytosol has the potential to activate innate immune sensors. We hypothesized that HIV-1 infection would compromise cellular control of L1 elements, resulting in the induction of retrotransposition events. Here, we show that HIV-1 infection enhances L1 retrotransposition in Jurkat cells in a Vif- and Vpr-dependent manner. In primary CD4(+) cells, HIV-1 infection results in the accumulation of L1 DNA, at least the majority of which is extrachromosomal. These data expose an unrecognized interaction between HIV-1 and endogenous retrotransposable elements, which may have implications for the innate immune response to HIV-1 infection, as well as for HIV-1-induced genomic instability and cytopathicity.

  12. Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection.

    Science.gov (United States)

    Yang, Hongbing; Yorke, Elisabeth; Hancock, Gemma; Clutton, Genevieve; Sande, Nellia; Angus, Brian; Smyth, Redmond; Mak, Johnson; Dorrell, Lucy

    2013-05-31

    The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10(-2) to 8×10(-5), and by nearly two-fold (pp24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs.

  13. Molecular mechanisms by which HERV-K Gag interferes with HIV-1 Gag assembly and particle infectivity.

    Science.gov (United States)

    Monde, Kazuaki; Terasawa, Hiromi; Nakano, Yusuke; Soheilian, Ferri; Nagashima, Kunio; Maeda, Yosuke; Ono, Akira

    2017-04-26

    Human endogenous retroviruses (HERVs), the remnants of ancient retroviral infections, constitute approximately 8% of human genomic DNA. Since HERV-K Gag expression is induced by HIV-1 Tat in T cells, induced HERV-K proteins could affect HIV-1 replication. Indeed, previously we showed that HERV-K Gag and HIV-1 Gag coassemble and that this appears to correlate with the effect of HERV-K Gag expression on HIV-1 particle release and its infectivity. We further showed that coassembly requires both MA and NC domains, which presumably serve as scaffolding for Gag via their abilities to bind membrane and RNA, respectively. Notably, however, despite possessing these abilities, MLV Gag failed to coassemble with HIV-1 Gag and did not affect assembly and infectivity of HIV-1 particles. It is unclear how the specificity of coassembly is determined. Here, we showed that coexpression of HERV-K Gag with HIV-1 Gag changed size and morphology of progeny HIV-1 particles and severely diminished infectivity of such progeny viruses. We further compared HERV-K-MLV chimeric constructs to identify molecular determinants for coassembly specificity and for inhibition of HIV-1 release efficiency and infectivity. We found that the CA N-terminal domain (NTD) of HERV-K Gag is important for the reduction of the HIV-1 release efficiency, whereas both CA-NTD and major homology region of HERV-K Gag contribute to colocalization with HIV-1 Gag. Interestingly, these regions of HERV-K Gag were not required for reduction of progeny HIV-1 infectivity. Our results showed that HERV-K Gag CA is important for reduction of HIV-1 release and infectivity but the different regions within CA are involved in the effects on the HIV-1 release and infectivity. Altogether, these findings revealed that HERV-K Gag interferes the HIV-1 replication by two distinct molecular mechanisms.

  14. Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein.

    Directory of Open Access Journals (Sweden)

    Simon Swingler

    2007-09-01

    Full Text Available Viruses have evolved strategies to protect infected cells from apoptotic clearance. We present evidence that HIV-1 possesses a mechanism to protect infected macrophages from the apoptotic effects of the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand. In HIV-1-infected macrophages, the viral envelope protein induced macrophage colony-stimulating factor (M-CSF. This pro-survival cytokine downregulated the TRAIL receptor TRAIL-R1/DR4 and upregulated the anti-apoptotic genes Bfl-1 and Mcl-1. Inhibition of M-CSF activity or silencing of Bfl-1 and Mcl-1 rendered infected macrophages highly susceptible to TRAIL. The anti-cancer agent Imatinib inhibited M-CSF receptor activation and restored the apoptotic sensitivity of HIV-1-infected macrophages, suggesting a novel strategy to curtail viral persistence in the macrophage reservoir.

  15. Use of silver nanoparticles increased inhibition of cell-associated HIV-1 infection by neutralizing antibodies developed against HIV-1 envelope proteins

    Directory of Open Access Journals (Sweden)

    Garza Treviño Elsa N

    2011-09-01

    Full Text Available Abstract Background HIV/AIDS pandemic is a worldwide public health issue. There is a need for new approaches to develop new antiviral compounds or other therapeutic strategies to limit viral transmission. The envelope glycoproteins gp120 and gp41 of HIV are the main targets for both silver nanoparticles (AgNPs and neutralizing antibodies. There is an urgency to optimize the efficiency of the neutralizing antibodies (NABs. In this study, we demonstrated that there is an additive effect between the four NABs and AgNPs when combined against cell-associated HIV-1 infection in vitro Results Four NABs (Monoclonal antibody to HIV-1 gp41 126-7, HIV-1 gp120 Antiserum PB1 Sub 2, HIV-1 gp120 Antiserum PB1, HIV-1 gp120 Monoclonal Antibody F425 B4e8 with or without AgNPs of 30-50 nm in size were tested against cell free and cell-associated HIVIIIB virus. All NABs inhibited HIV-1 cell free infection at a dose response manner, but with AgNPs an antiviral additive effect was not achieved Although there was no inhibition of infection with cell-associated virus by the NABs itself, AgNPs alone were able to inhibit cell associated virus infection and more importantly, when mixed together with NABs they inhibited the HIV-1 cell associated infection in an additive manner. Discussion The most attractive strategies to deal with the HIV problem are the development of a prophylactic vaccine and the development of effective topical vaginal microbicide. For two decades a potent vaccine that inhibits transmission of infection of HIV has been searched. There are vaccines that elicit NABs but none of them has the efficacy to stop transmission of HIV-1 infection. We propose that with the addition of AgNPs, NABs will have an additive effect and become more potent to inhibit cell-associated HIV-1 transmission/infection. Conclusions The addition of AgNPs to NABs has significantly increased the neutralizing potency of NABs in prevention of cell-associated HIV-1 transmission/infection

  16. Epigenetic analysis of HIV-1 proviral genomes from infected individuals: predominance of unmethylated CpG's.

    Science.gov (United States)

    Weber, Stefanie; Weiser, Barbara; Kemal, Kimdar S; Burger, Harold; Ramirez, Christina M; Korn, Klaus; Anastos, Kathryn; Kaul, Rupert; Kovacs, Colin; Doerfler, Walter

    2014-01-20

    Efforts to cure HIV-1 infections aim at eliminating proviral DNA. Integrated DNA from various viruses often becomes methylated de novo and transcriptionally inactivated. We therefore investigated CpG methylation profiles of 55 of 94 CpG's (58.5%) in HIV-1 proviral genomes including ten CpG's in each LTR and additional CpG's in portions of gag, env, nef, rev, and tat genes. We analyzed 33 DNA samples from PBMC's of 23 subjects representing a broad spectrum of HIV-1 disease. In 22 of 23 HIV-1-infected individuals, there were only unmethylated CpG's regardless of infection status. In one long term nonprogressor, however, methylation of proviral DNA varied between 0 and 75% over an 11-year period although the CD4+ counts remained stable. Hence levels of proviral DNA methylation can fluctuate. The preponderance of unmethylated CpG's suggests that proviral methylation is not a major factor in regulating HIV-1 proviral activity in PBMC's. Unmethylated CpG's may play a role in HIV-1 immunopathogenesis. © 2013 Elsevier Inc. All rights reserved.

  17. Inhibition of HIV-1 infection by synthetic peptides derived CCR5 fragments.

    Science.gov (United States)

    Imai, Masaki; Baranyi, Lajos; Okada, Noriko; Okada, Hidechika

    2007-02-23

    HIV-1 infection requires interaction of viral envelope protein gp160 with CD4 and a chemokine receptor, CCR5 or CXCR4 as entry coreceptor. We designed HIV-inhibitory peptides targeted to CCR5 using a novel computer program (ANTIS), which searched all possible sense-antisense amino acid pairs between proteins. Seven AHBs were found in CCR5 receptor. All AHB peptides were synthesized and tested for their ability to prevent HIV-1 infection to human T cells. A peptide fragment (LC5) which is a part of the CCR5 receptor corresponding to the loop between the fifth and sixth transmembrane regions (amino acids 222-240) proved to inhibit HIV-1IIIB infection of MT-4 cells. Interaction of these antisense peptides could be involved in sustaining HIV-1 infectivity. LC5 effectively indicated dose-dependent manner, and the suppression was enhanced additively by T20 peptide, which inhibits infection in vitro by disrupting the gp41 conformational changes necessary for membrane fusion. Thus, these results indicate that CCR5-derived AHB peptides could provide a useful tool to define the mechanism(s) of HIV infection, and may provide insight which will contribute to the development of an anti-HIV-1 reagent.

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

    Science.gov (United States)

    Ruffin, Nicolas; Thang, Pham Hong; Rethi, Bence; Nilsson, Anna; Chiodi, Francesca

    2011-01-01

    One important pathogenic feature of human immunodeficiency virus (HIV)-1 infection is chronic immune activation and impaired survival of T and B cells. A decline of resting memory B cells was reported to occur in both children and adults infected with HIV-1; these cells are responsible for 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 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.

  19. 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.

  20. Predictors of Impaired HDL Function in HIV-1 Infected Compared to Uninfected Individuals.

    Science.gov (United States)

    Kelesidis, Theodoros; Oda, Michael N; Borja, Mark S; Yee, Yumin; Ng, Kit F; Huynh, Diana; Elashoff, David; Currier, Judith S

    2017-07-01

    High-density lipoprotein (HDL) function rather than absolute level may be a more accurate indicator for cardiovascular disease (CVD). Novel methods can measure HDL function using patient samples. The objective of this study is to identify factors that may contribute to HDL dysfunction in chronic treated HIV-1 infection. Retrospective study of HDL function measured in 2 ways in HIV-1-infected men with low overall CVD risk and healthy men with no known CVD risk matched by race to the HIV-1-infected participants. We examined patient-level factors associated with 2 different measures of HDL dysfunction: reduced antioxidant function (oxidized HDL, HDLox) and reduced HDL-apoA-I exchange (HAE), a measure of HDL remodeling, in the HIV infected and control men. Multivariable-adjusted linear regression analyses were used adjusting for false discovery rate, age, race, body mass index (BMI), CD4 count, viremia, CVD risk, smoking, lipids, apoA-I, and albumin. In multivariate analysis among HIV-1-infected men (n = 166) (median age 45 years, CD4 T-cell count 505 cells/mm, 30.1% were viremic), higher BMI, lower apoA-I, and lower albumin were among the most notable correlates of higher HDLox and lower HAE (P HDL dysfunction in chronic HIV-1 infection using 2 independent methods.

  1. The impact of pregnancy on the HIV-1-specific T cell function in infected pregnant women.

    Science.gov (United States)

    Hygino, Joana; Vieira, Morgana M; Kasahara, Taissa M; Xavier, Luciana F; Blanco, Bernardo; Guillermo, Landi V C; Filho, Renato G S; Saramago, Carmen S M; Lima-Silva, Agostinho A; Oliveira, Ariane L; Guimarães, Vander; Andrade, Arnaldo F B; Bento, Cleonice A M

    2012-12-01

    Evidences indicate that pregnancy can alter the Ag-specific T-cell responses. This work aims to evaluate the impact of pregnancy on the in vitro HIV-1-specific immune response. As compared with non-pregnant patients, lower T-cell proliferation and higher IL-10 production were observed in T-cell cultures from pregnant patients following addition of either mitogens or HIV-1 antigens. In our system, the main T lymphocyte subset involved in producing IL-10 was CD4(+)FoxP3(-). Depletion of CD4(+) cells elevated TNF-α and IFN-γ production. Interestingly, the in vitro HIV-1 replication was lower in cell cultures from pregnant patients, and it was inversely related to IL-10 production. In these cultures, the neutralization of IL-10 by anti-IL-10 mAb elevated TNF-α release and HIV-1 replication. In conclusion, our results reveal that pregnancy-related events should favor the expansion of HIV-1-specific IL-10-secreting CD4(+) T-cells in HIV-1-infected women, which should, in the scenario of pregnancy, help to reduce the risk of vertical HIV-1 transmission.

  2. HIV-1 infected and immune competent mononuclear phagocytes induce quantitative alterations in neuronal dendritic arbor: relevance for HIV-1-associated dementia.

    Science.gov (United States)

    Zheng, J; Thylin, M R; Cotter, R L; Lopez, A L; Ghorpade, A; Persidsky, Y; Xiong, H; Leisman, G B; Che, M H; Gendelman, H E

    2001-10-01

    Neuronal loss, alterations in dendritic arbor, and decreased synaptic density, in infected brain tissue, are neuropathological signatures of HIV-1-associated dementia (HAD). Brain mononuclear phagocyte (MP) (macrophage and microglia) secretory products can effect neuronal compromise, although the underlying mechanism(s) remain incompletely defined. To these ends, we quantitatively assessed the effects of virus-infected and/or immune activated MP secretory products on multiple aspects of neuronal morphology. Rat cortical and hippocampal neurons were exposed to secretory products from HIV-1-infected and lipopolysaccharide (LPS)-activated human monocyte-derived macrophage (MDM). Our assays for alterations in neuronal dendritic arbor and cell loss included the quantification of neurofilament (NF), neuron-specific enolase (NSE), and MAP-2 by ELISA and cellular morphology. MDM conditioned media (MCM) enhanced neuronal survival. HIV-1 infection or activation by LPS had modest neurotoxic effects. In contrast, the combination of HIV-1 infection and activation of MDM produced significant neurotoxicity. Such MDM products altered dendritic arbor, decreased synaptic density, and increased LDH release. Comparable neurotrophic/toxic responses were observed when neurons were exposed to MCM collected from 12 separate human donors. Similar responses were observed with MCM from human fetal microglia, further supporting the role of HIV-1-infected and immune-activated brain MP in the overall neurotoxic responses. This work provides quantitative measures of neuronal damage by which virus infected and activated MP can elicit neuronal injury in HAD.

  3. Regulatory T cells expanded from HIV-1-infected individuals maintain phenotype, TCR repertoire and suppressive capacity.

    Directory of Open Access Journals (Sweden)

    Mathieu Angin

    Full Text Available While modulation of regulatory T cell (Treg function and adoptive Treg transfer are being explored as therapeutic modalities in the context of autoimmune diseases, transplantation and cancer, their role in HIV-1 pathogenesis remains less well defined. Controversy persists regarding their beneficial or detrimental effects in HIV-1 disease, which warrants further detailed exploration. Our objectives were to investigate if functional CD4(+ Tregs can be isolated and expanded from HIV-1-infected individuals for experimental or potential future therapeutic use and to determine phenotype and suppressive capacity of expanded Tregs from HIV-1 positive blood and tissue. Tregs and conventional T cell controls were isolated from blood and gut-associated lymphoid tissue of individuals with HIV-1 infection and healthy donors using flow-based cell-sorting. The phenotype of expanded Tregs was assessed by flow-cytometry and quantitative PCR. T-cell receptor ß-chain (TCR-β repertoire diversity was investigated by deep sequencing. Flow-based T-cell proliferation and chromium release cytotoxicity assays were used to determine Treg suppressive function. Tregs from HIV-1 positive individuals, including infants, were successfully expanded from PBMC and GALT. Expanded Tregs expressed high levels of FOXP3, CTLA4, CD39 and HELIOS and exhibited a highly demethylated TSDR (Treg-specific demethylated region, characteristic of Treg lineage. The TCRß repertoire was maintained following Treg expansion and expanded Tregs remained highly suppressive in vitro. Our data demonstrate that Tregs can be expanded from blood and tissue compartments of HIV-1+ donors with preservation of Treg phenotype, function and TCR repertoire. These results are highly relevant for the investigation of potential future therapeutic use, as currently investigated for other disease states and hold great promise for detailed studies on the role of Tregs in HIV-1 infection.

  4. Cell-type specific requirements for thiol/disulfide exchange during HIV-1 entry and infection.

    Science.gov (United States)

    Stantchev, Tzanko S; Paciga, Mark; Lankford, Carla R; Schwartzkopff, Franziska; Broder, Christopher C; Clouse, Kathleen A

    2012-12-03

    The role of disulfide bond remodeling in HIV-1 infection is well described, but the process still remains incompletely characterized. At present, the data have been predominantly obtained using established cell lines and/or CXCR4-tropic laboratory-adapted virus strains. There is also ambiguity about which disulfide isomerases/reductases play a major role in HIV-1 entry, as protein disulfide isomerase (PDI) and/or thioredoxin (Trx) have emerged as the two enzymes most often implicated in this process. We have extended our previous findings and those of others by focusing on CCR5-using HIV-1 strains and their natural targets--primary human macrophages and CD4+ T lymphocytes. We found that the nonspecific thiol/disulfide exchange inhibitor, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), significantly reduced HIV-1 entry and infection in cell lines, human monocyte-derived macrophages (MDM), and also phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC). Subsequent studies were performed using specific anti-PDI or Trx monoclonal antibodies (mAb) in HIV-1 envelope pseudotyped and wild type (wt) virus infection systems. Although human donor-to-donor variability was observed as expected, Trx appeared to play a greater role than PDI in HIV-1 infection of MDM. In contrast, PDI, but not Trx, was predominantly involved in HIV-1 entry and infection of the CD4+/CCR5+ T cell line, PM-1, and PHA-stimulated primary human T lymphocytes. Intriguingly, both PDI and Trx were present on the surface of MDM, PM-1 and PHA-stimulated CD4+ T cells. However, considerably lower levels of Trx were detected on freshly isolated CD4+ lymphocytes, compared to PHA-stimulated cells. Our findings clearly demonstrate the role of thiol/disulfide exchange in HIV-1 entry in primary T lymphocytes and MDM. They also establish a cell-type specificity regarding the involvement of particular disulfide isomerases/reductases in this process and may provide an explanation for differences

  5. Cell-type specific requirements for thiol/disulfide exchange during HIV-1 entry and infection

    Directory of Open Access Journals (Sweden)

    Stantchev Tzanko S

    2012-12-01

    Full Text Available Abstract Background The role of disulfide bond remodeling in HIV-1 infection is well described, but the process still remains incompletely characterized. At present, the data have been predominantly obtained using established cell lines and/or CXCR4-tropic laboratory-adapted virus strains. There is also ambiguity about which disulfide isomerases/ reductases play a major role in HIV-1 entry, as protein disulfide isomerase (PDI and/or thioredoxin (Trx have emerged as the two enzymes most often implicated in this process. Results We have extended our previous findings and those of others by focusing on CCR5-using HIV-1 strains and their natural targets - primary human macrophages and CD4+ T lymphocytes. We found that the nonspecific thiol/disulfide exchange inhibitor, 5,5'-dithiobis(2-nitrobenzoic acid (DTNB, significantly reduced HIV-1 entry and infection in cell lines, human monocyte-derived macrophages (MDM, and also phytohemagglutinin (PHA-stimulated peripheral blood mononuclear cells (PBMC. Subsequent studies were performed using specific anti-PDI or Trx monoclonal antibodies (mAb in HIV-1 envelope pseudotyped and wild type (wt virus infection systems. Although human donor-to-donor variability was observed as expected, Trx appeared to play a greater role than PDI in HIV-1 infection of MDM. In contrast, PDI, but not Trx, was predominantly involved in HIV-1 entry and infection of the CD4+/CCR5+ T cell line, PM-1, and PHA-stimulated primary human T lymphocytes. Intriguingly, both PDI and Trx were present on the surface of MDM, PM-1 and PHA-stimulated CD4+ T cells. However, considerably lower levels of Trx were detected on freshly isolated CD4+ lymphocytes, compared to PHA-stimulated cells. Conclusions Our findings clearly demonstrate the role of thiol/disulfide exchange in HIV-1 entry in primary T lymphocytes and MDM. They also establish a cell-type specificity regarding the involvement of particular disulfide isomerases/reductases in this

  6. Acute risk for hepatitis E virus infection among HIV-1-positive pregnant women in central Africa

    Directory of Open Access Journals (Sweden)

    Caron Mélanie

    2012-10-01

    Full Text Available Abstract Background Hepatitis E virus (HEV, an enterically transmitted pathogen, is highly endemic in several African countries. Pregnant women are at particularly high risk for acute or severe hepatitis E. In Gabon, a central African country, the prevalence of antibodies to HEV among pregnant women is 14.1%. Recent studies have demonstrated unusual patterns of hepatitis E (chronic hepatitis, cirrhosis among immunodeficient patients. Findings We investigated the prevalence of antibodies to HEV among pregnant women infected with HIV-1 or HTLV-1 in Gabon. Of 243 samples collected, 183 were positive for HIV-1 and 60 for HTLV-1; 16 women (6.6% had IgG antibodies to HEV. The seroprevalence was higher among HIV-1-infected women (7.1% than HTLV-1-infected women (5.0%. Moreover, the HIV-1 viral load was significantly increased (p ≤ 0.02 among women with past-HEV exposure (1.3E+05 vs 5.7E+04 copies per ml, whereas no difference was found in HTLV-1 proviral load (9.0E+01 vs 1.1E+03 copies per ml. Conclusions These data provide evidence that HIV-1-infected women are at risk for acute or severe infection if they are exposed to HEV during pregnancy, with an increased viral load.

  7. Comparative efficiency of HIV-1-infected T cell killing by NK cells, monocytes and neutrophils.

    Science.gov (United States)

    Smalls-Mantey, Adjoa; Connors, Mark; Sattentau, Quentin J

    2013-01-01

    HIV-1 infected cells are eliminated in infected individuals by a variety of cellular mechanisms, the best characterized of which are cytotoxic T cell and NK cell-mediated killing. An additional antiviral mechanism is antibody-dependent cellular cytotoxicity. Here we use primary CD4(+) T cells infected with the BaL clone of HIV-1 as target cells and autologous NK cells, monocytes, and neutrophils as effector cells, to quantify the cytotoxicity mediated by the different effectors. This was carried out in the presence or absence of HIV-1-specific antiserum to assess antibody-dependent cellular cytotoxicity. We show that at the same effector to target ratio, NK cells and monocytes mediate similar levels of both antibody-dependent and antibody-independent killing of HIV-1-infected T cells. Neutrophils mediated significant antibody-dependent killing of targets, but were less effective than monocytes or NK cells. These data have implications for acquisition and control of HIV-1 in natural infection and in the context of vaccination.

  8. Psoralen/UV inactivation of HIV-1-infected cells for use in cytologic and immunologic procedures

    Energy Technology Data Exchange (ETDEWEB)

    Watson, A.J.; Klaniecki, J.; Hanson, C.V. (Oncogen Corporation, Seattle, WA (USA))

    1990-04-01

    A rapid procedure for the inactivation of HIV-1-infected cells using psoralen and ultraviolet (UV) light is described. Exposure of HIV-1-infected cells to 5 micrograms/ml psoralen followed by UV irradiation (320-380 nm) for 5 minutes yields cells that are noninfectious as assessed by extended infectivity assays. The psoralen/UV inactivation procedure described is effective with cells chronically or acutely infected with HIV-1 and is unaffected by cell densities up to 12 x 10(6)/ml. At 5 micrograms/ml psoralen does little damage to cellular permeability as shown by the ability of treated cells to exclude trypan blue and propidium iodide. Psoralen/UV treatment of HIV-1-infected cells does not cause a significant decrease in the reactivity of HIV-1 core and envelope antigens or cellular antigens to monoclonal antibodies. Experiments are presented demonstrating the use of these cells for flow cytometry studies and for cell surface labeling using the lactoperoxidase {sup 125}I iodination procedure.

  9. The integrated HIV-1 provirus in patient sperm chromosome and its transfer into the early embryo by fertilization.

    Directory of Open Access Journals (Sweden)

    Dian Wang

    Full Text Available Complete understanding of the route of HIV-1 transmission is an important prerequisite for curbing the HIV/AIDS pandemic. So far, the known routes of HIV-1 transmission include sexual contact, needle sharing, puncture, transfusion and mother-to-child transmission. Whether HIV can be vertically transmitted from human sperm to embryo by fertilization is largely undetermined. Direct research on embryo derived from infected human sperm and healthy human ova have been difficult because of ethical issues and problems in the collection of ova. However, the use of inter-specific in vitro fertilization (IVF between human sperm and hamster ova can avoid both of these problems. Combined with molecular, cytogenetical and immunological techniques such as the preparation of human sperm chromosomes, fluorescent in situ hybridization (FISH, and immunofluorescence assay (IFA, this study mainly explored whether any integrated HIV provirus were present in the chromosomes of infected patients' sperm, and whether that provirus could be transferred into early embryos by fertilization and maintain its function of replication and expression. Evidence showed that HIV-1 nucleic acid was present in the spermatozoa of HIV/AIDS patients, that HIV-1 provirus is present on the patient sperm chromosome, that the integrated provirus could be transferred into early embryo chromosomally integrated by fertilization, and that it could replicate alongside the embryonic genome and subsequently express its protein in the embryo. These findings indicate the possibility of vertical transmission of HIV-1 from the sperm genome to the embryonic genome by fertilization. This study also offers a platform for the research into this new mode of transmission for other viruses, especially sexually transmitted viruses.

  10. Impact of HIV-1 infection on the feto-maternal crosstalk and consequences for pregnancy outcome and infant health.

    Science.gov (United States)

    Altfeld, Marcus; Bunders, Madeleine J

    2016-11-01

    Adaptation of the maternal immune system to establish maternal/fetal equilibrium is required for a successful pregnancy. Viral infections, including HIV-1 infection, can alter this maternal/fetal equilibrium, with significant consequences for pregnancy outcome, including miscarriages, impaired fetal growth, and premature delivery. Furthermore, maternal HIV-1 infection has been shown to have a long-term impact on the developing fetal immune system also when the infant is not infected with the virus. In this review, we discuss the consequences of maternal HIV-1 infection and antiretroviral therapy on pregnancy outcome and the health of the uninfected HIV-1-exposed infant.

  11. Performance of the Alere Determine™ HIV-1/2 Ag/Ab Combo Rapid Test with specimens from HIV-1 seroconverters from the US and HIV-2 infected individuals from Ivory Coast.

    Science.gov (United States)

    Masciotra, Silvina; Luo, Wei; Youngpairoj, Ae S; Kennedy, M Susan; Wells, Susan; Ambrose, Krystin; Sprinkle, Patrick; Owen, S Michele

    2013-12-01

    FDA-approved HIV Antigen/Antibody combo (4th generation) immunoassays (IAs) can identify HIV-1 infections before the Western blot (WB) becomes positive. In the US, increased detection of acute HIV infections has been facilitated by using 4th generation IAs, but there is no FDA-approved 4th generation rapid test (RT). The Alere Determine™ HIV-1/2 Ag/Ab Combo (Determine Combo) RT detects and distinguishes HIV p24 Antigen (Ag) from Antibody (Ab) to HIV-1+HIV-2 and thus has the potential to improve diagnosis of acute HIV infection. To evaluate the ability of Determine Combo RT to detect acute/early HIV-1 infections and HIV-2 antibody in well-characterized plasma specimens. In HIV-1 seroconverters from the US, Determine Combo reactivity was evaluated by performing the 50% cumulative frequency analysis and by comparing with 3rd and 4th generation IAs' reactivity. HIV-2 plasma specimens from Ivory Coast were tested with Determine Combo. The 50% cumulative frequency analysis in 17 seroconverters placed Determine Combo (Ag+/Ab-, Ag+Ab+, Ag-/Ab+) and Ab-component reactivity at 15.5 and 7 days before WB positivity, respectively. In 26 seroconverters, Determine Combo was reactive in 99.0% and 92.5% of 3rd and 4th generation IAs-reactive specimens, respectively. All HIV-2 plasma specimens were Ab-reactive/Ag-non-reactive by Determine Combo. Based on previous results with the same seroconversion panels, combined Ag/Ab reactivity of the Determine Combo appears between FDA-approved 4th and 3rd generation laboratory IAs. These data indicate that this RT could detect HIV-1 infection earlier than other RTs and it performs well in HIV-2 specimens. Published by Elsevier B.V.

  12. Residual viraemia in HIV-1-infected patients with plasma viral load

    DEFF Research Database (Denmark)

    Ostrowski, S.R.; Katzenstein, T.L.; Pedersen, Bente Klarlund

    2008-01-01

    antiretroviral therapy (HAART)-treated HIV-1-infected patients with plasma HIV-1 RNA or=1 episode with TMA-RV whereas 9 patients had undetectable TMA-RV throughout the study-period. Time-points with TMA-RV and PCR-RV were associated with higher circulating sTNFrII (+0.234 ng/ml, P = 0.030) and beta(2......)-microglobulin (+22 nmol/l, P = 0.016) and time-points with PCR-RV were also associated with higher IgA (+0.82 micromol/l, P = 0.035) and CD8-count (+1.18-fold, P = 0.001). Patients with TMA-RV in the study-period had higher HIV-1 RNA pre-HAART (P = 0.032). RV was not associated with proviral-HIV-1-DNA, CD4...

  13. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection

    DEFF Research Database (Denmark)

    Cooper, David A; Steigbigel, Roy T; Gatell, Jose M;

    2008-01-01

    BACKGROUND: We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS: We......, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide...... and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57...

  14. HIV-1 diversity and drug-resistant mutations in infected individuals in Changchun, China.

    Directory of Open Access Journals (Sweden)

    Ming Yan

    Full Text Available OBJECTIVES: Human immunodeficiency virus type 1 (HIV-1 infection has been detected in all provinces of China. Although epidemiological and phylogenetic studies have been conducted in many regions, such analyses are lacking from Jilin province in northeastern China. METHOD: Epidemiological and phylogenetic analyses, as well as detection of drug-resistant mutations, were conducted on 57 HIV-1 infected patients from Changchun city identified and confirmed through annual surveillance by local Centers for Disease Control in Jilin province of northeastern China in 2012. RESULTS: Sexual contact was determined to be the major pathway for HIV-1 transmission in Jilin, where hetero- and homosexual activities contributed almost equally. Phylogenetic analyses detected multiple subtypes of HIV-1 including subtype G circulating in Jilin, with multiple origins for each of them. Both subtype B and CRF01_AE were dominant, and evidence of subtype B transmitting between different high-risk groups was observed. Mutations in the viral protease at position 71 indicated the presence of a selective pressure. Several drug-resistant mutations were detected, although they were predicted with low-level resistance to antiviral treatments. CONCLUSIONS: Information from this study fills the gap in knowledge of HIV-1 transmission in Changchun city, Jilin province, China. By revealing the origin and evolutionary status of local HIV-1 strains, this work contributes to ongoing efforts in the control and prevention of AIDS.

  15. Human papillomavirus infection in HIV-1 infected women in Catalonia (Spain: implications for prevention of cervical cancer.

    Directory of Open Access Journals (Sweden)

    Valeria Stuardo

    Full Text Available BACKGROUND: High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women. METHODS: We enrolled 479 HIV-1-infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis. RESULTS: Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL was 3.8%. The most common genotypes were 16(23%, 53(20.3%, and 52(16.2%. The factor associated with HR-HPV infection was age 500 cells/mm(3 (OR,8.4; 95%CI,3.7-19.2, HIV-1 viral load >10,000 copies/mL versus <400 copies/mL (OR,2.1; 95%CI,1.0-4.4, and use of oral contraceptives (OR,2.0; 95%CI,1.0-3.9. Sixty percent of HIV-1-infected women had had one Pap smear within the last 2 years. CONCLUSIONS: The high prevalence of HPV infection and cervical lesions in the HIV-1-infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1-infected women.

  16. Role of Bruton’s Tyrosine Kinase inhibitors in HIV-1 infected cells

    Science.gov (United States)

    Guendel, Irene; Iordanskiy, Sergey; Sampey, Gavin C; Van Duyne, Rachel; Calvert, Valerie; Petricoin, Emanuel; Saifuddin, Mohammed; Kehn-Hall, Kylene; Kashanchi, Fatah

    2015-01-01

    Many cellular cofactors have been documented to be critical for various stages of viral replication. Using high throughput proteomic assays, we have previously identified Bruton’s tyrosine kinase (BTK) as a host protein that was uniquely up-regulated in the plasma membrane of HIV-1 infected T-cells. Here, we have further characterized the BTK expression in HIV-1 infection and show that this cellular factor is specifically expressed in infected myeloid cells. Significant up-regulation of the phosphorylated form of BTK was observed in infected cells. Using size exclusion chromatography, we found BTK to be virtually absent in the uninfected U937 cells, however new BTK protein complexes were identified and distributed in both high molecular weight (~600 kDa) and a small molecular weight complex (~60–120 kDa) in the infected U1 cells. BTK levels were highest in cells either chronically expressing virus or induced/infected myeloid cells and that BTK translocated to the membrane following induction of the infected cells. BTK knockdown in HIV-1 infected cells using siRNA resulted in selective death of infected, but not uninfected, cells. Using BTK specific antibody and small molecule inhibitors including LFM-A13 and a FDA approved compound, Ibrutinib (PCI – 32765), we have found that HIV-1 infected cells are sensitive to apoptotic cell death and result in a decrease in virus production. Overall, our data suggests that HIV-1 infected cells are sensitive to treatments targeting BTK expressed in infected cells. PMID:25672887

  17. Role of Bruton's tyrosine kinase inhibitors in HIV-1-infected cells.

    Science.gov (United States)

    Guendel, Irene; Iordanskiy, Sergey; Sampey, Gavin C; Van Duyne, Rachel; Calvert, Valerie; Petricoin, Emanuel; Saifuddin, Mohammed; Kehn-Hall, Kylene; Kashanchi, Fatah

    2015-06-01

    Many cellular cofactors have been documented to be critical for various stages of viral replication. Using high-throughput proteomic assays, we have previously identified Bruton's tyrosine kinase (BTK) as a host protein that was uniquely upregulated in the plasma membrane of human immunodeficiency virus (HIV-1)-infected T cells. Here, we have further characterized the BTK expression in HIV-1 infection and show that this cellular factor is specifically expressed in infected myeloid cells. Significant upregulation of the phosphorylated form of BTK was observed in infected cells. Using size exclusion chromatography, we found BTK to be virtually absent in the uninfected U937 cells; however, new BTK protein complexes were identified and distributed in both high molecular weight (∼600 kDa) and a small molecular weight complex (∼60-120 kDa) in the infected U1 cells. BTK levels were highest in cells either chronically expressing virus or induced/infected myeloid cells and that BTK translocated to the membrane following induction of the infected cells. BTK knockdown in HIV-1-infected cells using small interfering RNA (siRNA) resulted in selective death of infected, but not uninfected, cells. Using BTK-specific antibody and small-molecule inhibitors including LFM-A13 and a FDA-approved compound, ibrutinib (PCI-32765), we have found that HIV-1-infected cells are sensitive to apoptotic cell death and result in a decrease in virus production. Overall, our data suggests that HIV-1-infected cells are sensitive to treatments targeting BTK expressed in infected cells.

  18. Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: a randomised placebo-controlled study.

    Science.gov (United States)

    Harrer, Thomas; Plettenberg, Andreas; Arastéh, Keikawus; Van Lunzen, Jan; Fätkenheuer, Gerd; Jaeger, Hans; Janssens, Michel; Burny, Wivine; Collard, Alix; Roman, François; Loeliger, Alfred; Koutsoukos, Marguerite; Bourguignon, Patricia; Lavreys, Ludo; Voss, Gerald

    2014-05-07

    The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4(+) and CD8(+) T-cell responses, absolute CD4(+) T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4(+) T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (pVaccine-induced HIV-1-specific CD4(+) T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8(+) T-cells or change in CD8(+) T-cell activation marker expression profile was detected. Absolute CD4(+) T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4(+) T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4(+) T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Medroxyprogesterone acetate increases HIV-1 infection of unstimulated peripheral blood mononuclear cells in vitro.

    Science.gov (United States)

    Sampah, Maame Efua S; Laird, Gregory M; Blankson, Joel N; Siliciano, Robert F; Coleman, Jenell S

    2015-06-19

    Several observational studies suggest that medroxyprogesterone acetate (MPA) injectable contraceptives may increase a woman's risk of sexual HIV-1 acquisition. In-vitro studies are conflicting, mainly due to differences in the type of progestin studied or activation status of the primary cells. We sought to determine whether MPA increases infection of unstimulated peripheral blood mononuclear cells (PBMCs). Freshly isolated PBMCs from normal blood donors were treated with physiologic MPA concentrations ranging from 0.003 to 5 ng/ml and infected with GFP-tagged R5-tropic or X4-tropic HIV-1 pseudoviruses by spinoculation. The infection was limited to a single cycle. Cells were stained with CD3, CD8 and CD14. Infection was quantified as the percentage of GFP cells by flow cytometry. Absolute infection was greater among unstimulated MPA-treated CD3⁺CD8⁻ T cells vs. untreated cells across MPA concentrations of 0.003-3 ng/ml using R5 (P  0.5). The CD3⁺CD8⁻ T-cell population of MPA-treated unstimulated PBMCs were more susceptible to HIV-1 infection than untreated cells. The increased infection was partly due to monocytes and was lost when PBMC were exogenously stimulated. These data provide confirmation of a biological association between MPA exposure and increased susceptibility to HIV-1 infection, particularly among women who inject drugs.

  20. Ampelopsin, a Small Molecule Inhibitor of HIV-1 Infection Targeting HIV Entry

    Institute of Scientific and Technical Information of China (English)

    DE-YU LIU; JIAN-TAO YE; WEN-HUI YANG; JIN YAN; CHANG-HONG ZENG; SA ZENG

    2004-01-01

    Objective To investigate the anti-HIV effects of ampelopsin and its interaction with HIV-1 coreceptor CXCR4. Methods Through anti-virus experiments in vitro, the inhibitory effect of ampelopsin on HIV-1 infection was verified. Chemotaxis assay was performed to show the ability to induce PBMCs migration by ampelopsin, RANTES and SDF-1(. Fluorescence labelling monoclonal antibody was utilized to observe the interaction of ampelopsin and CXCR4. Mice immunosuppressant model was also established to detail the role ampelopsin played in regulating cellular immunological functions. Results Ampelopsin could protect sensitive cells against HIV-1 infection and dramatically reduce HIV-1 antigen P24 expression. HIV-1SF33 attaching to MT-4 cells was interfered by ampelopsin, and the EC50 was 0.175 mg/mL for cellular protection and 0.024 mg/mL for P24 inhibition. At co-cultivating phase, EC50 was 0.229 mg/mL and 0.197 mg/mL respectively. Furthermore, the EC50 was 0.179 mg/mL and 0.348 mg/mL in acute infection. Human PBMCs migration was induced after being challenged with ampelopsin or chemokines, and synergistic action was observed during co-treatment. Ampelopsin alone resulted in maximal chemotaxis at 1 mg/mL. HIV-1 co-receptor CXCR4 on the surface of PBMCs was decreased by internalization, which indicated the effect of ampelopsin on CXCR4. About 70% CXCR4 was reduced by ampelopsin at 1 mg/mL. Ampelopsin also augmented cellular immunological functions in immunosuppressive mice. Conclusion Ampelopsin displays a strong inhibitive role during HIV-1 absorption, incubation and acute infection. These results are coincident with its immune enhancement.

  1. Mutagen-mediated enhancement of HIV-1 replication in persistently infected cells.

    Science.gov (United States)

    Sánchez-Jiménez, Carmen; Olivares, Isabel; de Ávila Lucas, Ana Isabel; Toledano, Víctor; Gutiérrez-Rivas, Mónica; Lorenzo-Redondo, Ramón; Grande-Pérez, Ana; Domingo, Esteban; López-Galíndez, Cecilio

    2012-03-15

    Lethal mutagenesis, a new antiviral strategy to extinguish virus through elevated mutation rates, was explored in H61-D cells an HIV-1 persistently infected lymphoid cell line. Three mutagenic agents: 5-hydroxy-2(')-deoxycytidine (5-OHdC), 5-fluorouracil (5-FU) and 2,2(')-difluoro-2(')-deoxycytidine (gemcitabine) were used. After 54 passages, treatments with 5-FU and gemcitabine reduced virus infectivity, p24 and RT activity. Treatment with the pyrimidine analog 5-OHdC resulted in increases of p24 production, RT activity and infectivity. Rise in viral replication by 5-OHdC during HIV-1 persistence is in contrast with its inhibitory effect in acute infections. Viral replication enhancement by 5-OHdC was associated with an increase in intracellular HIV-1 RNA mutations. Mechanisms of HIV-1 replication enhancement by 5-OHdC are unknown but some potential factors are discussed. Increase of HIV-1 replication by 5-OHdC cautions against the use, without previous analyses, of mutagenic nucleoside analogs for AIDS treatment.

  2. Targeted femtosecond laser driven drug delivery within HIV-1 infected cells: in-vitro studies

    Science.gov (United States)

    Maphanga, Charles; Ombinda-Lemboumba, Saturnin; Manoto, Sello; Maaza, Malik; Mthunzi-Kufa, Patience

    2017-02-01

    Human immunodeficiency virus (HIV-1) infection still remains one amongst the world's most challenging infections since its discovery. Antiretroviral therapy is the recommended treatment of choice for HIV-1 infection taken by patients orally. The highly active antiretroviral therapy (HAART) prevents the replication of HIV-1 and further destruction of the immune system, therefore enabling the body to fight opportunistic life-threatening infections, cancers, and also arrest HIV infection from advancing to AIDS. The major challenge with HAART is the inability to reach the viral reservoirs where the HIV-1 remains latent and persistent, leading to inability to fully eradicate the virus. This study is aimed at initially designing and assembling a fully functional optical translocation setup to optically deliver antiretroviral drugs into HIV-1 infected cells in a targeted manner using Gaussian beam mode femtosecond laser pulses in-vitro. The main objective of our study is to define the in-vitro drug photo-translocation parameters to allow future design of an efficient drug delivery device with potential in-vivo drug delivery applications. In our experiments, HEK 293T cells were used to produce HIV-1 enveloped pseudovirus (ZM53) to infect TZM-bl cells which were later treated with laser pulses emitted by a titanium sapphire laser (800 nm, 1KHz, 113 fs, 6.5 μW) to create sub-microscopic pores on the cell membrane enabling influx of extracellular media. Following laser treatment, changes in cellular responses were analysed using cell morphology studies, cytotoxicity, and luciferase assay studies. Controls included laser untreated cells incubated with the drug for 72 hours. The data in this study was statistically analysed using the SigmaPlot software version 13.

  3. KI and WU Polyomaviruses and CD4+ Cell Counts in HIV-1infected Patients, Italy

    Science.gov (United States)

    Babakir-Mina, Muhammed; Ciccozzi, Massimo; Farchi, Francesca; Bergallo, Massimiliano; Cavallo, Rossana; Adorno, Gaspare; Perno, Carlo Federico

    2010-01-01

    To investigate an association between KI and WU polyomavirus (KIPyV and WUPyV) infections and CD4+ cell counts, we tested HIV-1–positive patients and blood donors. No association was found between cell counts and virus infections in HIV-1–positive patients. Frequency of KIPyV infection was similar for both groups. WUPyV was more frequent in HIV-1–positive patients. PMID:20735940

  4. Acceleration of age-associated methylation patterns in HIV-1-infected adults.

    Directory of Open Access Journals (Sweden)

    Tammy M Rickabaugh

    Full Text Available Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC of young (20-35 and older (36-56 adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x 10(-200 and 0.47, p<1 x 10(-200. Weighted gene correlation network analysis (WGCNA identified 17 co-methylation modules; module 3 (ME3 was significantly correlated with age (cor=0.70 and HIV-1 status (cor=0.31. Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015. In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: βage=0.007088, p=2.08 x 10(-9; βHIV=0.099574, p=0.0011; Data set 2: βage=0.008762, p=1.27 x 10(-5; βHIV=0.128649, p=0.0001. Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10(-6, odds ratio=1.91. These data demonstrate that HIV-1 infection is associated with methylation patterns that

  5. HIV-1 infection causes a down-regulation of genes involved in ribosome biogenesis.

    Directory of Open Access Journals (Sweden)

    Claudia L Kleinman

    Full Text Available HIV-1 preferentially infects CD4+ T cells, causing fundamental changes that eventually lead to the release of new viral particles and cell death. To investigate in detail alterations in the transcriptome of the CD4+ T cells upon viral infection, we sequenced polyadenylated RNA isolated from Jurkat cells infected or not with HIV-1. We found a marked global alteration of gene expression following infection, with an overall trend toward induction of genes, indicating widespread modification of the host biology. Annotation and pathway analysis of the most deregulated genes showed that viral infection produces a down-regulation of genes associated with the nucleolus, in particular those implicated in regulating the different steps of ribosome biogenesis, such as ribosomal RNA (rRNA transcription, pre-rRNA processing, and ribosome maturation. The impact of HIV-1 infection on genes involved in ribosome biogenesis was further validated in primary CD4+ T cells. Moreover, we provided evidence by Northern Blot experiments, that host pre-rRNA processing in Jurkat cells might be perturbed during HIV-1 infection, thus strengthening the hypothesis of a crosstalk between nucleolar functions and viral pathogenesis.

  6. Alterations in the nuclear proteome of HIV-1 infected T-cells

    Energy Technology Data Exchange (ETDEWEB)

    DeBoer, Jason [Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178 (United States); Jagadish, Teena; Haverland, Nicole A. [Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 (United States); Madson, Christian J. [Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178 (United States); Ciborowski, Pawel [Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198 (United States); The Nebraska Center for Virology, University of Nebraska, Lincoln 68583 (United States); Belshan, Michael, E-mail: michaelbelshan@creighton.edu [Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha, NE 68178 (United States); The Nebraska Center for Virology, University of Nebraska, Lincoln 68583 (United States)

    2014-11-15

    Virus infection of a cell involves the appropriation of host factors and the innate defensive response of the cell. The identification of proteins critical for virus replication may lead to the development of novel, cell-based inhibitors. In this study we mapped the changes in T-cell nuclei during human immunodeficiency virus type 1 (HIV-1) at 20 hpi. Using a stringent data threshold, a total of 13 and 38 unique proteins were identified in infected and uninfected cells, respectively, across all biological replicates. An additional 15 proteins were found to be differentially regulated between infected and control nuclei. STRING analysis identified four clusters of protein–protein interactions in the data set related to nuclear architecture, RNA regulation, cell division, and cell homeostasis. Immunoblot analysis confirmed the differential expression of several proteins in both C8166-45 and Jurkat E6-1 T-cells. These data provide a map of the response in host cell nuclei upon HIV-1 infection. - Highlights: • We identify changes in the expression of nuclear proteins during HIV-1 infection. • 163 nuclear proteins were found differentially regulated during HIV-1 infection. • Bioinformatic analysis identified several nuclear pathways altered by HIV infection. • Candidate factors were validated in two independent cell lines.

  7. Characterization of HIV-1 Gag-specific T cell responses in chronically infected Indian population

    Science.gov (United States)

    Kaushik, S; Vajpayee, M; Wig, N; Seth, P

    2005-01-01

    India is at the epicentre of the global HIV/AIDS epidemic in South-east Asia, predominated by subtype C infections. It is important to characterize HIV-1-specific T cell responses in this particular population with the aim of identifying protective correlates of immunity to control HIV-1 infection. In this study, we performed a comprehensive analysis of the breadth and magnitude of T cell responses directed at HIV-1 subtype C Gag, one of the most conserved HIV-1 proteins. The study population consisted of antiretroviral naive, chronic HIV-1 subtype C-infected individuals at various stages of infection. We used recent advanced techniques such as enzyme-linked immunospot (ELISPOT) assay and intracellular cytokine staining to quantify the total CD4+ and CD8+ T cell response to HIV-1 gag at single peptide level, regardless of HLA haplotype of the infected individual. The p24-Gag was identified as the most frequently recognized subunit protein with the greatest magnitude of CD4+ and CD8+ T cell responses. Stronger and broader CD8 T cell responses were recognized, contrasting with the weaker and narrower CD4 T cell responses with regard to Gag protein subunits. The magnitude of the HIV-specific interferon (IFN)-γ responses was observed to be higher than the corresponding interleukin (IL)-2 response, indicating the persistence of antigenic load in chronically infected Indian population due to the probable dysfunction of HIV-specific, IFN-γ-secreting CD8 T cells in absence of IL-2 help. PMID:16232229

  8. Impaired Phenotype and Function of T Follicular Helper Cells in HIV-1-Infected Children Receiving ART.

    Science.gov (United States)

    Bekele, Yonas; Amu, Sylvie; Bobosha, Kidist; Lantto, Rebecka; Nilsson, Anna; Endale, Birtukan; Gebre, Meseret; Aseffa, Abraham; Rethi, Bence; Howe, Rawleigh; Chiodi, Francesca

    2015-07-01

    T follicular helper (Tfh) cells are important components in development of specific humoral immune responses; whether the number and biology of Tfh cells is impaired in HIV-1-infected children is not yet studied.The frequency, phenotype, and function of Tfh cells and B cells were determined in blood of HIV-1-infected children receiving antiretroviral therapy (ART) and age-matched controls. Flow cytometry was used to characterize the frequency of Tfh cells and B cell subsets. Cytokine expression was measured after in vitro activation of Tfh cells.A reduced frequency of memory Tfh cells (P < 0.001) was identified in HIV-1-infected children and, on these cells, a reduced expression of programmed death-1 (PD-1) and inducible T cell costimulator (ICOS) (P < 0.001 and P < 0.01). Upon activation, the capacity of Tfh cells to express IL-4, an important cytokine for B cell function, was impaired in HIV-1-infected children.B cell subpopulations in HIV-1-infected children displayed significant differences from the control group: the frequency of resting memory (RM) B cells was reduced (P < 0.01) whereas the frequency of exhausted memory B cells increased (P < 0.001). Interestingly, the decline of RM cells correlated with the reduction of memory Tfh cells (P = 0.02).Our study shows that function and phenotype of Tfh cells, pivotal cells for establishment of adaptive B cell responses, are impaired during HIV-1 infection in children. A consistent reduction of memory Tfh cells is associated with declined frequencies of RM B cells, creating a novel link between dysfunctional features of these cell types, major players in establishment of humoral immunity.

  9. Different pattern of immunoglobulin gene usage by HIV-1 compared to non-HIV-1 antibodies derived from the same infected subject.

    Directory of Open Access Journals (Sweden)

    Liuzhe Li

    Full Text Available A biased usage of immunoglobulin (Ig genes is observed in human anti-HIV-1 monoclonal antibodies (mAbs resulting probably from compensation to reduced usage of the VH3 family genes, while the other alternative suggests that this bias usage is due to antigen requirements. If the antigen structure is responsible for the preferential usage of particular Ig genes, it may have certain implications for HIV vaccine development by the targeting of particular Ig gene-encoded B cell receptors to induce neutralizing anti-HIV-1 antibodies. To address this issue, we have produced HIV-1 specific and non-HIV-1 mAbs from an infected individual and analyzed the Ig gene usage. Green-fluorescence labeled virus-like particles (VLP expressing HIV-1 envelope (Env proteins of JRFL and BaL and control VLPs (without Env were used to select single B cells for the production of 68 recombinant mAbs. Ten of these mAbs were HIV-1 Env specific with neutralizing activity against V3 and the CD4 binding site, as well as non-neutralizing mAbs to gp41. The remaining 58 mAbs were non-HIV-1 Env mAbs with undefined specificities. Analysis revealed that biased usage of Ig genes was restricted only to anti-HIV-1 but not to non-HIV-1 mAbs. The VH1 family genes were dominantly used, followed by VH3, VH4, and VH5 among anti-HIV-1 mAbs, while non-HIV-1 specific mAbs preferentially used VH3 family genes, followed by VH4, VH1 and VH5 families in a pattern identical to Abs derived from healthy individuals. This observation suggests that the biased usage of Ig genes by anti-HIV-1 mAbs is driven by structural requirements of the virus antigens rather than by compensation to any depletion of VH3 B cells due to autoreactive mechanisms, according to the gp120 superantigen hypothesis.

  10. The relationship between maternal-infant antibody levels and vertical transmission of HIV-1 infection.

    Science.gov (United States)

    Moodley, D; Coovadia, H M; Bobat, R A; Madurai, S; Sullivan, J L

    1997-04-01

    This study assesses the predictive value of the ratio of HIV-1 antibodies in the newborn at birth to that in the mother for perinatally transmitted infection confirmed subsequently by age 18 months. The ratio of HIV-1 (EIA) antibody levels in the baby at birth to that in the seropositive mother after the first trimester (sequenstration index SI) was available in 114 of a perinatal cohort of 137 infants. We related this ratio to the HIV infection status of the children by 18 months, HIV-1 DNA PCR and HIV-specific IgA antibody detection at birth, between 3 and 6 months, and morbidity and mortality. Thirty-five of the 137 (26 per cent) children were diagnosed as infected by 18 months. The mean (SD) HIV SI was 1.57 (0.88) in 29 infected and 0.83 (0.42) in 85 uninfected infants (P infection were 41 and 98 per cent, respectively. The reason for the higher SI in the infected babies is the combination of lower antibody titres in the transmitting mothers with raised levels in the infected babies. A similar analysis of antibody ratios showed no statistical differences for measles and tetanus (P > 0.1) between HIV infected and uninfected groups. There was a tendency to increased morbidity (Pearson's correlation coefficient r = 0.31) and more severe disease in those with higher HIV-1 SI. Three of 17 (18 per cent) peripheral blood samples from infected children at birth were PCR positive; all had SI's above the threshold. Overall sensitivity and specificity of PCR were 85 per cent each. Eleven of the 29 infected children were HIV-1 specific IgA positive at birth; six (64 per cent) of these had an SI > 1.27. This simple SI of HIV-1 EIA antibodies at birth is comparable to elaborate techniques in its power to predict perinatally acquired infection. It may be a cheap, reliable and rapid screening test for vertically transmitted HIV-1 infection.

  11. Antibody 10-1074 suppresses viremia in HIV-1-infected individuals.

    Science.gov (United States)

    Caskey, Marina; Schoofs, Till; Gruell, Henning; Settler, Allison; Karagounis, Theodora; Kreider, Edward F; Murrell, Ben; Pfeifer, Nico; Nogueira, Lilian; Oliveira, Thiago Y; Learn, Gerald H; Cohen, Yehuda Z; Lehmann, Clara; Gillor, Daniel; Shimeliovich, Irina; Unson-O'Brien, Cecilia; Weiland, Daniela; Robles, Alexander; Kümmerle, Tim; Wyen, Christoph; Levin, Rebeka; Witmer-Pack, Maggi; Eren, Kemal; Ignacio, Caroline; Kiss, Szilard; West, Anthony P; Mouquet, Hugo; Zingman, Barry S; Gulick, Roy M; Keler, Tibor; Bjorkman, Pamela J; Seaman, Michael S; Hahn, Beatrice H; Fätkenheuer, Gerd; Schlesinger, Sarah J; Nussenzweig, Michel C; Klein, Florian

    2017-02-01

    Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

  12. 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.

  13. SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Bonifati, Serena [Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH (United States); Daly, Michele B. [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); St Gelais, Corine; Kim, Sun Hee [Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH (United States); Hollenbaugh, Joseph A.; Shepard, Caitlin [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); Kennedy, Edward M. [Department of Molecular Genetics and Microbiology, Duke University, Durham, NC (United States); Kim, Dong-Hyun [Department of Pharmacy, School of Pharmacy, Kyung-Hee University, Seoul (Korea, Republic of); Schinazi, Raymond F. [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); Kim, Baek, E-mail: baek.kim@emory.edu [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); Department of Pharmacy, School of Pharmacy, Kyung-Hee University, Seoul (Korea, Republic of); Wu, Li, E-mail: wu.840@osu.edu [Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH (United States)

    2016-08-15

    SAMHD1 limits HIV-1 infection in non-dividing myeloid cells by decreasing intracellular dNTP pools. HIV-1 restriction by SAMHD1 in these cells likely prevents activation of antiviral immune responses and modulates viral pathogenesis, thus highlighting a critical role of SAMHD1 in HIV-1 physiopathology. Here, we explored the function of SAMHD1 in regulating cell proliferation, cell cycle progression and apoptosis in monocytic THP-1 cells. Using the CRISPR/Cas9 technology, we generated THP-1 cells with stable SAMHD1 knockout. We found that silencing of SAMHD1 in cycling cells stimulates cell proliferation, redistributes cell cycle population in the G{sub 1}/G{sub 0} phase and reduces apoptosis. These alterations correlated with increased dNTP levels and more efficient HIV-1 infection in dividing SAMHD1 knockout cells relative to control. Our results suggest that SAMHD1, through its dNTPase activity, affects cell proliferation, cell cycle distribution and apoptosis, and emphasize a key role of SAMHD1 in the interplay between cell cycle regulation and HIV-1 infection.

  14. Peptide Inhibitors of HIV-1 Virus Infection Based on Cullin-5

    Institute of Scientific and Technical Information of China (English)

    ZHU Ke-tong; ZHANG Xi-zhen; LOU Chao-ping; GUO Bo; DU Juan; WANG Xiao-dan; WU Yong-ge; KONG Wei; YU Xiang-hui

    2008-01-01

    Virion infectivity factor(Vif) is one of the six accessory proteins of HIV-1 and is necessary for viral infectivity. Human Apolipoprotein B editing complex protein 3G(h-APOBEC3G) is a cytidine deaminase only expressed in "nonpermissive" cells and exhibits virus suppressive activity. With the aid of a Cullin-5 E3 ligase, Vif induces h-APOBEC3G degradation and with the destruction of this ligase, Vif is functionally inactive. Therefore, it is expected that blocking this E3 pathway would be a new therapeutic strategy against HIV-1 infection. In this article, the authors' took sequence alignment of the N-termini of Cullin-5 and three other members of the Cullin protein family,respectively. A set of small peptides has been synthesized based on the sequence comparison results and possible Vif-Cullin-5 interaction domains. Moreover, it has been demonstrated that several peptides can reduce virus infectivity in "nonpermissive" cells with a dose-responsive manner, but not in "permissive" cells. The results also indicate that the loss of viral infectivity may be because of the increase of APOBEC3G amount in the peptide-treated cells. It is concluded that peptides derived from Cullin-5 can block the APOBEC3G degradation induced by Vif and suppress HIV-1 infectivity. Therefore this study starts a novel strategy for the development of a new HIV-1 inhibitor.

  15. Infection of rhesus macaques with a pool of simian immunodeficiency virus with the envelope genes from acute HIV-1 infections.

    Science.gov (United States)

    Krebs, Kendall C; Tian, Meijuan; Asmal, Mohammed; Ling, Binhua; Nelson, Kenneth; Henry, Kenneth; Gibson, Richard; Li, Yuejin; Han, Weining; Shattock, Robin J; Veazey, Ronald S; Letvin, Norman; Arts, Eric J; Gao, Yong

    2016-11-25

    New simian-human immunodeficiency chimeric viruses with an HIV-1 env (SHIVenv) are critical for studies on HIV pathogenesis, vaccine development, and microbicide testing. Macaques are typically exposed to single CCR5-using SHIVenv which in most instances does not reflect the conditions during acute/early HIV infection (AHI) in humans. Instead of individual and serial testing new SHIV constructs, a pool of SHIVenv_B derived from 16 acute HIV-1 infections were constructed using a novel yeast-based SHIV cloning approach and then used to infect macaques. Even though none of the 16 SHIVenvs contained the recently reported mutations in env genes that could significantly enhance their binding affinity to RhCD4, one SHIVenv (i.e. SHIVenv_B3-PRB926) established infection in macaques exposed to this pool. AHI SHIVenv_B viruses as well as their HIVenv_B counterparts were analyzed for viral protein content, function, and fitness to identify possible difference between SHIVenv_B3-PRB926 and the other 15 SHIVenvs in the pool. All of the constructs produced SHIV or HIV chimeric with wild type levels of capsid (p27 and p24) content, reverse transcriptase (RT) activity, and expressed envelope glycoproteins that could bind to cell receptors CD4/CCR5 and mediate virus entry. HIV-1env_B chimeric viruses were propagated in susceptible cell lines but the 16 SHIVenv_B variants showed only limited replication in macaque peripheral blood mononuclear cells (PBMCs) and 174×CEM.CCR5 cell line. AHI chimeric viruses including HIVenv_B3 showed only minor variations in cell entry efficiency and kinetics as well as replicative fitness in human PBMCs. Reduced number of N-link glycosylation sites and slightly greater CCR5 affinity/avidity was the only distinguishing feature of env_B3 versus other AHI env's in the pool, a feature also observed in the HIV establishing new infections in humans. Despite the inability to propagate in primary cells and cell lines, a pool of 16 SHIVenv viruses could

  16. Blocking of HIV-1 Infectivity by a Soluble, Secreted Form of the CD4 Antigen

    Science.gov (United States)

    Smith, Douglas H.; Byrn, Randal A.; Marsters, Scot A.; Gregory, Timothy; Groopman, Jerome E.; Capon, Daniel J.

    1987-12-01

    The initial event in the infection of human T lymphocytes, macrophages, and other cells by human immunodeficiency virus (HIV-1) is the attachment of the HIV-1 envelope glycoprotein gp120 to its cellular receptor, CD4. As a step toward designing antagonists of this binding event, soluble, secreted forms of CD4 were produced by transfection of mammalian cells with vectors encoding versions of CD4 lacking its transmembrane and cytoplasmic domains. The soluble CD4 so produced binds gp120 with an affinity and specificity comparable to intact CD4 and is capable of neutralizing the infectivity of HIV-1. These studies reveal that the high-affinity CD4-gp120 interaction does not require other cell or viral components and may establish a novel basis for therapeutic intervention in the acquired immune deficiency syndrome (AIDS).

  17. Origin and dynamics of HIV-1 subtype C infection in India.

    Directory of Open Access Journals (Sweden)

    Chengli Shen

    Full Text Available OBJECTIVE: To investigate the geographical origin and evolution dynamics of HIV-1 subtype C infection in India. DESIGN: Ninety HIV-1 subtype C env gp120 subtype C sequences from India were compared with 312 env gp120 reference subtype C sequences from 27 different countries obtained from Los Alamos HIV database. All the HIV-1 subtype C env gp120 sequences from India were used for the geographical origin analysis and 61 subtype C env gp120 sequences with known sampling year (from 1991 to 2008 were employed to determine the origin of HIV infection in India. METHODS: Phylogenetic analysis of HIV-1 env sequences was used to investigate the geographical origin and tMRCA of Indian HIV-1 subtype C. Evolutionary parameters including origin date and demographic growth patterns of Indian subtype C were estimated using a Bayesian coalescent-based approach under relaxed molecular clock models. FINDINGS: The majority of the analyzed Indian and South African HIV-1 subtype C sequences formed a single monophyletic cluster. The most recent common ancestor date was calculated to be 1975.56 (95% HPD, 1968.78-1981.52. Reconstruction of the effective population size revealed three phases of epidemic growth: an initial slow growth, followed by exponential growth, and then a plateau phase approaching present time. Stabilization of the epidemic growth phase correlated with the foundation of National AIDS Control Organization in India. INTERPRETATION: Indian subtype C originated from a single South African lineage in the middle of 1970s. The current study emphasizes not only the utility of HIV-1 sequence data for epidemiological studies but more notably highlights the effectiveness of community or government intervention strategies in controlling the trend of the epidemic.

  18. Prevalence of XMRV Nucleic Acid and Antibody in HIV-1-Infected Men and in Men at Risk for HIV-1 Infection

    Directory of Open Access Journals (Sweden)

    J. Spindler

    2011-01-01

    Full Text Available Xenotropic MLV-Related Virus (XMRV was recently reported to be associated with prostate cancer and chronic fatigue syndrome (CFS. Infection was also reported in 3.7% of healthy individuals. These highly reported frequencies of infection prompted concerns about the possibility of a new, widespread retroviral epidemic. The Multicenter AIDS Cohort Study (MACS provides an opportunity to assess the prevalence of XMRV infection and its association with HIV-1 infection among men who have sex with men. Reliable detection of XMRV infection requires the application of multiple diagnostic methods, including detection of human antibodies to XMRV and detection of XMRV nucleic acid. We, therefore, tested 332 patient plasma and PBMC samples obtained from recent visits in a subset of patients in the MACS cohort for XMRV antibodies using Abbott prototype ARCHITECT chemiluminescent immunoassays (CMIAs and for XMRV RNA and proviral DNA using a XMRV single-copy qPCR assay (X-SCA. Although 9 of 332 (2.7% samples showed low positive reactivity against a single antigen in the CMIA, none of these samples or matched controls were positive for plasma XMRV RNA or PBMC XMRV DNA by X-SCA. Thus, we found no evidence of XMRV infection among men in the MACS regardless of HIV-1 serostatus.

  19. Aqueous Extracts of the Marine Brown Alga Lobophora variegata Inhibit HIV-1 Infection at the Level of Virus Entry into Cells

    KAUST Repository

    Kremb, Stephan

    2014-08-21

    In recent years, marine algae have emerged as a rich and promising source of molecules with potent activities against various human pathogens. The widely distributed brown alga Lobophora variegata that is often associated with tropical coral reefs exerts strong antibacterial and antiprotozoal effects, but so far has not been associated with specific anti-viral activities. This study investigated potential HIV-1 inhibitory activity of L. variegata collected from different geographical regions, using a cell-based full replication HIV-1 reporter assay. Aqueous L. variegata extracts showed strong inhibitory effects on several HIV-1 strains, including drug-resistant and primary HIV-1 isolates, and protected even primary cells (PBMC) from HIV-1-infection. Anti-viral potency was related to ecological factors and showed clear differences depending on light exposition or epiphyte growth. Assays addressing early events of the HIV-1 replication cycle indicated that L. variegata extracts inhibited entry of HIV-1 into cells at a pre-fusion step possibly by impeding mobility of virus particles. Further characterization of the aqueous extract demonstrated that even high doses had only moderate effects on viability of cultured and primary cells (PBMCs). Imaging-based techniques revealed extract effects on the plasma membrane and actin filaments as well as induction of apoptosis at concentrations exceeding EC50 of anti-HIV-1 activity by more than 400 fold. In summary, we show for the first time that L. variegata extracts inhibit HIV-1 entry, thereby suggesting this alga as promising source for the development of novel HIV-1 inhibitors.

  20. Silibinin inhibits HIV-1 infection by reducing cellular activation and proliferation.

    Science.gov (United States)

    McClure, Janela; Lovelace, Erica S; Elahi, Shokrollah; Maurice, Nicholas J; Wagoner, Jessica; Dragavon, Joan; Mittler, John E; Kraft, Zane; Stamatatos, Leonidas; Stamatatos, Leonidis; Horton, Helen; De Rosa, Stephen C; Coombs, Robert W; Polyak, Stephen J

    2012-01-01

    Purified silymarin-derived natural products from the milk thistle plant (Silybum marianum) block hepatitis C virus (HCV) infection and inhibit T cell proliferation in vitro. An intravenous formulation of silibinin (SIL), a major component of silymarin, displays anti-HCV effects in humans and also inhibits T-cell proliferation in vitro. We show that SIL inhibited replication of HIV-1 in TZM-bl cells, PBMCs, and CEM cells in vitro. SIL suppression of HIV-1 coincided with dose-dependent reductions in actively proliferating CD19+, CD4+, and CD8+ cells, resulting in fewer CD4+ T cells expressing the HIV-1 co-receptors CXCR4 and CCR5. SIL inhibition of T-cell growth was not due to cytotoxicity measured by cell cycle arrest, apoptosis, or necrosis. SIL also blocked induction of the activation markers CD38, HLA-DR, Ki67, and CCR5 on CD4+ T cells. The data suggest that SIL attenuated cellular functions involved in T-cell activation, proliferation, and HIV-1 infection. Silymarin-derived compounds provide cytoprotection by suppressing virus infection, immune activation, and inflammation, and as such may be relevant for both HIV mono-infected and HIV/HCV co-infected subjects.

  1. Silibinin inhibits HIV-1 infection by reducing cellular activation and proliferation.

    Directory of Open Access Journals (Sweden)

    Janela McClure

    Full Text Available Purified silymarin-derived natural products from the milk thistle plant (Silybum marianum block hepatitis C virus (HCV infection and inhibit T cell proliferation in vitro. An intravenous formulation of silibinin (SIL, a major component of silymarin, displays anti-HCV effects in humans and also inhibits T-cell proliferation in vitro. We show that SIL inhibited replication of HIV-1 in TZM-bl cells, PBMCs, and CEM cells in vitro. SIL suppression of HIV-1 coincided with dose-dependent reductions in actively proliferating CD19+, CD4+, and CD8+ cells, resulting in fewer CD4+ T cells expressing the HIV-1 co-receptors CXCR4 and CCR5. SIL inhibition of T-cell growth was not due to cytotoxicity measured by cell cycle arrest, apoptosis, or necrosis. SIL also blocked induction of the activation markers CD38, HLA-DR, Ki67, and CCR5 on CD4+ T cells. The data suggest that SIL attenuated cellular functions involved in T-cell activation, proliferation, and HIV-1 infection. Silymarin-derived compounds provide cytoprotection by suppressing virus infection, immune activation, and inflammation, and as such may be relevant for both HIV mono-infected and HIV/HCV co-infected subjects.

  2. SEROPREVALENCE OF HTLV IN A POPULATION OF HIV1-INFECTED PATIENTS IN MIDWESTERN BRAZIL

    Science.gov (United States)

    KOZLOWSKI, Aline Garcia; de MATOS, Márcia Alves Dias; CARNEIRO, Megmar Aparecida dos Santos; LOPES, Carmen Luci Rodrigues; TELES, Sheila Araújo; VICENTE, Carolina Paulo; MARTINS, Regina Maria Bringel

    2016-01-01

    SUMMARY Human T-cell lymphotropic virus (HTLV) may affect the clinical course of human immunodeficiency virus 1 (HIV1). Both infections are common in endemic areas because these viruses share similar routes of transmission. The aim of this study was to estimate the seroprevalence of HTLV1/2 in a population of HIV1-infected patients in the state of Goiás, Midwestern Brazil. Of the 505 studied patients, four (0.79%) were positive for anti-HTLV1/2 by enzyme-linked immunosorbent assay (ELISA), with HTLV1 infection confirmed by line immunoassay (LIA) and polymerase chain reaction (PCR) in all of the ELISA-positive samples. No cases of HTLV2 infection were observed. The prevalence of HTLV1/HIV1 coinfection was 0.79% (4/505; 95% CI: 0.25-2.16). All the coinfected patients reported sexual risk behaviors and only one reported intravenous drug use. Sequencing of the viral long terminal repeat (LTR) region and phylogenetic analysis revealed that the four HTLV1 isolates belonged to the Transcontinental a subgroup of the Cosmopolitan (1a) subtype, the most frequent subgroup detected in Brazil. This study shows a low prevalence of HTLV1/2 in HIV1-infected patients in Midwestern Brazil. PMID:27828621

  3. Identification of full-length transmitted/founder viruses and their progeny in primary HIV-1 infection

    Energy Technology Data Exchange (ETDEWEB)

    Korber, Bette [Los Alamos National Laboratory; Hraber, Peter [Los Alamos National Laboratory; Giorgi, Elena [Los Alamos National Laboratory; Bhattacharya, T [Los Alamos National Laboratory

    2009-01-01

    Identification of transmitted/founder virus genomes and their progeny by is a novel strategy for probing the molecular basis of HIV-1 transmission and for evaluating the genetic imprint of viral and host factors that act to constrain or facilitate virus replication. Here, we show in a cohort of twelve acutely infected subjects (9 clade B; 3 clade C), that complete genomic sequences of transmitted/founder viruses could be inferred using single genome amplification of plasma viral RNA, direct amplicon sequencing, and a model of random virus evolution. This allowed for the precise identification, chemical synthesis, molecular cloning, and biological analysis of those viruses actually responsible for productive clinical infection and for a comprehensive mapping of sequential viral genomes and proteomes for mutations that are necessary or incidental to the establishment of HIV-1 persistence. Transmitted/founder viruses were CD4 and CCR5 tropic, replicated preferentially in activated primary T-Iymphocytes but not monocyte-derived macrophages, and were effectively shielded from most heterologous or broadly neutralizing antibodies. By 3 months of infection, the evolving viral quasispecies in three subjects showed mutational fixation at only 2-5 discreet genomic loci. By 6-12 months, mutational fixation was evident at 18-27 genomic loci. Some, but not all, of these mutations were attributable to virus escape from cytotoxic Tlymphocytes or neutralizing antibodies, suggesting that other viral or host factors may influence early HIV -1 fitness.

  4. Combining epidemiological and genetic networks signifies the importance of early treatment in HIV-1 transmission

    NARCIS (Netherlands)

    Zarrabi, N.; Prosperi, M.; Belleman, R.G.; Colafigli, M.; De Luca, A.; Sloot, P.M.A.

    2012-01-01

    Inferring disease transmission networks is important in epidemiology in order to understand and prevent the spread of infectious diseases. Reconstruction of the infection transmission networks requires insight into viral genome data as well as social interactions. For the HIV-1 epidemic, current res

  5. Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women

    NARCIS (Netherlands)

    Colbers, A.; Best, B.; Schalkwijk, S.J.; Wang, J; Stek, A.; Tenorio, C.H.; Hawkins, D.; Taylor, G.; Kreitchmann, R.; Burchett, S.; Haberl, A.; Kabeya, K.; Kasteren, M.E.E. van; Smith, E.; Capparelli, E.; Burger, D.M.; Mirochnick, M.; Ven, A. van der

    2015-01-01

    OBJECTIVE: To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum. METHODS: HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed

  6. Adjuvanted HLA-supertype restricted subdominant peptides induce new T-cell immunity during untreated HIV-1-infection

    DEFF Research Database (Denmark)

    Karlsson, Ingrid; Brandt, Lea; Vinner, Lasse

    2013-01-01

    -cell responses specific for one or more vaccine epitopes were induced in 10/10 vaccinees. The responses were dominated by CD107a and MIP1β expression. There were no significant changes in HIV-1 viral load or CD4 T-cell counts. Our study demonstrates that the peptide/CAF01 vaccine is safe and that it is possible......We investigated the potential of inducing additional T-cell immunity during chronic HIV-1 infection directed to subdominant HIV-1 epitopes from common HLA-supertypes. Ten treatment-naïve HIV-1-infected individuals were immunized with peptides in the adjuvant CAF01. One individual received placebo...... to generate new HIV-1 T-cell responses to defined epitopes in treatment-naïve HIV-1-infected individuals....

  7. LILRB2 interaction with HLA class I correlates with control of HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Arman A Bashirova

    2014-03-01

    Full Text Available Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC class I locus, and the CD8+ T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1 by changing interactions of human leukocyte antigen (HLA class I molecules with leukocyte immunoglobulin-like receptors (LILR, a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs. We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126 to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2. Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11-10(-9 and African (p = 10(-5-10(-3 descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement.

  8. New therapy to revert dysfunctional antibody responses during HIV-1 infection

    Science.gov (United States)

    Chiodi, Francesca

    2010-01-01

    Individuals infected with HIV-1 progress to AIDS at different rates. Rapid progressors develop AIDS within 2–5 years of initial infection, compared with approximately 10 years in typical progressors. Progression to AIDS is associated with impaired humoral and cellular immunity. In this issue of the JCI, Titanji and colleagues report that activated memory B (mBAct) cells are depleted in SIV-infected macaques defined as rapid progressors. Depletion was mediated by programmed death-1 (PD-1) and resulted in reduction of antibody titers specific for SIV and bacterial antigens. Interestingly, blockade of PD-1 in infected animals protected B cells from apoptosis and increased levels of SIV-specific antibodies in blood. These findings pave the way for a new therapeutic strategy aimed at improving humoral immunity in HIV-1 infection. PMID:20972328

  9. The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals.

    NARCIS (Netherlands)

    Koks, C.H.W.; Crommentuyn, K.M.; Hoetelmans, R.M.; Burger, D.M.; Koopmans † , P.P.; Mathô t, R.A.A.; Mulder, J.W.; Meenhorst, P.L.; Beijnen, J.H.

    2001-01-01

    AIMS: To study the effect of fluconazole on the steady-state pharmacokinetics of the protease inhibitors ritonavir and saquinavir in HIV-1-infected patients. METHODS: Five subjects treated with saquinavir and three with ritonavir received the protease inhibitor alone (saquinavir 1200 mg three times

  10. HIV-1 Encephalopathy among Perinatally Infected Children: Neuropathogenesis and Response to Highly Active Antiretroviral Therapy

    Science.gov (United States)

    Mitchell, Charles D.

    2006-01-01

    HIV-1 encephalopathy among perinatally infected children in the United States was initially defined by a classic triad of findings that included: (1) developmental delay, (2) secondary or acquired microcephaly, and (3) pyramidal tract neuromotor deficits. The most severe form of this disorder typically occurred among young children who developed…

  11. Safeguard against DNA sensing: The role of TREX1 in HIV-1 infection and autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Nan eYan

    2014-04-01

    Full Text Available Innate immune recognition is crucial for host responses against viral infections, including infection by human immunodeficiency virus 1 (HIV-1. Human cells detect such invading pathogens with a collection of pattern recognition receptors (PRRs that activate the production of antiviral proteins, such as the cytokine interferon-type I, to initiate antiviral responses immediately as well as the adaptive immune response for long-term protection. To establish infection in the host, many viruses have thus evolved strategies for subversion of these mechanisms of innate immunity. For example, acute infection by HIV-1 and other retroviruses have long been thought to be non-immunogenic, signifying suppression of host defenses by these pathogens. Studies in the past few years have begun to uncover a multifaceted scheme of how HIV-1 evades innate immune detection, especially of its DNA, by exploiting host proteins. This review will discuss the host mechanisms of HIV-1 DNA sensing and viral immune evasion, with a particular focus on TREX1, a host 3’ to 5’ exodeoxyribonuclease (also known as DNase III.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Inhibition of HIV-1 lentiviral particles infectivity by Gynostemma ...

    African Journals Online (AJOL)

    Yomi

    2012-01-24

    Jan 24, 2012 ... study in which the inhibition of viral vector infectivity of HeLa cells was assessed flow cytometrically by measuring the expression .... plant Gynostemma pentaphyllum (Cucurbitaceae) for ..... sapogenins and differentiation from.

  14. Differential Expression of CD163 on Monocyte Subsets in Healthy and HIV-1 Infected Individuals

    Science.gov (United States)

    Tippett, Emma; Cheng, Wan-Jung; Westhorpe, Clare; Cameron, Paul U.; Brew, Bruce J.; Lewin, Sharon R.; Jaworowski, Anthony; Crowe, Suzanne M.

    2011-01-01

    CD163, a haptoglobin-hemoglobin (Hp-Hb) scavenger receptor, expressed by monocytes and macrophages, is important in resolution of inflammation. Age-related non-AIDS co-morbidities in HIV-infected individuals, particularly dementia and cardiovascular disease, result in part from effects of HIV-1 infection on monocyte and macrophage biology. CD163 co-expression on CD14+CD16++ monocytes has been proposed as a useful biomarker for HIV-1 disease progression and the presence of HIV associated dementia. Here we investigated CD163 expression on monocyte subsets ex vivo, on cultured macrophages, and soluble in plasma, in the setting of HIV-1 infection. Whole blood immunophenotyping revealed CD163 expression on CD14++CD16- monocytes but not on CD14+CD16++ monocytes (P = 0.004), supported by CD163 mRNA levels. Incubation with M-CSF induced CD163 protein expression on CD14+CD16++ monocytes to the same extent as CD14++CD16− monocytes. CD163 expression on CD14++CD16+ monocytes from HIV-infected subjects was significantly higher than from uninfected individuals, with a trend towards increased expression on CD14++CD16− monocytes (P = 0.019 and 0.069 respectively), which is accounted for by HIV-1 therapy including protease inhibitors. Shedding of CD163 was shown to predominantly occur from the CD14++CD16− subset after Ficoll isolation and LPS stimulation. Soluble CD163 concentration in plasma from HIV-1 infected donors was similar to HIV-1 uninfected donors. Monocyte CD163 expression in HIV-1 infected patients showed a complicated relationship with classical measures of disease progression. Our findings clarify technical issues regarding CD163 expression on monocyte subsets and further elucidates its role in HIV-associated inflammation by demonstrating that CD163 is readily lost from CD14++CD16− monocytes and induced in pro-inflammatory CD14+CD16++ monocytes by M-CSF. Our data show that all monocyte subsets are potentially capable of differentiating into CD163

  15. Differential expression of CD163 on monocyte subsets in healthy and HIV-1 infected individuals.

    Directory of Open Access Journals (Sweden)

    Emma Tippett

    Full Text Available CD163, a haptoglobin-hemoglobin (Hp-Hb scavenger receptor, expressed by monocytes and macrophages, is important in resolution of inflammation. Age-related non-AIDS co-morbidities in HIV-infected individuals, particularly dementia and cardiovascular disease, result in part from effects of HIV-1 infection on monocyte and macrophage biology. CD163 co-expression on CD14+CD16++ monocytes has been proposed as a useful biomarker for HIV-1 disease progression and the presence of HIV associated dementia. Here we investigated CD163 expression on monocyte subsets ex vivo, on cultured macrophages, and soluble in plasma, in the setting of HIV-1 infection. Whole blood immunophenotyping revealed CD163 expression on CD14++CD16- monocytes but not on CD14+CD16++ monocytes (P = 0.004, supported by CD163 mRNA levels. Incubation with M-CSF induced CD163 protein expression on CD14+CD16++ monocytes to the same extent as CD14++CD16- monocytes. CD163 expression on CD14++CD16+ monocytes from HIV-infected subjects was significantly higher than from uninfected individuals, with a trend towards increased expression on CD14++CD16- monocytes (P = 0.019 and 0.069 respectively, which is accounted for by HIV-1 therapy including protease inhibitors. Shedding of CD163 was shown to predominantly occur from the CD14++CD16- subset after Ficoll isolation and LPS stimulation. Soluble CD163 concentration in plasma from HIV-1 infected donors was similar to HIV-1 uninfected donors. Monocyte CD163 expression in HIV-1 infected patients showed a complicated relationship with classical measures of disease progression. Our findings clarify technical issues regarding CD163 expression on monocyte subsets and further elucidates its role in HIV-associated inflammation by demonstrating that CD163 is readily lost from CD14++CD16- monocytes and induced in pro-inflammatory CD14+CD16++ monocytes by M-CSF. Our data show that all monocyte subsets are potentially capable of differentiating into CD

  16. Changes in biomarkers of cardiovascular risk after a switch to abacavir in HIV-1-infected individuals receiving combination antiretroviral therapy

    DEFF Research Database (Denmark)

    Kristoffersen, U S; Kofoed, K; Kronborg, G;

    2009-01-01

    OBJECTIVES: To investigate, using a longitudinal design, whether biomarkers of cardiovascular risk change after a switch to an abacavir (ABC)-containing regimen in HIV-1-infected individuals already receiving combination antiretroviral therapy (ART). METHODS: Thirty-five HIV-1-infected individuals...

  17. Induction of cyclooxygenase-2 expression during HIV-1-infected monocyte-derived macrophage and human brain microvascular endothelial cell interactions

    NARCIS (Netherlands)

    Pereira, CF; Boven, LA; Middel, J; Verhoef, J; Nottet, HSLM

    2000-01-01

    Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD) is a neurodegenerative disease characterized by HIV infection and replication in brain tissue. HIV-1-infected monocytes overexpress inflammatory molecules that facilitate their entry into the brain. Prostanoids are lipid mediators

  18. Transcriptional Regulation of CXCL5 in HIV-1-Infected Macrophages and Its Functional Consequences on CNS Pathology.

    Science.gov (United States)

    Guha, Debjani; Klamar, Cynthia R; Reinhart, Todd; Ayyavoo, Velpandi

    2015-05-01

    Human immunodeficiency virus-1 (HIV-1)-infected monocytes/macrophages and microglia release increased levels of proinflammatory cytokines and chemokines, including ELR+ (containing glutamic acid-leucine-arginine motif) chemokines. To investigate the role of HIV-1 infection on chemokine regulation, monocyte-derived macrophages (MDMs) from normal donors were infected with HIV-1 and the expression of chemokines and their downstream biological functions were evaluated. Among the tested chemokines, CXCL5 was upregulated significantly both at the mRNA and protein level in the HIV-1-infected MDMs compared with mock-infected cultures. Upregulation of CXCL5 in the HIV-1-infected MDMs is, in part, regulated by increased interleukin-1β (IL-1β) production and phosphorylation of ERK1/2. Functional analyses indicate that HIV-1-induced overexpression of CXCL5 has enhanced the ability to attract neutrophils, as observed by chemotaxis assay. However, exposure of NT2, SH-SY5Y cells, and primary neurons to HIV-1-infected MDM supernatants resulted in cell death that was not rescued by anti-CXCL5 antibody suggesting that CXCL5 does not have direct effect on neuronal death. Together, these results suggest that the increased level of CXCL5 in tissue compartments, including the central nervous system of HIV-1-infected individuals might alter the inflammatory response through the infiltration of neutrophils into tissue compartment, thus causing secondary effects on resident cells.

  19. High prevalence and genetic diversity of HCV among HIV-1 infected people from various high-risk groups in China.

    Directory of Open Access Journals (Sweden)

    Hong Shang

    Full Text Available BACKGROUND: Co-infection with HIV-1 and HCV is a significant global public health problem and a major consideration for anti-HIV-1 treatment. HCV infection among HIV-1 positive people who are eligible for the newly launched nationwide anti-HIV-1 treatment program in China has not been well characterized. METHODOLOGY: A nationwide survey of HIV-1 positive injection drug uses (IDU, former paid blood donors (FBD, and sexually transmitted cases from multiple provinces including the four most affected provinces in China was conducted. HCV prevalence and genetic diversity were determined. We found that IDU and FBD have extremely high rates of HCV infection (97% and 93%, respectively. Surprisingly, people who acquired HIV-1 through sexual contact also had a higher rate of HCV infection (20% than the general population. HIV-1 subtype and HCV genotypes were amazingly similar among FBD from multiple provinces stretching from Central to Northeast China. However, although patterns of overland trafficking of heroin and distinct HIV-1 subtypes could be detected among IDU, HCV genotypes of IDU were more diverse and exhibited significant regional differences. CONCLUSION: Emerging HIV-1 and HCV co-infection and possible sexual transmission of HCV in China require urgent prevention measures and should be taken into consideration in the nationwide antiretroviral treatment program.

  20. T-lymphocytes from AIDS patients are unable to synthesize ribonucleotides de novo in response to mitogenic stimulation. Impaired pyrimidine responses are already evident at early stages of HIV-1 infection.

    Science.gov (United States)

    Bofill, M; Fairbanks, L D; Ruckemann, K; Lipman, M; Simmonds, H A

    1995-12-15

    Proliferative defects have been reported at the level of DNA synthesis, even in T-lymphocytes from asymptomatic human immunodeficiency virus type-1+ (HIV-1+) patients. Since purine and pyrimidine ribonucleotide availability is crucial for proliferation, we compared the ability of HIV-1- and HIV-1+ T-lymphocytes (> 95% CD4+ and CD8+) to activate de novo biosynthetic and salvage pathways following phytohemagglutinin stimulation using 14C-labeled precursors. The striking abnormality already detectable in asymptomatic patients' cells was the impaired ability of CTP, UDP-Glc, and UTP pools to expand over 72 h (44-70% of control), although ATP and GTP pools and responses were normal. In symptomatic patients, resting T-cells showed markedly reduced pyrimidine pools (53-74% of control) with no change following activation. Relatively normal ATP, GTP, and NAD pools masked the same impaired response of de novo synthesis to activation, with ATP and GTP being reduced by 50% at 48 h. Purine salvage was more active than the control in unstimulated HIV-1+ cells. This impaired de novo synthesis in HIV-1+ T-lymphocytes severely restricts the availability of ribonucleotides for vital growth-related activities such as membrane expansion and strand break repair as well as DNA and RNA synthesis. The data indicate that resting T-lymphocytes from symptomatic patients survive through enhanced salvage, but the stimulation induces metabolic cell death, and provide an explanation for the activation-associated lymphocyte death seen in HIV-1+ T-lymphocytes.

  1. Alterations in the gut microbiota associated with HIV-1 infection.

    Science.gov (United States)

    Lozupone, Catherine A; Li, Marcella; Campbell, Thomas B; Flores, Sonia C; Linderman, Derek; Gebert, Matthew J; Knight, Rob; Fontenot, Andrew P; Palmer, Brent E

    2013-09-11

    Understanding gut microbiota alterations associated with HIV infection and factors that drive these alterations may help explain gut-linked diseases prevalent with HIV. 16S rRNA sequencing of feces from HIV-infected individuals revealed that HIV infection is associated with highly characteristic gut community changes, and antiretroviral therapy does not consistently restore the microbiota to an HIV-negative state. Despite the chronic gut inflammation characteristic of HIV infection, the associated microbiota showed limited similarity with other inflammatory states and instead showed increased, rather than decreased, diversity. Meta-analysis revealed that the microbiota of HIV-infected individuals in the U.S. was most similar to a Prevotella-rich community composition typically observed in healthy individuals in agrarian cultures of Malawi and Venezuela and related to that of U.S. individuals with carbohydrate-rich, protein- and fat-poor diets. By evaluating innate and adaptive immune responses to lysates from bacteria that differ with HIV, we explore the functional drivers of these compositional differences. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Noninvasive micromanipulation of live HIV-1 infected cells via laser light

    Science.gov (United States)

    Mthunzi, Patience

    2015-12-01

    Live mammalian cells from various tissues of origin can be aseptically and noninvasively micromanipulated via lasers of different regimes. Laser-driven techniques are therefore paving a path toward the advancement of human immuno-deficiency virus (HIV-1) investigations. Studies aimed at the interaction of laser light, nanomaterials, and biological materials can also lead to an understanding of a wealth of disease conditions and result in photonics-based therapies and diagnostic tools. Thus, in our research, both continuous wave and pulsed lasers operated at varying wavelengths are employed, as they possess special properties that allow classical biomedical applications. This paper discusses photo-translocation of antiretroviral drugs into HIV-1 permissive cells and preliminary results of low-level laser therapy (LLLT) in HIV-1 infected cells.

  3. Central and peripheral nervous system functions are independently disturbed in HIV-1 infected patients.

    Science.gov (United States)

    von Giesen, Hans-Jürgen; Köller, Hubertus; Hefter, Harald; Arendt, Gabriele

    2002-06-01

    We examined the peripheral nervous system (PNS) (nerve conduction velocity (NCV)) and the central nervous system (CNS) (basal ganglia-mediated psychomotor speed) in 93 males seropositive for human immunodeficiency virus type 1 (HIV-1) with no prior history of opportunistic brain disease, antiretroviral treatment or intravenous drug use. Patients with different degrees of slowing of peroneal and sural NCV showed no significant differences in psychomotor speed as assessed by tremor peak frequency, most rapid alternating movements, reaction times and contraction times. There was no significant correlation between psychomotor measures and NCV. Psychomotor slowing test findings were independent from peripheral nervous system damage indicating uncorrelated disturbances of CNS and PNS function in HIV-1 infection. Differences in HIV-1 viral quasispecies or host responses may determine the predominance of CNS or PNS injury.

  4. Noninvasive micromanipulation of live HIV-1 infected cells via laser light

    Energy Technology Data Exchange (ETDEWEB)

    Mthunzi, Patience [National Laser Centre, Council for Scientific and Industrial Research, Pretoria (South Africa)

    2015-12-31

    Live mammalian cells from various tissues of origin can be aseptically and noninvasively micromanipulated via lasers of different regimes. Laser-driven techniques are therefore paving a path toward the advancement of human immuno-deficiency virus (HIV-1) investigations. Studies aimed at the interaction of laser light, nanomaterials, and biological materials can also lead to an understanding of a wealth of disease conditions and result in photonics-based therapies and diagnostic tools. Thus, in our research, both continuous wave and pulsed lasers operated at varying wavelengths are employed, as they possess special properties that allow classical biomedical applications. This paper discusses photo-translocation of antiretroviral drugs into HIV-1 permissive cells and preliminary results of low-level laser therapy (LLLT) in HIV-1 infected cells.

  5. Predicting bacteremic pneumonia in HIV-1-infected patients consulting the ED.

    Science.gov (United States)

    Perelló, Rafael; Miró, Oscar; Marcos, María Angeles; Almela, Manel; Bragulat, Ernest; Sánchez, Miquel; Agustí, Carlos; Miro, José M; Moreno, Asunción

    2010-05-01

    HIV-1-infected patients have higher incidence of community-acquired pneumonia (CAP) and risk of complications. Bacteremia has been associated with a higher risk of complications in such patients. We investigated factors associated with bacteremia in HIV-1-infected patients with CAP presenting at the emergency department. We included HIV-1-infected patients with CAP for 3 years (March 2005-February 2008). Only patients in whom blood cultures were performed were finally included. Clinical data (age; sex; CD4(+) count; serum HIV viral load; previous or current intravenous drug use and antiretroviral treatment; systolic blood pressure; and cardiac and respiratory rates), analytical data (leukocyte count, arterial oxygen content, C-reactive protein value, and urgent Streptococcus pneumoniae and Legionella spp antigen urine detection), and APACHE-II (Acute Physiology and Chronic Health Evaluation) score were compiled. The need for intensive care unit admission, mechanical ventilation, mortality, and for patients finally discharged, duration of admission were retrospectively obtained from the clinical history. A multivariate analysis using logistic regression was performed to find independent predictors of bacteremia. We diagnosed 129 HIV-1-infected patients with CAP. Blood cultures were performed in 118 cases (91%). Bacteremia was present in 28 (24%). Independent predictors of bacteremia were the detection of S pneumoniae antigen in urine (odds ratio, 9.0; 95% confidence interval, 1.9-42.0) and the absence of current antiretroviral treatment (odds ratio, 7.1; 95% confidence interval, 1.4-33.3). In-hospital mortality was higher in patients with bacteremia (15% vs 0%). HIV-1-infected patients with CAP who are not on current antiretroviral therapy and have positive S pneumoniae antigenuria are at increased risk of having bacteremia. Bacteremic patients have a poor outcome. (c) 2010 Elsevier Inc. All rights reserved.

  6. Tyrosine-sulfated V2 peptides inhibit HIV-1 infection via coreceptor mimicry

    Directory of Open Access Journals (Sweden)

    Raffaello Cimbro

    2016-08-01

    Full Text Available Tyrosine sulfation is a post-translational modification that facilitates protein-protein interaction. Two sulfated tyrosines (Tys173 and Tys177 were recently identified within the second variable (V2 loop of the major HIV-1 envelope glycoprotein, gp120, and shown to contribute to stabilizing the intramolecular interaction between V2 and the third variable (V3 loop. Here, we report that tyrosine-sulfated peptides derived from V2 act as structural and functional mimics of the CCR5 N-terminus and potently block HIV-1 infection. Nuclear magnetic and surface plasmon resonance analyses indicate that a tyrosine-sulfated V2 peptide (pV2α-Tys adopts a CCR5-like helical conformation and directly interacts with gp120 in a CD4-dependent fashion, competing with a CCR5 N-terminal peptide. Sulfated V2 mimics, but not their non-sulfated counterparts, inhibit HIV-1 entry and fusion by preventing coreceptor utilization, with the highly conserved C-terminal sulfotyrosine, Tys177, playing a dominant role. Unlike CCR5 N-terminal peptides, V2 mimics inhibit a broad range of HIV-1 strains irrespective of their coreceptor tropism, highlighting the overall structural conservation of the coreceptor-binding site in gp120. These results document the use of receptor mimicry by a retrovirus to occlude a key neutralization target site and provide leads for the design of therapeutic strategies against HIV-1.

  7. Protein kinase C-delta regulates HIV-1 replication at an early post-entry step in macrophages

    Directory of Open Access Journals (Sweden)

    Contreras Xavier

    2012-05-01

    Full Text Available Abstract Background Macrophages, which are CD4 and CCR5 positive, can sustain HIV-1 replication for long periods of time. Thus, these cells play critical roles in the transmission, dissemination and persistence of viral infection. Of note, current antiviral therapies do not target macrophages efficiently. Previously, it was demonstrated that interactions between CCR5 and gp120 stimulate PKC. However, the PKC isozymes involved were not identified. Results In this study, we identified PKC-delta as a major cellular cofactor for HIV-1 replication in macrophages. Indeed, PKC-delta was stimulated following the interaction between the virus and its target cell. Moreover, inhibition of PKC-delta blocked the replication of R5-tropic viruses in primary human macrophages. However, this inhibition did not have significant effects on receptor and co-receptor expression or fusion. Additionally, it did not affect the formation of the early reverse transcription product containing R/U5 sequences, but did inhibit the synthesis of subsequent cDNAs. Importantly, the inhibition of PKC-delta altered the redistribution of actin, a cellular cofactor whose requirement for the completion of reverse transcription was previously established. It also prevented the association of the reverse transcription complex with the cytoskeleton. Conclusion This work highlights the importance of PKC-delta during early steps of the replicative cycle of HIV-1 in human macrophages.

  8. Syphilis and HIV-1 co-infection: influence on CD4 T cell count, HIV-1 viral load and treatment response

    DEFF Research Database (Denmark)

    Kofoed, Kristian; Gerstoft, Jan; Mathiesen, Lars Reinhardt

    2006-01-01

    OBJECTIVES: To assess the effect of human immunodeficiency virus (HIV)-1 and syphilis coinfection on HIV-ribonucleic acid (RNA) viral load, CD4 cell count, and the response in rapid plasmin reagin (RPR) to treatment of the syphilis infection. STUDY DESIGN: Cases of syphilis diagnosed during 1 yea...

  9. The Effects of the Recombinant CCR5 T4 Lysozyme Fusion Protein on HIV-1 Infection.

    Directory of Open Access Journals (Sweden)

    Qingwen Jin

    Full Text Available Insertion of T4 lysozyme (T4L into the GPCR successfully enhanced GPCR protein stability and solubilization. However, the biological functions of the recombinant GPCR protein have not been analyzed.We engineered the CCR5-T4L mutant and expressed and purified the soluble recombinant protein using an E.coli expression system. The antiviral effects of this recombinant protein in THP-1 cell lines, primary human macrophages, and PBMCs from different donors were investigated. We also explored the possible mechanisms underlying the observed antiviral effects.Our data showed the biphasic inhibitory and promotion effects of different concentrations of soluble recombinant CCR5-T4L protein on R5 tropic human immunodeficiency virus-1 (HIV-1 infection in THP-1 cell lines, human macrophages, and PBMCs from clinical isolates. We demonstrated that soluble recombinant CCR5-T4L acts as a HIV-1 co-receptor, interacts with wild type CCR5, down-regulates the surface CCR5 expression in human macrophages, and interacts with CCL5 to inhibit macrophage migration. Using binding assays, we further determined that recombinant CCR5-T4L and [125I]-CCL5 compete for the same binding site on wild type CCR5.Our results suggest that recombinant CCR5-T4L protein marginally promotes HIV-1 infection at low concentrations and markedly inhibits infection at higher concentrations. This recombinant protein may be helpful in the future development of anti-HIV-1 therapeutic agents.

  10. Do tests devised to detect recent HIV-1 infection provide reliable estimates of incidence in Africa?

    Science.gov (United States)

    Sakarovitch, Charlotte; Rouet, Francois; Murphy, Gary; Minga, Albert K; Alioum, Ahmadou; Dabis, Francois; Costagliola, Dominique; Salamon, Roger; Parry, John V; Barin, Francis

    2007-05-01

    The objective of this study was to assess the performance of 4 biologic tests designed to detect recent HIV-1 infections in estimating incidence in West Africa (BED, Vironostika, Avidity, and IDE-V3). These tests were assessed on a panel of 135 samples from 79 HIV-1-positive regular blood donors from Abidjan, Côte d'Ivoire, whose date of seroconversion was known (Agence Nationale de Recherches sur le SIDA et les Hépatites Virales 1220 cohort). The 135 samples included 26 from recently infected patients (180 days), and 15 from patients with clinical AIDS. The performance of each assay in estimating HIV incidence was assessed through simulations. The modified commercial assays gave the best results for sensitivity (100% for both), and the IDE-V3 technique gave the best result for specificity (96.3%). In a context like Abidjan, with a 10% HIV-1 prevalence associated with a 1% annual incidence, the estimated test-specific annual incidence rates would be 1.2% (IDE-V3), 5.5% (Vironostika), 6.2% (BED), and 11.2% (Avidity). Most of the specimens falsely classified as incident cases were from patients infected for >180 days but <1 year. The authors conclude that none of the 4 methods could currently be used to estimate HIV-1 incidence routinely in Côte d'Ivoire but that further adaptations might enhance their accuracy.

  11. Human Immunodeficiency Virus type 1 in seronegative infants born to HIV-1-infected mothers

    Directory of Open Access Journals (Sweden)

    G Reyes-Terán

    2006-06-01

    Full Text Available Abstract Background Some individuals repeatedly exposed to Human Immunodeficiency Virus do not seroconvert and are resistant to HIV infection. Here, in a pediatric cohort of HIV seronegative infants born of HIV-infected mothers, we have studied eight non-breastfed children in whom viral DNA was detected in their PBMC. Our objective was to assess whether silent infection in these children can be explained by the presence of integrated viral DNA. Methods The presence of viral DNA was corroborated by nested PCR with primers for gag and the nef/LTR regions of HIV-1. Integration of HIV DNA into the host genome was assessed by an Alu-LTR PCR. Amplicons were sequenced and phylogenetic analyzes were done. Results HIV-1 DNA was detected in the earliest available PBMC sample from all eight infants, and two of them tested positive for HIV DNA at 2 years of age. Nested PCR resulted in the amplification of gag, nef/LTR and Alu-LTR fragments, which demostrated that HIV-1 DNA was integrated in the host cell genome. Each individual has a characteristic sequence pattern and is different from the LTR sequence of HXB2 prototype virus and other Mexican isolates. Conclusion HIV-1 DNA was observed in PBMC from HIV exposed seronegative children in this pediatric cohort.

  12. HLA-C increases HIV-1 infectivity and is associated with gp120

    Directory of Open Access Journals (Sweden)

    Beretta Alberto

    2008-08-01

    Full Text Available Abstract Background A recently identified genetic polymorphism located in the 5' region of the HLA-C gene is associated with individual variations in HIV-1 viral load and with differences in HLA-C expression levels. HLA-C has the potential to restrict HIV-1 by presenting epitopes to cytotoxic T cells but it is also a potent inhibitor of NK cells. In addition, HLA-C molecules incorporated within the HIV-1 envelope have been shown to bind to the envelope glycoprotein gp120 and enhance viral infectivity. We investigated this last property in cell fusion assays where the expression of HLA-C was silenced by small interfering RNA sequences. Syncytia formation was analyzed by co-cultivating cell lines expressing HIV-1 gp120/gp41 from different laboratory and primary isolates with target cells expressing different HIV-1 co-receptors. Virus infectivity was analyzed using pseudoviruses. Molecular complexes generated during cell fusion (fusion complexes were purified and analyzed for their HLA-C content. Results HLA-C positive cells co-expressing HIV-1 gp120/gp41 fused more rapidly and produced larger syncytia than HLA-C negative cells. Transient transfection of gp120/gp41 from different primary isolates in HLA-C positive cells resulted in a significant cell fusion increase. Fusion efficiency was reduced in HLA-C silenced cells compared to non-silenced cells when co-cultivated with different target cell lines expressing HIV-1 co-receptors. Similarly, pseudoviruses produced from HLA-C silenced cells were significantly less infectious. HLA-C was co-purified with gp120 from cells before and after fusion and was associated with the fusion complex. Conclusion Virionic HLA-C molecules associate to Env and increase the infectivity of both R5 and X4 viruses. Genetic polymorphisms associated to variations in HLA-C expression levels may therefore influence the individual viral set point not only by means of a regulation of the virus-specific immune response but also

  13. Relationships between humoral factors in HIV-1-infected mothers and the occurrence of HIV infection in their infants.

    Science.gov (United States)

    Mabondzo, A; Rouvier, P; Raoul, H; Le Naour, R; Courpotin, C; Hervé, F; Parnet-Mathieu, F; Lasfargues, G; Dormont, D

    1995-12-01

    Based on what is known about the biology of HIV-1 vertical transmission, the HIV burden of the mother, maternal immune factors and the integrity of the placental barrier are likely to play major roles. We therefore sought to determine whether the presence of antibodies in sera from 47 HIV-1-infected mothers, including 30 non-transmitting and 17 transmitting mothers, affected the risk of HIV-1 transmission to infants. Our findings showed no significant correlation between the capacity of antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) and their capacity to induce protection of the child from HIV-1 infection (P = 0.14). Furthermore, no correlation was found between the capacity of maternal antibodies to neutralize in vitro lymphocyte or macrophage heterologous viral infection and the occurrence of in vivo HIV-1 infection in the infant. Sera recovered from five of 12 transmitting mothers and from five of 11 non-transmitting mothers were compared in their capacity to neutralize the viruses drawn from the same individuals. Four out of five maternal isolates from transmitting mothers and all maternal isolates from non-transmitting mothers were sensitive to enhancement of infection mediated by the maternal serum.

  14. Bone marrow plasma cells are a primary source of serum HIV-1-specific antibodies in chronically infected individuals.

    Science.gov (United States)

    Montezuma-Rusca, Jairo M; Moir, Susan; Kardava, Lela; Buckner, Clarisa M; Louie, Aaron; Kim, Leo J Y; Santich, Brian H; Wang, Wei; Fankuchen, Olivia R; Diaz, Gabriella; Daub, Janine R; Rosenzweig, Sergio D; Chun, Tae-Wook; Li, Yuxing; Braylan, Raul C; Calvo, Katherine R; Fauci, Anthony S

    2015-03-15

    Several potent and broadly neutralizing Abs to HIV-1 have been isolated recently from peripheral blood B cells of infected individuals, based on prescreening of Ab activity in the serum. However, little is known regarding the cells that make the Abs that circulate in the blood. Accordingly, we investigated the most likely source, the bone marrow, of chronically HIV-1-infected individuals who were not receiving antiretroviral therapy. Increased frequencies of plasma cells, as well as B cell precursors, namely preB-I and preB-II, and decreased frequencies of mature B cells were observed in bone marrow aspirates of these individuals compared with HIV-negative counterparts. Increased frequencies of bone marrow plasma cells are consistent with known hallmarks of HIV-1 infection, namely hypergammaglobulinemia and increased frequencies of peripheral blood plasmablasts. Levels of HIV-1 envelope (Env)-binding and HIV-1-neutralizing Abs were measured in serum, and corresponding frequencies of Ab-secreting or Env-binding cells were measured in the blood (plasmablasts and memory B cells) and in the bone marrow (plasma cells). A strong correlation was observed between serum HIV-1-specific Abs and Env-specific bone marrow-derived plasma cells, but not circulating plasmablasts or memory B cells. These findings demonstrate that, despite HIV-1-induced phenotypic and functional B cell dysregulation in the peripheral blood and secondary lymphoid tissues, bone marrow plasma cells remain a primary source for circulating HIV-1-specific Abs in HIV-1-infected individuals.

  15. The HIV-1 antisense protein (ASP) induces CD8 T cell responses during chronic infection.

    Science.gov (United States)

    Bet, Anne; Maze, Emmanuel Atangana; Bansal, Anju; Sterrett, Sarah; Gross, Antoine; Graff-Dubois, Stéphanie; Samri, Assia; Guihot, Amélie; Katlama, Christine; Theodorou, Ioannis; Mesnard, Jean-Michel; Moris, Arnaud; Goepfert, Paul A; Cardinaud, Sylvain

    2015-02-10

    CD8+ T cells recognize HIV-1 epitopes translated from a gene's primary reading frame (F1) and any one of its five alternative reading frames (ARFs) in the forward (F2, F3) or reverse (R1-3) directions. The 3' end of HIV-1's proviral coding strand contains a conserved sequence that is directly overlapping but antiparallel to the env gene (ARF R2) and encodes for a putative antisense HIV-1 protein called ASP. ASP expression has been demonstrated in vitro using HIV-transfected cell lines or infected cells. Although antibodies to ASP were previously detected in patient sera, T cell recognition of ASP-derived epitopes has not been evaluated. We therefore investigated the ex vivo and in vitro induction of ASP-specific T cell responses as a measure of immune recognition and protein expression during HIV-1 infection. A panel of overlapping peptides was initially designed from the full-length ASP sequence to perform a global assessment of T cell responses. Recognition of ASP-derived antigens was evaluated in an IFN-γELISpot assay using PBMCs from HIV-1 seropositive and seronegative individuals. Eight of 25 patients had positive responses to ASP antigens and none of the seronegative donors responded. As a complimentary approach, a second set of antigens was designed using HLA-I binding motifs and affinities. Two ASP-derived peptides with high predicted binding affinities for HLA-A*02 (ASP-YL9) and HLA-B*07 (ASP-TL10) were tested using PBMCs from HIV-1 seropositive and seronegative individuals who expressed the matching HLA-I-restricting allele. We found that HLA-I-restricted ASP peptides were only recognized by CD8+ T cells from patients with the relevant HLA-I and did not induce responses in any of the seronegative donors or patients who do not express the restrictive HLA alleles. Further, ASP-YL9-specific CD8+ T cells had functional profiles that were similar to a previously described HLA-A*02-restricted epitope (Gag-SL9). Specific recognition of ASP-YL9 by CD8+ T cells

  16. Darunavir Concentrations in Cerebrospinal Fluid and Blood in HIV-1Infected Individuals

    OpenAIRE

    Yilmaz, Aylin; Izadkhashti, Arash; Price, Richard W.; Mallon, Patrick W.; De Meulder, Marc; Timmerman, Philip; Gisslén, Magnus

    2009-01-01

    Darunavir is the most recently licensed protease inhibitor currently used in treatment-experienced HIV-infected individuals. Our objective was to determine darunavir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing ritonavir-boosted darunavir. Darunavir concentrations were determined by liquid chromatography tandem mass spectrometry in 14 paired CSF and plasma samples from eight HIV-1-infected individuals. The lower limi...

  17. IL-23 in Infections, Inflammation, Autoimmunity and Cancer: Possible Role in HIV-1 and AIDS

    OpenAIRE

    Yannam, Govardhana Rao; Gutti, Tanuja; Poluektova, Larisa Y.

    2011-01-01

    The growing family of interleukin (IL)-12-like cytokines produced by activated macrophages and dendritic cells became the important players in the control of infections, development of inflammation, autoimmunity and cancer. However, the role of one of them—heterodimer IL-23, which consists of IL12p40 and the unique p19 subunit in HIV-1 infection pathogenesis and progression to AIDS, represent special interest. We overviewed findings of IL-23 involvement in control of peripheral bacterial path...

  18. Antigen-presenting cells represent targets for R5 HIV-1 infection in the first trimester pregnancy uterine mucosa.

    Directory of Open Access Journals (Sweden)

    Romain Marlin

    Full Text Available BACKGROUND: During the first trimester of pregnancy, HIV-1 mother-to-child transmission is relatively rare despite the permissivity of placental cells to cell-to-cell HIV-1 infection. The placenta interacts directly with maternal uterine cells (decidual cells but the physiological role of the decidua in the control of HIV-1 transmission and whether decidua could be a source of infected cells is unknown. METHODOLOGY/PRINCIPAL FINDINGS: To answer to this question, decidual mononuclear cells were exposed to HIV-1 in vitro. Decidual cells were shown to be more susceptible to infection by an R5 HIV-1, as compared to an X4 HIV-1. Infected cells were identified by flow cytometry analysis. The results showed that CD14(+ cells were the main targets of HIV-1 infection in the decidua. These infected CD14(+ cells expressed DC-SIGN, CD11b, CD11c, the Fc gamma receptor CD16, CD32 and CD64, classical MHC class-I and class-II and maturation and activation molecules CD83, CD80 and CD86. The permissivity of decidual tissue was also evaluated by histoculture. Decidual tissue was not infected by X4 HIV-1 but was permissive to R5 HIV-1. Different profiles of infection were observed depending on tissue localization. CONCLUSIONS/SIGNIFICANCE: The presence of HIV-1 target cells in the decidua in vitro and the low rate of in utero mother-to-child transmission during the first trimester of pregnancy suggest that a natural control occurs in vivo limiting cell-to-cell infection of the placenta and consequently infection of the fetus.

  19. KIF5B and Nup358 Cooperatively Mediate the Nuclear Import of HIV-1 during Infection.

    Directory of Open Access Journals (Sweden)

    Adarsh Dharan

    2016-06-01

    Full Text Available Following envelope mediated fusion, the HIV-1 core is released into the cytoplasm of the target cell and undergoes a series of trafficking and replicative steps that result in the nuclear import of the viral genome, which ultimately leads to the integration of the proviral DNA into the host cell genome. Previous studies have found that disruption of microtubules, or depletion of dynein or kinesin motors, perturb the normal uncoating and trafficking of the viral genome. Here, we show that the Kinesin-1 motor, KIF5B, induces a relocalization of the nuclear pore component Nup358 into the cytoplasm during HIV-1 infection. This relocalization of NUP358 is dependent on HIV-1 capsid, and NUP358 directly associates with viral cores following cytoplasmic translocation. This interaction between NUP358 and the HIV-1 core is dependent on multiple capsid binding surfaces, as this association is not observed following infection with capsid mutants in which a conserved hydrophobic binding pocket (N74D or the cyclophilin A binding loop (P90A is disrupted. KIF5B knockdown also prevents the nuclear entry and infection by HIV-1, but does not exert a similar effect on the N74D or P90A capsid mutants which do not rely on Nup358 for nuclear import. Finally, we observe that the relocalization of Nup358 in response to CA is dependent on cleavage protein and polyadenylation factor 6 (CPSF6, but independent of cyclophilin A. Collectively, these observations identify a previously unappreciated role for KIF5B in mediating the Nup358 dependent nuclear import of the viral genome during infection.

  20. Chemokine control of HIV-1 infection: Beyond a binding competition

    Directory of Open Access Journals (Sweden)

    Wu Yuntao

    2010-10-01

    Full Text Available Abstract A recent paper by Cameron et al. demonstrated that certain chemokines such as CCL19 activate cofilin and actin dynamics, promoting HIV nuclear localization and integration into resting CD4 T cells. Apparently, these chomokines synergize with the viral envelope protein, triggering cofilin and actin dynamics necessary for the establishment of viral latency. This study opens a new avenue for understanding chemokine interaction with HIV. Traditionally, chemokine control of HIV infection focuses on competitive binding and down-modulation of the corecptors, particularly CCR5. This new study suggests that a diverse group of chemokines may also affect HIV infection through synergistic or antagonistic interaction with the viral coreceptor signaling pathways.

  1. Recombinant viruses initiated the early HIV-1 epidemic in Burkina Faso.

    Directory of Open Access Journals (Sweden)

    Peter N Fonjungo

    Full Text Available We analyzed genetic diversity and phylogenetic relationships among 124 HIV-1 and 19 HIV-2 strains in sera collected in 1986 from patients of the state hospital in Ouagadougou, Burkina Faso. Phylogenetic analysis of the HIV-1 env gp41 region of 65 sequences characterized 37 (56.9% as CRF06_cpx strains, 25 (38.5% as CRF02_AG, 2 (3.1% as CRF09_cpx, and 1 (1.5% as subtype A. Similarly, phylogenetic analysis of the protease (PR gene region of 73 sequences identified 52 (71.2% as CRF06_cpx, 15 (20.5% as CRF02_AG, 5 (6.8% as subtype A, and 1 (1.4% was a unique strain that clustered along the B/D lineage but basal to the node connecting the two lineages. HIV-2 PR or integrase (INT groups A (n = 17 [89.5%] and B (n = 2 [10.5%] were found in both monotypic (n = 11 and heterotypic HIV-1/HIV-2 (n = 8 infections, with few HIV-2 group B infections. Based on limited available sampling, evidence suggests two recombinant viruses, CRF06_cpx and CRF02_AG, appear to have driven the beginning of the mid-1980s HIV-1 epidemic in Burkina Faso.

  2. Unique and differential protein signatures within the mononuclear cells of HIV-1 and HCV mono-infected and co-infected patients

    OpenAIRE

    Boukli Nawal M; Shetty Vivekananda; Cubano Luis; Ricaurte Martha; Coelho-dos-Reis Jordana; Nickens Zacharie; Shah Punit; Talal Andrew H; Philip Ramila; Jain Pooja

    2012-01-01

    Abstract Background Pathogenesis of liver damage in patients with HIV and HCV co-infection is complex and multifactorial. Although global awareness regarding HIV-1/HCV co-infection is increasing little is known about the pathophysiology that mediates the rapid progression to hepatic disease in the co-infected individuals. Results In this study, we investigated the proteome profiles of peripheral blood mononuclear cells from HIV-1 mono-, HCV mono-, and HIV-1/HCV co-infected patients. The resul...

  3. Quantification of infectious HIV-1 plasma viral load using a boosted in vitro infection protocol.

    Science.gov (United States)

    Rusert, Peter; Fischer, Marek; Joos, Beda; Leemann, Christine; Kuster, Herbert; Flepp, Markus; Bonhoeffer, Sebastian; Günthard, Huldrych F; Trkola, Alexandra

    2004-08-15

    Methods currently used for HIV-1 viral load measurements are very sensitive, but cannot distinguish between infectious and noninfectious particles. Here we describe the development of a novel, sensitive, and highly reproducible method that allows rapid isolation and quantification of infectious particles from patient plasma. By immobilizing HIV-1 particles in human plasma to platelets using polybrene, we observed a 10- to 1000-fold increase in infectivity over infection protocols using free virus particles. Using this method, we evaluated infectivity in plasma from 52 patients at various disease stages. At plasma viral loads of 1000-10000 HIV-1 RNA copies/ml 18%, at 10,000-50,000 copies/ml 73%, at 50,000-100,000 copies/ml 90%, and above 100,000 copies 96% of cultures were positive. We found that infectious titers among patients vary distinctively but are characteristic for a patient over extended time periods. Furthermore, we demonstrate that by evaluating infectious titers in conjunction with total HIV RNA loads, subtle effects of treatment intervention on viremia levels can be detected. The immobilization procedure does not interfere with viral entry and does not restore the infectivity of neutralized virus. Therefore, this assay system can be utilized to investigate the influence of substances that specifically affect virion infectivity such as neutralizing antibodies, soluble CD4, or protease inhibitors. Measuring viral infectivity may thereby function as an additional, useful marker in monitoring disease progression and evaluating efficacy of antivirals in vivo.

  4. HIV-1 Trans Infection of CD4+ T Cells by Professional Antigen Presenting Cells

    Directory of Open Access Journals (Sweden)

    Charles R. Rinaldo

    2013-01-01

    Full Text Available Since the 1990s we have known of the fascinating ability of a complex set of professional antigen presenting cells (APCs; dendritic cells, monocytes/macrophages, and B lymphocytes to mediate HIV-1 trans infection of CD4+ T cells. This results in a burst of virus replication in the T cells that is much greater than that resulting from direct, cis infection of either APC or T cells, or trans infection between T cells. Such APC-to-T cell trans infection first involves a complex set of virus subtype, attachment, entry, and replication patterns that have many similarities among APC, as well as distinct differences related to virus receptors, intracellular trafficking, and productive and nonproductive replication pathways. The end result is that HIV-1 can sequester within the APC for several days and be transmitted via membrane extensions intracellularly and extracellularly to T cells across the virologic synapse. Virus replication requires activated T cells that can develop concurrently with the events of virus transmission. Further research is essential to fill the many gaps in our understanding of these trans infection processes and their role in natural HIV-1 infection.

  5. Variable patterns of neuropsychological performance in HIV-1 infection.

    Science.gov (United States)

    Dawes, S; Suarez, P; Casey, C Y; Cherner, M; Marcotte, T D; Letendre, S; Grant, I; Heaton, R K

    2008-08-01

    Based upon prior findings with group means, a "prototypical pattern" of neuropsychological results with HIV infection has emerged: impaired executive functioning, motor skills, speed of information processing, and learning, with intact memory retention, most language skills, and visuospatial functioning. We examined neuropsychological results from 553 HIV+ adults to determine the number of patterns seen among individuals with HIV infection. Factor analysis of a relatively comprehensive neuropsychological battery identified 6 component factors: verbal memory (VeM), visual memory (ViM), processing speed (PS), attention/working memory (A/WM), executive function (EF), and motor (M). These factor scores were submitted to hierarchical cluster analysis, to determine the appropriate number of clusters or patterns in the cohort. Final cluster membership was then determined by K-means analysis, based on the Lange, Iverson, Senior, and Chelune (2002) method. A 6-cluster solution was found to be most appropriate. The definitions of the clusters were based upon ipsative scoring of factor scores to indicate relative strengths and weaknesses (independent of overall level of performance): Cluster 1: strong EF; Cluster 2: strong M, weak VeM and EF; Cluster 3: strong PS, weak ViM and EF; Cluster 4: strong VeM, weak M; Cluster 5: strong A/WM; Cluster 6: strong VeM, weak EF. Neuropsychological-impairment rates differed across clusters, but all 6 clusters contained substantial numbers of impaired and unimpaired individuals. Cluster membership was not explained by demographic variables or psychiatric or neuromedical confounds. Thus, there does not appear to be a single, prototypical pattern of neuropsychological impairment associated with HIV infection for this battery of representative neuropsychological tests.

  6. Plasma proteomic profiling in HIV-1 infected methamphetamine abusers.

    Directory of Open Access Journals (Sweden)

    Gwenael Pottiez

    Full Text Available We wanted to determine whether methamphetamine use affects a subset of plasma proteins in HIV-infected persons. Plasma samples from two visits were identified for subjects from four groups: HIV+, ongoing, persistent METH use; HIV+, short-term METH abstinent; HIV+, long term METH abstinence; HIV negative, no history of METH use. Among 390 proteins identified, 28 showed significant changes in expression in the HIV+/persistent METH+ group over the two visits, which were not attributable to HIV itself. These proteins were involved in complement, coagulation pathways and oxidative stress. Continuous METH use is an unstable condition, altering levels of a number of plasma proteins.

  7. 三、四代酶联免疫吸附试验应用于HIV-1早期感染者的比较%The comparison of the performance between third generation ELISA and fourth generation ELISA on acute and early HIV infection

    Institute of Scientific and Technical Information of China (English)

    韩晓旭; 欧阳金鸣; 孙宏; 楚振兴; 徐俊杰; 安明晖; 赵彬; 杨志军; 尚红

    2012-01-01

    目的 评价三代ELISA及四代ELISA对于HIV早期感染血样的灵敏度、窗口期和一致率.方法 收集2008至2010年在沈阳市的男男同性恋人群随访中发现HIV抗体阳转及中国医科大学附属第一医院就诊患者中发现的蛋白印迹试验(WB)确认带型不全患者HIV早期感染者血浆67份,进行三代ELISA、四代ELISA、WB确认试验及HIV-1 RNA检测.比较三代ELISA、四代ELISA对阳转期标本的检测灵敏度、一致率并动态观察血清阳转过程分析窗口期.三代与四代ELISA试剂灵敏度比较卡方检验进行统计学分析.结果 67份早期HIV-1感染者血清标本中,三代ELISA检出56份阳性,11份阴性,灵敏度83.6%(95% CI72.5%~91.5%),四代ELISA检出63份阳性,1份灰区,3份阴性,灵敏度94.0%(95% CI 85.4%~98.3%),四代ELISA灵敏度高于三代ELISA(x2=16.1,P<0.01).三代ELISA与四代ELISA一致率86.6%(95% CI76.0%~93.7%).三代ELISA阳性者感染时间最早为16 d,四代ELISA阳性者感染时间最早为9d.三、四代ELISA窗口期存在明显的个体差异.结论 四代ELISA对于HIV早期感染标本的检测灵敏度明显高于三代ELISA,窗口期更短.四代ELISA更适用于高危人群中的HIV早期感染的筛查.%Objective To evaluate the performance of the third generation ELISA and the fourth generation ELISA for HIV-1 diagnosis assays on acute and early HIV-1 infected samples.Methods Sixtyseven acute/early HIV-1 infected samples were collected from the follow-up gays with seroconversion in Shen Yang city and from clinical patients in the First Affiliated Hospital of China Medical University with incomplete HIV-1 specific bands in western blot between 2008 and 2010.Third generation ELISA,fourth generation ELISA,western blot and HIV-1 viral load detecting were used for detecting these samples.The sensitivity,consistency were compared between third generation ELISA and fourth generation ELISA to detect the seroconversion

  8. Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection.

    Science.gov (United States)

    Mellgren, A; Price, R W; Hagberg, L; Rosengren, L; Brew, B J; Gisslén, M

    2007-10-09

    Increased levels of the light-chain neurofilament protein (NFL) in CSF provide a marker of CNS injury in several neurodegenerative disorders and have been reported in the AIDS dementia complex (ADC). We examined the effects of highly active antiretroviral treatment (HAART) on CSF NFL in HIV-1-infected subjects with and without ADC who underwent repeated lumbar punctures (LPs). NFL was measured by ELISA (normal reference value NFL at baseline, with a median level of 780 ng/L and an intraquartile range (IQR) of 480 to 7300. After 3 months of treatment, NFL concentrations had fallen to normal in 48% (10/21), and the median decreased to 340 ng/L (IQR NFL levels. Thirty-two subjects had normal NFL at baseline, and all but one remained normal at follow-up. These effects on CSF NFL were seen in association with clinical improvement in ADC patients, decreases in plasma and CSF HIV-1 RNA and CSF neopterin, and increases in blood CD4 T cell counts. HAART seems to halt the neurodegenerative process(es) caused by HIV-1, as shown by the significant decrease in CSF NFL after treatment initiation. CSF NFL may serve as a useful marker in monitoring CNS injury in HIV-1 infection and in evaluating CNS efficacy of antiretroviral therapy.

  9. High IP-10 levels decrease T cell function in HIV-1-infected individuals on ART

    Science.gov (United States)

    Ramirez, L. A.; Arango, T. A.; Thompson, E.; Naji, M.; Tebas, P.; Boyer, J. D.

    2014-01-01

    HIV-1-infected subjects, despite control of viral replication with ART, have an altered immune cytokine/chemokine milieu. Changes in systemic cytokines and chemokines can alter immune responses. IP-10, in particular, has been associated with pathogenesis in a number of conditions, and we found that IP-10 is increased in serum in subjects who are HIV-1 infected and on stable ART compared with HIV-1-uninfected individuals. In a series of in vitro studies, we found that PBMCs exposed to IP-10 showed a significant decrease in the number of cells capable of secreting IFN-γ, as well as other cytokines, when stimulated with recall antigens. Furthermore, treatment with IP-10 led to decreased antigen-specific calcium signaling and MAPK38 phosphorylation. Importantly, the cytokines, as well as proliferative responses, could be enhanced with an IP-10 Nab. Our findings suggest that IP-10-modulating drugs may potentially enhance T cell responses to vaccination and HIV-1 in HIV+ subjects on ART. PMID:25157027

  10. Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

    Science.gov (United States)

    Pensieroso, Simone; Cagigi, Alberto; Palma, Paolo; Nilsson, Anna; Capponi, Claudia; Freda, Elio; Bernardi, Stefania; Thorstensson, Rigmor; Chiodi, Francesca; Rossi, Paolo

    2009-01-01

    HIV-1 infection induces a progressive disruption of the B cell compartment impairing long-term immune responses to routine immunizations. Depletion of specific memory B cell pools occurs during the 1st stages of the infection and cannot be reestablished by antiretroviral treatment. We reasoned that an early control of viral replication through treatment could preserve the normal development of the memory B cell compartment and responses to routine childhood vaccines. Accordingly, we evaluated the effects of different highly-active antiretroviral therapy (HAART) schedules in 70 HIV-1 vertically-infected pediatric subjects by B cell phenotypic analyses, antigen-specific B cell enzyme-linked immunosorbent spot (ELISpot) and ELISA for common vaccination and HIV-1 antigens. Initiation of HAART within the 1st year of life permits the normal development and maintenance of the memory B cell compartment. On the contrary, memory B cells from patients treated later in time are remarkably reduced and their function is compromised regardless of viral control. A cause for concern is that both late-treated HIV-1 controllers and noncontrollers loose protective antibody titers against common vaccination antigens. Timing of HAART initiation is the major factor predicting the longevity of B cell responses in vaccinated HIV-1-infected children. PMID:19416836

  11. CD4:CD8 Lymphocyte Ratio as a Quantitative Measure of Immunologic Health in HIV-1 Infection: Findings from an African Cohort with Prospective Data

    Directory of Open Access Journals (Sweden)

    Jianming eTang

    2015-07-01

    Full Text Available In individuals with human immunodeficiency virus type 1 (HIV-1 infection, CD4:CD8 lymphocyte ratio is often recognized as a quantitative outcome that reflects the critical role of both CD4+ and CD8+ T-cells in HIV-1 pathogenesis or disease progression. Our work aimed to first establish the dynamics and clinical relevance of CD4:CD8 ratio in a cohort of native Africans and then to examine its association with viral and host factors, including: (i length of infection, (ii demographics, (iii HIV-1 viral load (VL, (iv change in CD4+ T-lymphocyte count (CD4 slope, (v HIV-1 subtype, and (vi host genetics, especially human leukocyte antigen (HLA variants. Data from 499 HIV-1 seroconverters with frequent (monthly to quarterly follow-up revealed that CD4:CD8 ratio was stable in the first three years of infection, with a modest correlation with VL and CD4 slope. A relatively normal CD4:CD8 ratio (>1.0 in early infection was associated with a substantial delay in disease progression to severe immunodeficiency (1.0, but HLA variants (e.g., HLA-B*57 and HLA-B*81 previously associated with VL and/or CD4 trajectories in eastern and southern Africans had no obvious impact on CD4:CD8 ratio. Collectively, these findings suggest that CD4:CD8 ratio is a robust measure of immunologic health with both clinical and epidemiological implications.

  12. Prevalence of maternal HIV-1 infection in Thames regions: results from anonymous unlinked neonatal testing.

    Science.gov (United States)

    Ades, A E; Parker, S; Berry, T; Holland, F J; Davison, C F; Cubitt, D; Hjelm, M; Wilcox, A H; Hudson, C N; Briggs, M

    1991-06-29

    To monitor the spread of human immunodeficiency virus (HIV) in the heterosexual population, residues of blood samples collected routinely on absorbent paper for neonatal screening (Guthrie cards) in NE, NW, and SW Thames Regions in England have been tested for antibodies to HIV-1 since June, 1988. 323,369 dried blood spots were analysed to end March, 1991. Prevalence of anti-HIV-1 in newborn babies has remained stable in outer London and non-metropolitan districts whereas prevalence in inner London has increased from 1 in 2000 in the 12 months beginning June, 1988, to 1 in 500 in the first 3 months of 1991. Either exponential or linear growth in the numbers of new seropositives could account for the results. That obstetricians were aware of maternal HIV infection in only 20% of infected pregnancies, indicates the extent to which HIV infection goes unrecognised in the heterosexual community.

  13. Temporal expression of HIV-1 envelope proteins in baculovirus-infected insect cells: Implications for glycosylation and CD4 binding

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, C.I.; Lennick, M.; Lehar, S.M.; Beltz, G.A.; Young, E. (Cambridge Bioscience Corporation, Worcester, MA (USA))

    1990-10-01

    Three different human immunodeficiency virus type I (HIV-1) envelope derived recombinant proteins and the full length human CD4 polypeptide were expressed in Spodoptera frugiperda (Sf9) cells. DNA constructs encoding CD4, gp120, gp160, and gp160 delta were cloned into the baculovirus expression vector pVL941 or a derivative and used to generate recombinant viruses in a cotransfection with DNA from Autographa californica nuclear polyhedrosis virus (AcMNPV). Western blotting of cell extracts of the recombinant HIV-1 proteins showed that for each construct two major bands specifically reacted with anti-HIV-1 envelope antiserum. These bands corresponded to glycosylated and nonglycosylated versions of the HIV proteins as determined by 3H-mannose labeling and tunicamycin treatment of infected cells. A time course of HIV envelope expression revealed that at early times post-infection (24 hours) the proteins were fully glycosylated and soluble in nonionic detergents. However, at later times postinfection (48 hours), expression levels of recombinant protein reached a maximum but most of the increase was due to a rise in the level of the nonglycosylated species, which was largely insoluble in nonionic detergents. Thus, it appears that Sf9 cells cannot process large amounts of glycosylated recombinant proteins efficiently. As a measure of biological activity, the CD4 binding ability of both glycosylated and nonglycosylated recombinant HIV envelope proteins was tested in a coimmunoprecipitation assay. The results showed that CD4 and the glycosylated versions of recombinant gp120 or gp160 delta specifically associated with one another in this analysis. Nonglycosylated gp120 or gp160 delta proteins from tunicamycin-treated cultures did immunoprecipitate with anti-HIV-1 antiserum but did not interact with CD4.

  14. HLA-associated susceptibility to HIV-1 infection.

    Science.gov (United States)

    Fabio, G; Scorza, R; Lazzarin, A; Marchini, M; Zarantonello, M; D'Arminio, A; Marchisio, P; Plebani, A; Luzzati, R; Costigliola, P

    1992-01-01

    We studied HLA antigen distribution of 50 heterosexual partners of HIV+ drug abusers with more than 1 year of sexual exposure to HIV, 36 children born to seropositive mothers and 61 haemophiliac patients exposed to presumably infectious clotting factor concentrates. B52 and B44 antigens were associated with HIV resistance while B51 was associated with HIV susceptibility. Forty-nine HIV+ drug abusers, spouses of heterosexual partners studied and 25 HIV+ mothers of the children were also typed. DR11 phenotype was associated with infectiousness of HIV+ subjects. Our data suggest that the HLA region controls susceptibility to infection with HIV and infectiousness of HIV+ subjects in different risk groups. PMID:1733633

  15. HIV-1 DNA vaccine with adjuvant cytokines induces specific immune responses against HIV-1 infection in mice

    Institute of Scientific and Technical Information of China (English)

    WANG Fu-xiang; SUN Yong-tao; WANG Lin-xu; LIU Juan

    2006-01-01

    @@ There is mounting evidence that the induction of strong mucosal and cell-mediated immune responses is key element to consider in constructing efficacious HIV-1 vaccine. Therapeutic vaccines that induce high levels of CTL specific to HIV are currently being developed worldwide.

  16. Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes.

    Directory of Open Access Journals (Sweden)

    David R Collins

    2015-07-01

    Full Text Available Vpr is a conserved primate lentiviral protein that promotes infection of T lymphocytes in vivo by an unknown mechanism. Here we demonstrate that Vpr and its cellular co-factor, DCAF1, are necessary for efficient cell-to-cell spread of HIV-1 from macrophages to CD4+ T lymphocytes when there is inadequate cell-free virus to support direct T lymphocyte infection. Remarkably, Vpr functioned to counteract a macrophage-specific intrinsic antiviral pathway that targeted Env-containing virions to LAMP1+ lysosomal compartments. This restriction of Env also impaired virological synapses formed through interactions between HIV-1 Env on infected macrophages and CD4 on T lymphocytes. Treatment of infected macrophages with exogenous interferon-alpha induced virion degradation and blocked synapse formation, overcoming the effects of Vpr. These results provide a mechanism that helps explain the in vivo requirement for Vpr and suggests that a macrophage-dependent stage of HIV-1 infection drives the evolutionary conservation of Vpr.

  17. Human papillomavirus infection in oral fluids of HIV-1-positive men: prevalence and risk factors.

    Science.gov (United States)

    Gaester, Karen; Fonseca, Luiz A M; Luiz, Olinda; Assone, Tatiane; Fontes, Adriele Souza; Costa, Fernando; Duarte, Alberto J S; Casseb, Jorge

    2014-10-17

    Human papillomavirus is one of the most common sexually transmitted diseases worldwide. The natural history of oral HPV infection is unclear, and its risk factors have not been explored. Immunocompromised individuals, as exemplified by HIV patients, are at high risk for HPV-related diseases. The mean of this study is to determine the prevalence of HPV in the oral tract of HIV-1-positive male subjects and its association with risk factors. A total of 283 oral wash samples from HIV-1-positive men were tested. The oral fluid samples were used for DNA extraction and conventional PCR amplification; HPV genotyping was performed by hybridization. HPV genotyping revealed that nine samples (3.5%) were positive for HPV DNA; the major high-risk HPV types identified were 51 and 66. Worldwide studies have shown a variable prevalence of oral HPV. The diversity of genotypes and the high prevalence of multiple infections in HIV-infected subjects can be better explained by the effects of HIV-induced immunosuppression. The most important risk factors are unprotected sexual intercourse, but other factors for this infection have been described elsewhere including smoking, age and HIV-positive serostatus. In this study, smoking was the most important risk factor for acquiring oral HPV in HIV-1-infected subjects in Brazil.

  18. Human Papillomavirus Infection in HIV-1 Infected Women in Catalonia (Spain): Implications for Prevention of Cervical Cancer

    Science.gov (United States)

    Stuardo, Valeria; Agustí, Cristina; Godinez, José Manuel; Montoliu, Alexandra; Torné, Aureli; Tarrats, Antoni; Alcalde, Carmen; Martín, Dolores; Fernández-Montoli, Eulalia; Vanrell, Cristina; Solé, Josefa; Canet, Yolanda; Marqueta, José Manuel; Mohamed, Jadiyettu; Cuenca, Isabel; Lonca, Montserrat; Sirera, Guillem; Ferrer, Elena; Domingo, Pere; Lloveras, Belen; Miro, Josep María; De Sanjosé, Silvia; Casabona, Jordi

    2012-01-01

    Background High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women. Methods We enrolled 479 HIV-1infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis. Results Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age 500cells/mm3 (OR,8.4; 95%CI,3.7–19.2), HIV-1 viral load >10,000copies/mL versus <400copies/mL (OR,2.1; 95%CI,1.0–4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0–3.9). Sixty percent of HIV-1infected women had had one Pap smear within the last 2 years. Conclusions The high prevalence of HPV infection and cervical lesions in the HIV-1infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1infected women. PMID:23118894

  19. Quantifying Susceptibility of CD4+ Stem Memory T-Cells to Infection by Laboratory Adapted and Clinical HIV-1 Strains

    Directory of Open Access Journals (Sweden)

    Jacqueline K. Flynn

    2014-02-01

    Full Text Available CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1 infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4+ T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV reservoir. Using green fluorescent protein (GFP reporter strains of HIV-1 and multi parameter flow cytometry, we developed an assay to simultaneously quantify the susceptibility of stem memory (TSCM, central memory, effector memory, transitional memory and naïve CD4+ T cell subsets, to HIV-1 infection in vitro. We show that TSCM are susceptible to infection with laboratory adapted and clinical HIV-1 strains. Our system facilitates the quantitation of HIV-1 infection in alternative T cell subsets by CCR5- and CXCR4-using viruses across different HIV-1 subtypes, and will be useful for studies of HIV-1 pathogenesis and viral reservoirs.

  20. Quantifying susceptibility of CD4+ stem memory T-cells to infection by laboratory adapted and clinical HIV-1 strains.

    Science.gov (United States)

    Flynn, Jacqueline K; Paukovics, Geza; Cashin, Kieran; Borm, Katharina; Ellett, Anne; Roche, Michael; Jakobsen, Martin R; Churchill, Melissa J; Gorry, Paul R

    2014-02-10

    CD4+ T cells are principal targets for human immunodeficiency virus type 1 (HIV-1) infection. CD4+ T cell subsets are heterogeneous cell populations, divided by functional and phenotypic differences into naïve and memory T cells. The memory CD4+ T cells are further segregated into central, effector and transitional memory cell subsets by functional, phenotypic and homeostatic characteristics. Defining the distribution of HIV-1 infection in different T cell subsets is important, as this can play a role in determining the size and composition of the viral reservoir. Both central memory and transitional memory CD4+ T cells have been described as long-lived viral reservoirs for HIV. Recently, the newly described stem memory T cell subset has also been implicated as a long-lived HIV reservoir. Using green fluorescent protein (GFP) reporter strains of HIV-1 and multi parameter flow cytometry, we developed an assay to simultaneously quantify the susceptibility of stem memory (TSCM), central memory, effector memory, transitional memory and naïve CD4+ T cell subsets, to HIV-1 infection in vitro. We show that TSCM are susceptible to infection with laboratory adapted and clinical HIV-1 strains. Our system facilitates the quantitation of HIV-1 infection in alternative T cell subsets by CCR5- and CXCR4-using viruses across different HIV-1 subtypes, and will be useful for studies of HIV-1 pathogenesis and viral reservoirs.

  1. Human papillomavirus infection in HIV-1 infected women in Catalonia (Spain): implications for prevention of cervical cancer.

    Science.gov (United States)

    Stuardo, Valeria; Agustí, Cristina; Godinez, José Manuel; Montoliu, Alexandra; Torné, Aureli; Tarrats, Antoni; Alcalde, Carmen; Martín, Dolores; Fernández-Montoli, Eulalia; Vanrell, Cristina; Solé, Josefa; Canet, Yolanda; Marqueta, José Manuel; Mohamed, Jadiyettu; Cuenca, Isabel; Lonca, Montserrat; Sirera, Guillem; Ferrer, Elena; Domingo, Pere; Lloveras, Belen; Miro, Josep María; De Sanjosé, Silvia; Casabona, Jordi

    2012-01-01

    High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women. We enrolled 479 HIV-1-infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis. Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age 500 cells/mm(3) (OR,8.4; 95%CI,3.7-19.2), HIV-1 viral load >10,000 copies/mL versus Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1-infected women.

  2. Productive HIV-1 infection is enriched in CD4(-)CD8(-) double negative (DN) T cells at pleural sites of dual infection with HIV and Mycobacterium tuberculosis.

    Science.gov (United States)

    Meng, Qinglai; Canaday, David H; McDonald, David J; Mayanja-Kizza, Harriet; Baseke, Joy; Toossi, Zahra

    2016-01-01

    A higher human immunodeficiency virus 1 (HIV-1) viral load at pleural sites infected with Mycobacterium tuberculosis (MTB) than in peripheral blood has been documented. However, the cellular source of productive HIV infection in HIV-1/MTB-coinfected pleural fluid mononuclear cells (PFMCs) remains unclear. In this study, we observed significant quantities of HIV-1 p24(+) lymphocytes in PFMCs, but not in peripheral blood mononuclear cells (PBMCs). HIV-1 p24(+) lymphocytes were mostly enriched in DN T cells. Intracellular CD4 expression was detectable in HIV-1 p24(+) DN T cells. HIV-1 p24(+) DN T cells showed lower surface expression of human leukocyte antigen (HLA)-ABC and tetherin than did HIV-1 p24(+) CD4 T cells. Upon in vitro infection of PFMC CD4 T cells from TB mono-infected subjects, Nef- and/or Vpu-deleted HIV mutants showed lower generation of HIV-1 p24(+) DN T cells than the wild-type virus. These data indicate that productively HIV-1-infected DN T cells, generated through down-modulation of surface CD4, likely by HIV-1 Nef and Vpu, are the predominant source of HIV-1 at pleural sites of HIV/MTB coinfection.

  3. Low level of regulatory T cells and maintenance of balance between regulatory T cells and TH17 cells in HIV-1-infected elite controllers

    DEFF Research Database (Denmark)

    Brandt, Lea; Benfield, Thomas Lars; Mens, Helene

    2011-01-01

    A subgroup of HIV-1-infected individuals, elite controllers, have spontaneous viral control and offer an exceptional opportunity to study virological and immunolocigal factors of possible involvement in control of HIV-1 infection....

  4. Comparative expression profile of miRNA and mRNA in primary peripheral blood mononuclear cells infected with human immunodeficiency virus (HIV-1.

    Directory of Open Access Journals (Sweden)

    Ankit Gupta

    Full Text Available Host cells respond to exogenous infectious agents such as viruses, including HIV-1. Studies have evaluated the changes associated with virus infection at the transcriptional and translational levels of the cellular genes involved in specific pathways. While this approach is useful, in our view it provides only a partial view of genome-wide changes. Recently, technological advances in the expression profiling at the microRNA (miRNA and mRNA levels have made it possible to evaluate the changes in the components of multiple pathways. To understand the role of miRNA and its interplay with host cellular gene expression (mRNA during HIV-1 infection, we performed a comparative global miRNA and mRNA microarray using human PBMCs infected with HIV-1. The PBMCs were derived from multiple donors and were infected with virus generated from the molecular clone pNL4-3. The results showed that HIV-1 infection led to altered regulation of 21 miRNAs and 444 mRNA more than 2-fold, with a statistical significance of p<0.05. Furthermore, the differentially regulated miRNA and mRNA were shown to be associated with host cellular pathways involved in cell cycle/proliferation, apoptosis, T-cell signaling, and immune activation. We also observed a number of inverse correlations of miRNA and mRNA expression in infected PBMCs, further confirming the interrelationship between miRNA and mRNA regulation during HIV-1 infection. These results for the first time provide evidence that the miRNA profile could be an early indicator of host cellular dysfunction induced by HIV-1.

  5. Primary T-cells from human CD4/CCR5-transgenic rats support all early steps of HIV-1 replication including integration, but display impaired viral gene expression

    Directory of Open Access Journals (Sweden)

    Hermann Volker

    2007-07-01

    Full Text Available Abstract Background In vivo studies on HIV-1 pathogenesis and testing of antiviral strategies have been hampered by the lack of an immunocompetent small animal model that is highly susceptible to HIV-1 infection. Since native rodents are non-permissive, we developed transgenic rats that selectively express the HIV-1 receptor complex, hCD4 and hCCR5, on relevant target cells. These animals display a transient low-level plasma viremia after HIV-1YU-2 infection, demonstrating HIV-1 susceptibility in vivo. However, unlike macrophages, primary CD4 T-cells from double-transgenic animals fail to support viral spread ex vivo. To identify quantitative limitations or absolute blocks in this rodent species, we quantitatively assessed the efficiency of key steps in the early phase of the viral replication cycle in a side-by-side comparison in infected cell lines and primary T-cells from hCD4/hCCR5-transgenic rats and human donors. Results Levels of virus entry, HIV-1 cDNA synthesis, nuclear import, and integration into the host genome were shown to be remarkably similar in cell lines and, where technically accessible, in primary T-cells from both species. In contrast, a profound impairment at the level of early HIV gene expression was disclosed at the single-cell level in primary rat T-cells and most other rat-derived cells. Macrophages were a notable exception, possibly reflecting the unique transcriptional milieu in this evolutionarily conserved target cell of all lentiviruses. Importantly, transient trans-complementation by ex vivo nucleofection with the Tat-interacting protein Cyclin T1 of human origin markedly elevated HIV gene expression in primary rat T-cells. Conclusion This is the first study that has quantitatively determined the efficiency of consecutive steps in the HIV-1 replication cycle in infected primary HIV target cells from a candidate transgenic small animal and compared it to human cells. Unlike cells derived from mice or rabbits, rat

  6. HIV-1 vaccine-induced T-cell responses cluster in epitope hotspots that differ from those induced in natural infection with HIV-1.

    Directory of Open Access Journals (Sweden)

    Tomer Hertz

    Full Text Available Several recent large clinical trials evaluated HIV vaccine candidates that were based on recombinant adenovirus serotype 5 (rAd-5 vectors expressing HIV-derived antigens. These vaccines primarily elicited T-cell responses, which are known to be critical for controlling HIV infection. In the current study, we present a meta-analysis of epitope mapping data from 177 participants in three clinical trials that tested two different HIV vaccines: MRKAd-5 HIV and VRC-HIVAD014-00VP. We characterized the population-level epitope responses in these trials by generating population-based epitope maps, and also designed such maps using a large cohort of 372 naturally infected individuals. We used these maps to address several questions: (1 Are vaccine-induced responses randomly distributed across vaccine inserts, or do they cluster into immunodominant epitope hotspots? (2 Are the immunodominance patterns observed for these two vaccines in three vaccine trials different from one another? (3 Do vaccine-induced hotspots overlap with epitope hotspots induced by chronic natural infection with HIV-1? (4 Do immunodominant hotspots target evolutionarily conserved regions of the HIV genome? (5 Can epitope prediction methods be used to identify these hotspots? We found that vaccine responses clustered into epitope hotspots in all three vaccine trials and some of these hotspots were not observed in chronic natural infection. We also found significant differences between the immunodominance patterns generated in each trial, even comparing two trials that tested the same vaccine in different populations. Some of the vaccine-induced immunodominant hotspots were located in highly variable regions of the HIV genome, and this was more evident for the MRKAd-5 HIV vaccine. Finally, we found that epitope prediction methods can partially predict the location of vaccine-induced epitope hotspots. Our findings have implications for vaccine design and suggest a framework by which

  7. Amebiasis in HIV-1-Infected Japanese Men: Clinical Features and Response to Therapy

    Science.gov (United States)

    Watanabe, Koji; Gatanaga, Hiroyuki; Cadiz, Aleyla Escueta-de; Tanuma, Junko; Nozaki, Tomoyoshi; Oka, Shinichi

    2011-01-01

    Invasive amebic diseases caused by Entamoeba histolytica are increasing among men who have sex with men and co-infection of ameba and HIV-1 is an emerging problem in developed East Asian countries. To characterize the clinical and epidemiological features of invasive amebiasis in HIV-1 patients, the medical records of 170 co-infected cases were analyzed retrospectively, and E. histolytica genotype was assayed in 14 cases. In this series of HIV-1-infected patients, clinical presentation of invasive amebiasis was similar to that described in the normal host. High fever, leukocytosis and high CRP were associated with extraluminal amebic diseases. Two cases died from amebic colitis (resulting in intestinal perforation in one and gastrointestinal bleeding in one), and three cases died from causes unrelated to amebiasis. Treatment with metronidazole or tinidazole was successful in the other 165 cases. Luminal treatment was provided to 83 patients following metronidazole or tinidazole treatment. However, amebiasis recurred in 6 of these, a frequency similar to that seen in patients who did not receive luminal treatment. Recurrence was more frequent in HCV-antibody positive individuals and those who acquired syphilis during the follow-up period. Various genotypes of E. histolytica were identified in 14 patients but there was no correlation between genotype and clinical features. The outcome of metronidazole and tinidazole treatment of uncomplicated amebiasis was excellent even in HIV-1-infected individuals. Luminal treatment following metronidazole or tinidazole treatment does not reduce recurrence of amebiasis in high risk populations probably due to amebic re-infection. PMID:21931875

  8. Amebiasis in HIV-1-infected Japanese men: clinical features and response to therapy.

    Directory of Open Access Journals (Sweden)

    Koji Watanabe

    2011-09-01

    Full Text Available Invasive amebic diseases caused by Entamoeba histolytica are increasing among men who have sex with men and co-infection of ameba and HIV-1 is an emerging problem in developed East Asian countries. To characterize the clinical and epidemiological features of invasive amebiasis in HIV-1 patients, the medical records of 170 co-infected cases were analyzed retrospectively, and E. histolytica genotype was assayed in 14 cases. In this series of HIV-1-infected patients, clinical presentation of invasive amebiasis was similar to that described in the normal host. High fever, leukocytosis and high CRP were associated with extraluminal amebic diseases. Two cases died from amebic colitis (resulting in intestinal perforation in one and gastrointestinal bleeding in one, and three cases died from causes unrelated to amebiasis. Treatment with metronidazole or tinidazole was successful in the other 165 cases. Luminal treatment was provided to 83 patients following metronidazole or tinidazole treatment. However, amebiasis recurred in 6 of these, a frequency similar to that seen in patients who did not receive luminal treatment. Recurrence was more frequent in HCV-antibody positive individuals and those who acquired syphilis during the follow-up period. Various genotypes of E. histolytica were identified in 14 patients but there was no correlation between genotype and clinical features. The outcome of metronidazole and tinidazole treatment of uncomplicated amebiasis was excellent even in HIV-1-infected individuals. Luminal treatment following metronidazole or tinidazole treatment does not reduce recurrence of amebiasis in high risk populations probably due to amebic re-infection.

  9. Low dose rectal inoculation of rhesus macaques by SIV SME660 or SIV MAC251 recapitulates human mucosal infection by HIV-1

    Energy Technology Data Exchange (ETDEWEB)

    Koraber, Bette [Los Alamos National Laboratory; Perelson, Alan [Los Alamos National Laboratory; Hraber, Peter [Los Alamos National Laboratory; Giorgi, E [Los Alamos National Laboratory; Bhattacharya, T [Los Alamos National Laboratory

    2009-01-01

    Recently, we developed a novel approach to the identification of transmitted or early founder HIV -1 genomes in acutely infected humans based on single genome amplification and sequencing. Here we tested this approach in 18 acutely infected Indian rhesus macaques to determine the molecular features of SIV transmission. Animals were inoculated intrarectally (IR) or intravenously (IV) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV -1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA one to five weeks after infection. IR inoculation was followed by productive infection by one or few viruses (median 1; range 1-5) that diversified randomly with near star-like phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or few nuc1eotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder virus( es). IV infection was approximately 10,000-fold more efficient than IR infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV -1.

  10. Field evaluation of Abbott Real Time HIV-1 Qualitative test for early infant diagnosis using dried blood spots samples in comparison to Roche COBAS Ampliprep/COBAS TaqMan HIV-1 Qual test in Kenya.

    Science.gov (United States)

    Chang, Joy; Omuomo, Kenneth; Anyango, Emily; Kingwara, Leonard; Basiye, Frank; Morwabe, Alex; Shanmugam, Vedapuri; Nguyen, Shon; Sabatier, Jennifer; Zeh, Clement; Ellenberger, Dennis

    2014-08-01

    Timely diagnosis and treatment of infants infected with HIV are critical for reducing infant mortality. High-throughput automated diagnostic tests like Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Qual Test (Roche CAPCTM Qual) and the Abbott Real Time HIV-1 Qualitative (Abbott Qualitative) can be used to rapidly expand early infant diagnosis testing services. In this study, the performance characteristics of the Abbott Qualitative were evaluated using two hundred dried blood spots (DBS) samples (100 HIV-1 positive and 100 HIV-1 negative) collected from infants attending the antenatal facilities in Kisumu, Kenya. The Abbott Qualitative results were compared to the diagnostic testing completed using the Roche CAPCTM Qual in Kenya. The sensitivity and specificity of the Abbott Qualitative were 99.0% (95% CI: 95.0-100.0) and 100.0% (95% CI: 96.0-100.0), respectively, and the overall reproducibility was 98.0% (95% CI: 86.0-100.0). The limits of detection for the Abbott Qualitative and Roche CAPCTM Qual were 56.5 and 6.9copies/mL at 95% CIs (p=0.005), respectively. The study findings demonstrate that the Abbott Qualitative test is a practical option for timely diagnosis of HIV in infants.

  11. Large Isoform of Mammalian Relative of DnaJ is a Major Determinant of Human Susceptibility to HIV-1 Infection

    Directory of Open Access Journals (Sweden)

    Yu-Ping Chiang

    2014-12-01

    Full Text Available Individual differences in susceptibility to human immunodeficiency virus type 1 (HIV-1 infection have been of interest for decades. We aimed to determine the contribution of large isoform of Mammalian DnaJ (MRJ-L, a HIV-1 Vpr-interacting cellular protein, to this natural variation. Expression of MRJ-L in monocyte-derived macrophages was significantly higher in HIV-infected individuals (n = 31 than their uninfected counterparts (n = 27 (p = 0.009. Fifty male homosexual subjects (20 of them are HIV-1 positive were further recruited to examine the association between MRJ-L levels and occurrence of HIV infection. Bayesian multiple logistic regression revealed that playing a receptive role and increased levels of MRJ-L in macrophages were two risk factors for HIV-1 infection. A 1% rise in MRJ-L expression was associated with a 1.13 fold (95% CrI 1.06–1.29 increase in odds of contracting HIV-1 infection. Ex vivo experiments revealed that MRJ-L facilitated Vpr-dependent nuclear localization of virus. Infection of macrophage-tropic strain is a critical step in HIV-1 transmission. MRJ-L is a critical factor in this process; hence, subjects with higher macrophage MRJ-L levels are more vulnerable to HIV-1 infection.

  12. HIV-1 inhibits phagocytosis and inflammatory cytokine responses of human monocyte-derived macrophages to P. falciparum infected erythrocytes.

    Directory of Open Access Journals (Sweden)

    Louise E Ludlow

    Full Text Available HIV-1 infection increases the risk and severity of malaria by poorly defined mechanisms. We investigated the effect of HIV-1(Ba-L infection of monocyte-derived macrophages (MDM on phagocytosis of opsonised P. falciparum infected erythrocytes (IE and subsequent proinflammatory cytokine secretion. Compared to mock-infected MDM, HIV-1 infection significantly inhibited phagocytosis of IE (median (IQR (10 (0-28 versus (34 (27-108; IE internalised/100 MDM; p = 0.001 and decreased secretion of IL-6 (1,116 (352-3,387 versus 1,552 (889-6,331; pg/mL; p = 0.0078 and IL-1β (16 (7-21 versus 33 (27-65; pg/mL; p = 0.0078. Thus inadequate phagocytosis and cytokine production may contribute to impaired control of malaria in HIV-1 infected individuals.

  13. Ectopic expression of anti-HIV-1 shRNAs protects CD8{sup +} T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Kamata, Masakazu, E-mail: masa3k@ucla.edu [Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Kim, Patrick Y. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Ng, Hwee L. [Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O' Connor, Sean [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Yang, Otto O. [Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); UCLA AIDS Institute, Los Angeles, CA (United States); AIDS Healthcare Foundation, Los Angeles, CA (United States); Chen, Irvin S.Y. [Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); UCLA AIDS Institute, Los Angeles, CA (United States)

    2015-07-31

    Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8{sup +} T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8{sup +} T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8{sup +} T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24{sup Gag} in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8{sup +} T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8{sup +} T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8{sup +} T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8{sup +} T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection suppresses its cytopathic effect.

  14. BAG3 protein regulates caspase-3 activation in HIV-1-infected human primary microglial cells

    Science.gov (United States)

    Rosati, Alessandra; Khalili, Kamel; Deshmane, Satish L.; Radhakrishnan, Sujatha; Pascale, Maria; Turco, M. Caterina; Marzullo, Liberato

    2015-01-01

    BAG3, a member of the BAG co-chaperones family, is expressed in several cell types subjected to stressful conditions, such as exposure to high temperature, heavy metals, drugs. Furthermore, it is constitutively expressed in some tumors. Among the biological activities of the protein, there is apoptosis downmodulation; this appears to be exerted through BAG3 interaction with the heat shock protein (Hsp) 70, that influences cell apoptosis at several levels. We recently reported that BAG3 protein was detectable in the cytoplasm of reactive astrocytes in HIV-1-associated encephalopathy biopsies. Here we report that downmodulation of BAG3 protein levels allows caspase-3 activation by HIV-1 infection in human primary microglial cells. This is the first reported evidence of a role for BAG3 in the balance of death versus survival during viral infection. PMID:18821563

  15. Tetanus and diphtheria antibodies and response to a booster dose in Brazilian HIV-1-infected women.

    Science.gov (United States)

    Bonetti, Tatiana C S; Succi, Regina C M; Weckx, Lily Y; Tavares-Lopes, L; de Moraes-Pinto, M Isabel

    2004-09-09

    Tetanus and diphtheria (Td) antibodies were studied in HIV-1-infected women during puerperium. HIV group (n=61) was compared with Control group (n=101). Twenty-one women from HIV and 13 from Control group who had antibody levels lower than 0.1 IU/mL received a booster with Td vaccine. Antibodies were assessed by double antigen ELISA. Mean tetanus and diphtheria antibody levels from HIV group were lower than those from Control group. Multiple linear regression analysis showed that tetanus and diphtheria antibody levels were decreased by HIV-1-infection, and that was independent of the reduction due to the time interval between last booster and antibody assessment. After a booster dose, both groups had an increase in mean tetanus and diphtheria antibody levels, but in Control group the levels were higher than in HIV group.

  16. Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children

    Directory of Open Access Journals (Sweden)

    Gomez M Luisa

    2008-10-01

    Full Text Available Abstract Background Protease inhibitors (PIs have been associated with metabolic complications. There is a trend to switch to simpler therapy to improve these disturbances. We report a case-series describing the effects in metabolic abnormalities in seven HIV-infected children, previously treated with protease inhibitor (PI after switching to nevirapine. Methods Seven children with stable PI-containing regimen and a long lasting HIV-1 RNA Results Seven HIV-infected children were enrolled. Median age: 130 months (99,177. Median baseline CD4%: 32%. All had HIV-1 RNA Conclusion PI substitution with nevirapine improved lipid profile in our patients, although this strategy did not show significant changes in body fat or lipodystrophy.

  17. Frequency of class I anti-HLA alloantibodies in patients infected by HIV-1

    Directory of Open Access Journals (Sweden)

    Elza Regina Manzolli Leite

    2010-02-01

    Full Text Available The aim of this study was to evaluate the presence of class I anti-HLA alloantibodies in patients infected by HIV-1 and relate it with the different clinical courses of the disease. Blood samples were collected in EDTA tubes from 145 individuals. HIV-1 infection was confirmed by ELISA test. The presence of class I anti-HLA alloantibodies and HLA allele's were determined. Clinical evolution was set as fast (3 years. Class I anti-HLA alloantibodies presence was lower in healthy individuals than in those infected by HIV-1 (4.2% against 32.4%. However, an equal distribution of these alloantibodies was found among the individuals infected, independent on the clinical evolution. Thus, class I anti-HLA alloantibodies was not a determinant factor for patient worsening.O objetivo deste estudo foi avaliar a presença de aloanticorpos anti-HLA classe I em pacientes infectados pelo HIV-1 e relacioná-la aos diferentes cursos clínicos da doença. Amostras de sangue de 145 indivíduos HIV positivo foram coletadas em tubos com EDTA. A infecção pelo HIV-1 foi confirmada por teste ELISA e a presença de aloanticorpos anti-HLA classe I determinada em seguida. A evolução clínica foi definida como rápida (3 anos. A presença de aloanticorpos anti-HLA classe I foi menor em indivíduos saudáveis em relação aos infectados pelo HIV-1 (4,2% contra 32,4%. Porém, a distribuição destes aloanticorpos entre os indivíduos infectados foi igual, independente da evolução clínica. Deste modo, a presença de aloanticorpos anti-HLA classe I não é um fator determinante na piora clínica do paciente.

  18. PPARgamma Pro12Ala polymorphism in HIV-1-infected patients with HAART-related lipodystrophy.

    Science.gov (United States)

    Saumoy, Maria; Veloso, Sergi; Alonso-Villaverde, Carlos; Domingo, Pere; Chacón, Matilde R; Miranda, Merce; Aragonès, Gerard; Gutiérrez, Maria Mar; Viladés, Consuelo; Peraire, Joaquim; Sirvent, Joan-Josep; López-Dupla, Miguel; Aguilar, Carmen; Richart, Cristóbal; Vidal, Francesc

    2009-09-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in obesity and in some components of the metabolic syndrome in unselected population. To determine whether PPARgamma genetic variants are associated with the risk of developing lipodystrophy and its associated metabolic disturbances in HIV-1-infected patients treated with HAART and to assess PPARgamma mRNA expression in subcutaneous adipose tissue (SAT). The study group comprised 278 patients infected with HIV-1 and treated with antiretroviral drugs (139 with lipodystrophy and 139 without) and 105 uninfected controls (UC). The PPARgamma Pro12Ala (C%>G) single nucleotide polymorphism (SNP) was assessed using PCR-RFLPs on white cell DNA. PPARgamma mRNA expression in SAT was assessed in 38 patients (25 with lipodystrophy and 13 without) and in 21 UC by real-time PCR. Statistical analysis was based on Student's T tests, Chi(2) tests, Spearman's correlations tests and logistic regression tests. PPARgamma Pro12Ala genotype distribution and allele frequencies were non-significantly different between both HIV-1-infected categories, lipodystrophy vs non-lipodystrophy (p=0.9 and p=0.87, respectively). Lipodystrophic patients harbouring the rare X/Ala genotype (Ala/Ala plus Pro/Ala) had significantly greater plasma total and LDL cholesterol levels compared with carriers of the common Pro/Pro genotype (p=0.029 and p=0.016, respectively) at univariate analyses. At multivariate analyses these associations were no longer significant. There was a near-significant decreased SAT PPARgamma mRNA expression in patients with lipodystrophy compared to UC (p=0.054). PPARgamma Pro12Ala SNP has no effect on the risk of developing lipodystrophy in HIV-1-infected patients treated with HAART. PPARgamma mRNA SAT expression appears decreased in lipodystrophy.

  19. Polymorphisms in the IFNγ, IL-10, and TGFβ Genes May Be Associated with HIV-1 Infection

    Directory of Open Access Journals (Sweden)

    Felipe Bonfim Freitas

    2015-01-01

    Full Text Available Objective. This study investigated possible associations between the TNFα-308G/A, IFN+874A/T, IL-6-174C/G, IL-10-1082A/G, and TGFβ-509C/T polymorphisms with HIV-1 infection, in addition to correlation of the polymorphisms with clinical markers of AIDS progression, such as levels of CD4+/CD8+ T lymphocytes and plasma viral load. Methods. A total of 216 individuals who were infected with HIV-1 and on antiretroviral therapy (ART and 294 individuals from the uninfected control group were analyzed. Results. All individuals evaluated were negative for total anti-HBc, anti-HCV, anti-T. pallidum, and anti-HTLV-1/2. The polymorphisms were identified by PCR-RFLP. Individuals presenting the IFN+874A allele as well as the AA genotype were more frequent in the HIV-1 infected group compared to the control group (P<0.05, in addition to having lower levels of CD4+ T lymphocytes. The CD8+ T lymphocytes count was significantly lower in individuals with the IL-10-1082 GG genotype. The TGFβ-509TT genotype was associated with higher plasma viral load. Conclusions. The results suggest that the presence of the IFN+874A allele confers susceptibility to HIV-1 infection and a decrease in the number of CD4+ T lymphocytes. In addition, the genotype associated with high serum levels of TGFβ may be associated with an increase in plasma viral load.

  20. Asymptomatic Intestinal Amebiasis in Japanese HIV-1Infected Individuals

    Science.gov (United States)

    Watanabe, Koji; Nagata, Naoyoshi; Sekine, Katsunori; Watanabe, Kazuhiro; Igari, Toru; Tanuma, Junko; Kikuchi, Yoshimi; Oka, Shinichi; Gatanaga, Hiroyuki

    2014-01-01

    Seventy-one asymptomatic human immunodeficiency virus-1 (HIV-1) -infected individuals who underwent colonoscopy for detection of diseases other than amebiasis were included in this study. Ulcerative lesions caused by Entamoeba histolytica were identified by colonoscopy and biopsy in 11.3% (8 of 71) of individuals. Stool microscopic examination hardly identified Entamoeba, whereas serum antibody against E. histolytica was often elevated in patients with subclinical intestinal amebiasis. Human leukocyte antigen (HLA) class II allele against E. histolytica infection (DQB1*06:01) was frequently identified in these patients. This study emphasizes the endemic nature of E. histolytica infection in our cohort and the difficulties in epidemiological control. PMID:25048374

  1. Exacerbation of microcytic anemia associated with cessation of anti-retroviral therapy in an HIV-1-infected patient with beta thalassemia.

    Science.gov (United States)

    Furukawa, Yoshitaka; Hashiguchi, Teruto; Minami, Rumi; Yamamoto, Masahiro; Takashima, Hiroshi

    2014-06-01

    We report a patient with Japanese minor β thalassemia and HIV-1 infection. The patient showed prolonged anemia, which was originally attributed to chronic parvovirus B19 infection. Twelve years later, the patient presented with exacerbation of microcytic anemia following cessation of anti-retroviral therapy; the exacerbation resolved when anti-retroviral therapy was resumed. Sequencing of the β globin gene revealed heterozygosity for a four-nucleotides deletion at codon 41/42 and minor β thalassemia was confirmed. Because HIV-1-infected patients frequently show anemia due to nutritional deficiencies, opportunistic infections, AIDS-related malignancies, drug treatment and a direct effect of HIV-1 on the bone marrow, it is likely to overlook other causes of anemia. Thalassemia should be considered in the differential diagnosis of anemia even in HIV-1 infected patients, when microcytic anemia without iron deficiency is observed. Our case suggested that active HIV infection may have worsened β thalassemia, and early introduction of anti-retroviral therapy is beneficial for the recovery of anemia. Copyright © 2014 China Ordnance Society. Published by Elsevier Ltd. All rights reserved.

  2. Comprehensive longitudinal analysis of hepatitis C virus (HCV)-specific T cell responses during acute HCV infection in the presence of existing HIV-1 infection

    NARCIS (Netherlands)

    C.H.S.B. van den Berg; T.A. Ruys; N.M. Nanlohy; S.E. Geerlings; J.T. van der Meer; J.W. Mulder; J.A. Lange; D. van Baarle

    2009-01-01

    The aim of this study was to study the development of HCV-specific T cell immunity during acute HCV infection in the presence of an existing HIV-1 infection in four HIV-1 infected men having sex with men. A comprehensive analysis of HCV-specific T cell responses was performed at two time points duri

  3. Evaluation of dried blood spots with a multiplex assay for measuring recent HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Kelly A Curtis

    Full Text Available Laboratory-based HIV tests for recent infection (TRIs, which primarily measure a specific serological biomarker(s that distinguishes recent from long-term HIV infection, have facilitated the estimation of population-based incidence. Dried blood spots (DBS on filter paper are an attractive sample source for HIV surveillance, given the simplified and cost-effective methods of specimen collection, storage, and shipment. Here, we evaluated the use of DBS in conjunction with an in-house multiplex TRI, the HIV-1-specific Bio-Plex assay, which measures direct antibody binding and avidity to multiple HIV-1 analytes. The assay performance was comparable between matched plasma and DBS samples from HIV-1 infected individuals obtained from diverse sources. The coefficients of variation, comparing the median antibody reactivity for each analyte between plasma and DBS, ranged from 2.78% to 9.40% and the correlation coefficients between the two sample types ranged from 0.89 to 0.97, depending on the analyte. The correlation in antibody reactivity between laboratory and site-prepared DBS for each analyte ranged from 0.87 to 0.98 and from 0.90 to 0.97 between site-prepared DBS and plasma. The correlation in assay measures between plasma and DBS indicate that the sample types can be used interchangeably with the Bio-Plex format, without negatively impacting the misclassification rate of the assay.

  4. Mitochondrial Haplogroup Influences Motor Function in Long-Term HIV-1-Infected Individuals

    Science.gov (United States)

    Azar, Ashley; Giovannetti, Tania; Pirrone, Vanessa; Nonnemacher, Michael R.; Passic, Shendra; Kercher, Katherine; Williams, Jean W.; Wigdahl, Brian; Dampier, William; Libon, David J.; Sell, Christian

    2016-01-01

    Evolutionary divergence of the mitochondrial genome has given rise to distinct haplogroups. These haplogroups have arisen in specific geographical locations and are responsible for subtle functional changes in the mitochondria that may provide an evolutionary advantage in a given environment. Based on these functional differences, haplogroups could define disease susceptibility in chronic settings. In this study, we undertook a detailed neuropsychological analysis of a cohort of long-term HIV-1-infected individuals in conjunction with sequencing of their mitochondrial genomes. Stepwise regression analysis showed that the best model for predicting both working memory and declarative memory were age and years since diagnosis. In contrast, years since diagnosis and sub-haplogroup were significantly predictive of psychomotor speed. Consistent with this, patients with haplogroup L3e obtained better scores on psychomotor speed and dexterity tasks when compared to the remainder of the cohort, suggesting that this haplogroup provides a protective advantage when faced with the combined stress of HIV-1 infection and long-term antiretroviral therapies. Differential performance on declarative memory tasks was noted for individuals with other sub-L haplogroups, but these differences were not as robust as the association between L3e and psychomotor speed and dexterity tasks. This work provides evidence that mitochondrial haplogroup is related to neuropsychological test performance among patients in chronic disease settings such as HIV-1 infection. PMID:27711166

  5. The amino-terminal domain of the CCR2 chemokine receptor acts as coreceptor for HIV-1 infection.

    Science.gov (United States)

    Frade, J M; Llorente, M; Mellado, M; Alcamí, J; Gutiérrez-Ramos, J C; Zaballos, A; Real, G; Martínez-A, C

    1997-08-01

    The chemokines are a homologous serum protein family characterized by their ability to induce activation of integrin adhesion molecules and leukocyte migration. Chemokines interact with their receptors, which are composed of a single-chain, seven-helix, membrane-spanning protein coupled to G proteins. Two CC chemokine receptors, CCR3 and CCR5, as well as the CXCR4 chemokine receptor, have been shown necessary for infection by several HIV-1 virus isolates. We studied the effect of the chemokine monocyte chemoattractant protein 1 (MCP-1) and of a panel of MCP-1 receptor (CCR2)-specific monoclonal antibodies (mAb) on the suppression of HIV-1 replication in peripheral blood mononuclear cells. We have compelling evidence that MCP-1 has potent HIV-1 suppressive activity when HIV-1-infected peripheral blood lymphocytes are used as target cells. Furthermore, mAb specific for the MCP-1R CCR2 which recognize the third extracellular CCR2 domain inhibit all MCP-1 activity and also block MCP-1 suppressive activity. Finally, a set of mAb specific for the CCR2 amino-terminal domain, one of which mimics MCP-1 activity, has a potent suppressive effect on HIV-1 replication in M- and T-tropic HIV-1 viral isolates. We conjecture a role for CCR2 as a coreceptor for HIV-1 infection and map the HIV-1 binding site to the amino-terminal part of this receptor. This concurs with results showing that the CCR5 amino terminus is relevant in HIV-1 infection, although chimeric fusion of various extracellular domains shows that other domains are also implicated. We discuss the importance of CCR2 structure relative to its coreceptor role and the role of anti-CCR2 receptor antibodies in the prevention of HIV-1 infection.

  6. Viremic Control and Viral Coreceptor Usage in Two HIV-1-Infected Persons Homozygous for CCR5 Δ32

    Science.gov (United States)

    Henrich, Timothy J.; Hanhauser, Emily; Hu, Zixin; Stellbrink, Hans-Jürgen; Noah, Christian; Martin, Jeffrey N.; Deeks, Steven G.; Kuritzkes, Daniel R.; Pereyra, Florencia

    2015-01-01

    Objectives To determine viral and immune factors involved in transmission and control of HIV-1 infection in persons without functional CCR5 Design Understanding transmission and control of HIV-1 in persons homozygous for CCR5Δ32 is important given efforts to develop HIV-1 curative therapies aimed at modifying or disrupting CCR5 expression. Methods We identified two HIV-infected CCR5Δ32/Δ32 individuals among a cohort of patients with spontaneous control of HIV-1 infection without antiretroviral therapy and determined co-receptor usage of the infecting viruses. We assessed genetic evolution of full-length HIV-1 envelope sequences by single-genome analysis from one participant and his sexual partner, and explored HIV-1 immune responses and HIV-1 mutations following virologic escape and disease progression. Results Both participants experienced viremia of less than 4,000 RNA copies/ml with preserved CD4+ T cell counts off ART for at least 3.3 and 4.6 years after diagnosis, respectively. One participant had phenotypic evidence of X4 virus, had no known favorable HLA alleles, and appeared to be infected by minority X4 virus from a pool that predominately used CCR5 for entry. The second participant had virus that was unable to use CXCR4 for entry in phenotypic assay but was able to engage alternative viral coreceptors (e.g. CXCR6) in vitro. Conclusions Our study demonstrates that individuals may be infected by minority X4 viruses from a population that predominately uses CCR5 for entry, and that viruses may bypass traditional HIV-1 coreceptors (CCR5 and CXCR4) completely by engaging alternative coreceptors to establish and propagate HIV-1 infection. PMID:25730507

  7. Characterization of drug resistance mutations in ART-naïve HIV-1 infected children in Northern Vietnam

    Directory of Open Access Journals (Sweden)

    Thuy Thi Bich Phung

    2015-09-01

    Full Text Available Objective: To investigate the profile of drug resistance-associated mutations in pol gene of antiretroviral therapy-naïve HIV-1 infected children enrolled in National Hospital Pediatrics in Northern Vietnam. Methods: Genotyping was performed on 134 antiretroviral therapy-naïve plasma samples from HIV-1 infected children. HIV-1 pol gene was amplified using primers for protease and reverse transcriptase and sequenced using the BigDye chemistry. The mutations were analyzed based on the Stanford University HIV-1 Drug Resistance Database and ISA-USA list. Results: All the children were infected with HIV-1 CRF01_AE subtype. Major protease inhibitor resistance mutations were found in 2 children (2.3% and reverse-transcriptase inhibitor resistance mutations were found in 5 children (7.7%. The protease inhibitor mutations were observed M46L and L90M and reverse-transcriptase inhibitor mutations were M184I, K65R, Q151M, T69N, L210W, Y181C, M230L and K101E. Conclusions: This is the first study reporting the prevalence of drug resistance-associated mutation in naïve HIV-1 infected children in Northern Vietnam. These data also emphasize the importance of genotypic resistance testing of HIV-1 infected children before initiating treatment in order to achieve better clinical outcome.

  8. Analysis of HIV-1- and CMV-specific memory CD4 T-cell responses during primary and chronic infection.

    Science.gov (United States)

    Harari, Alexandre; Rizzardi, G Paolo; Ellefsen, Kim; Ciuffreda, Donatella; Champagne, Patrick; Bart, Pierre-Alexandre; Kaufmann, Daniel; Telenti, Amalio; Sahli, Roland; Tambussi, Giuseppe; Kaiser, Laurent; Lazzarin, Adriano; Perrin, Luc; Pantaleo, Giuseppe

    2002-08-15

    CD4 T-cell-specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1- and CMV-specific interferon-gamma-secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1-specific CD4 T-cell responses. A substantial proportion of CD4(+)CCR7(-) T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

  9. HSV-1/HSV-2 Infection-Related Cancers in Bantu Populations Driving HIV-1 Prevalence in Africa: Tracking the Origin of AIDS at the Onset of the 20th Century

    Directory of Open Access Journals (Sweden)

    Jacqueline Le Goaster

    2016-11-01

    Full Text Available Introduction: At the onset of the 20th century, ancient clinical observations of cancer epidemics in Bantu populations of Sub-Saharan Africa were discovered. They were reported from 1914 to 1960, but remained unexplained. In 1983, in San Francisco, Calif., USA, cancer epidemics were related to infections by the human immunodeficiency virus type 1 (HIV-1 known as AIDS disease. Yet since 1996, it is known that HIV-1 strains are not the only ones involved. In Sub-Saharan Africa, recurrent orobuccal herpes simplex virus type 1 (HSV-1 and genital recurrent herpes simplex virus type 2 (HSV-2 appeared many times prior to infection by HIV-1. Case Reports: Data on these ancient medical observations regarding African cancer epidemics can today be referred to as the relationship between the unfortunate immune deficiency of herpes in Bantu populations and HIV-1 viral strains. For centuries, the Bantu populations dispersed in forests were living in close proximity to chimpanzees infected by simian immunodeficiency virus (SIV and were exposed to SIV contamination which became HIV-1 in human beings. Presently, these unexplained Bantu cancer epidemics can be linked to the viral partnership of HSV-1/HSV-2 to HIV-1 strains. Conclusion: The key issue is now to prevent HSV-1/HSV-2 diseases related to HIV-1. An anti-herpes treatment administered early during childhood to Bantu populations will offer a mean of preventing herpes diseases related to HIV-1 infection and hence avoid cancer epidemics.

  10. Validation of the Gen-Probe Aptima qualitative HIV-1 RNA assay for diagnosis of human immunodeficiency virus infection in infants.

    Science.gov (United States)

    Fiscus, Susan A; McMillion, Takesha; Nelson, Julie A E; Miller, William C

    2013-12-01

    The qualitative Roche HIV-1 DNA Amplicor assay has been used for the past 20 years to diagnose HIV infection in infants and young children but is being phased out; hence, alternative assays must be found. The Gen-Probe Aptima qualitative HIV-1 RNA assay is currently the only FDA-cleared HIV-1 nucleic acid assay approved for diagnosis, but data on the use of this assay with infant plasma are limited. We assessed Aptima's performance using control material for reproducibility and limit of detection and 394 plasma samples (0.2 to 0.5 ml) from HIV-exposed infected and uninfected infants and children for analytical sensitivity and specificity. Assays to assess within-run repeatability and between-run reproducibility indicated that the controls with 10,000 (5 of 5), 200 (5 of 5), 100 (16 of 16), 50 (12 of 12), and 25 (20 of 20) HIV-1 RNA copies/ml (cp/ml) were always positive, and negatives were always negative (20 of 20). The limit of detection was 14 cp/ml, as determined by probit analysis. The analytic sensitivity of the assay was 99.5% (189/190 samples; 95% confidence interval [CI], 97.1 to 99.9%) and specificity was 99.5% (199/200 samples; 95% CI, 97.2 to 99.9%). These results suggest that the assay is suitable for early infant diagnosis of HIV-1.

  11. Peptide-derivatized SB105-A10 dendrimer inhibits the infectivity of R5 and X4 HIV-1 strains in primary PBMCs and cervicovaginal histocultures.

    Directory of Open Access Journals (Sweden)

    Isabella Bon

    Full Text Available Peptide dendrimers are a class of molecules that exhibit a large array of biological effects including antiviral activity. In this report, we analyzed the antiviral activity of the peptide-derivatized SB105-A10 dendrimer, which is a tetra-branched dendrimer synthetized on a lysine core, in activated peripheral blood mononuclear cells (PBMCs that were challenged with reference and wild-type human immunodeficiency virus type 1 (HIV-1 strains. SB105-A10 inhibited infections by HIV-1 X4 and R5 strains, interfering with the early phases of the viral replication cycle. SB105-A10 targets heparan sulfate proteoglycans (HSPGs and, importantly, the surface plasmon resonance (SPR assay revealed that SB105-A10 strongly binds gp41 and gp120, most likely preventing HIV-1 attachment/entry through multiple mechanisms. Interestingly, the antiviral activity of SB105-A10 was also detectable in an organ-like structure of human cervicovaginal tissue, in which SB105-A10 inhibited the HIV-1ada R5 strain infection without altering the tissue viability. These results demonstrated the strong antiviral activity of SB105-A10 and suggest a potential microbicide use of this dendrimer to prevent the heterosexual transmission of HIV-1.

  12. Investigation of HIV-1 infected and uninfected cells using the optical trapping technique

    Science.gov (United States)

    Ombinda-Lemboumba, S.; Malabi, R.; Lugongolo, M. Y.; Thobakgale, S. L.; Manoto, S.; Mthunzi-Kufa, P.

    2017-02-01

    Optical trapping has emerged as an essential tool for manipulating single biological material and performing sophisticated spectroscopy analysis on individual cell. The optical trapping technique has been used to grab and immobilize cells from a tightly focused laser beam emitted through a high numerical aperture objective lens. Coupling optical trapping with other technologies is possible and allows stable sample trapping, while also facilitating molecular, chemical and spectroscopic analysis. For this reason, we are exploring laser trapping combined with laser spectroscopy as a potential non-invasive method of interrogating individual cells with a high degree of specificity in terms of information generated. Thus, for the delivery of as much pathological information as possible, we use a home-build optical trapping and spectroscopy system for real time probing human immunodeficiency virus (HIV-1) infected and uninfected single cells. Briefly, our experimental rig comprises an infrared continuous wave laser at 1064 nm with power output of 1.5 W, a 100X high numerical aperture oil-immersion microscope objective used to capture and immobilise individual cell samples as well as an excitation source. Spectroscopy spectral patterns obtained by the 1064 nm laser beam excitation provide information on HIV-1 infected and uninfected cells. We present these preliminary findings which may be valuable for the development of an HIV-1 point of care detection system.

  13. Enhanced Th17 phenotype in uninfected neonates born from viremic HIV-1-infected pregnant women.

    Science.gov (United States)

    Hygino, Joana; Vieira, Morgana M; Guillermo, Landi V; Silva-Filho, Renato G; Saramago, Carmen; Lima-Silva, Agostinho A; Andrade, Regis M; Andrade, Arnaldao F B; Brindeiro, Rodrigo M; Tanuri, Amilcar; Guimarães, Vander; de Melo Bento, Cleonice Alves

    2011-04-01

    Our objective was to evaluate the in vitro functional profile of T cells from uninfected neonates born from HIV-1-infected pregnant women who controlled (G1) or not (G2) the virus replication. We demonstrated that the lymphoproliferation of T cell to polyclonal activators was higher in the G2 as compared with G1. Nevertheless, no detectable proliferative response was observed in response to HIV-1 antigens in both neonate groups. Cytokine dosage in the supernatants of these polyclonally activated T cell cultures demonstrated that, while IL-10 was the dominant cytokine produced in G1, Th17-related cytokines were significantly higher in G2 neonates. The higher Th17 phenotype tendency in G2 was related to high production of IL-23 by lipopolysaccharide-activated monocyte-derived dendritic cells from these neonates. Our results demonstrated immunological disorders in uninfected neonates born from viremic HIV-1-infected mothers that can help to explain why some of these children have elevated risk of clinical morbidity and mortality due to pathological hypersensitivity.

  14. Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214.

    Science.gov (United States)

    Schooley, R T; Spino, C; Kuritzkes, D; Walker, B D; Valentine, F A; Hirsch, M S; Cooney, E; Friedland, G; Kundu, S; Merigan, T C; McElrath, M J; Collier, A; Plaeger, S; Mitsuyasu, R; Kahn, J; Haslett, P; Uherova, P; deGruttola, V; Chiu, S; Zhang, B; Jones, G; Bell, D; Ketter, N; Twadell, T; Chernoff, D; Rosandich, M

    2000-11-01

    The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in 350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

  15. A Therapeutic Dendritic Cell-Based Vaccine for HIV-1 Infection

    Science.gov (United States)

    Climent, Núria; Assoumou, Lambert; Gil, Cristina; González, Nuria; Alcamí, José; León, Agathe; Romeu, Joan; Dalmau, Judith; Martínez-Picado, Javier; Lifson, Jeff; Autran, Brigitte; Costagliola, Dominique; Clotet, Bonaventura; Gatell, Josep M; Plana, Montserrat; Gallart, Teresa

    2011-01-01

    A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cells (MD-DCs) pulsed with heat inactivated autologous HIV-1 was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 after first vaccination (primary end point), a modest significant decrease in plasma viral load was observed in vaccine recipients, compared with control subjects (P = .03). In addition, the change in plasma viral load after vaccination tended to be inversely associated with the increase in HIV-specific T cell responses in vaccinated patients but tended to be directly correlated with HIV-specific T cell responses in control subjects. Clinical trial.gov NCT00402142 PMID:21233310

  16. Elevated Levels of Microbial Translocation Markers and CCL2 Among Older HIV-1Infected Men

    Science.gov (United States)

    Scully, Eileen; Lockhart, Ainsley; Huang, Lisa; Robles, Yvonne; Becerril, Carlos; Romero-Tejeda, Marisol; Albrecht, Mary A.; Palmer, Christine D.; Bosch, Ronald J; Altfeld, Marcus; Kuritzkes, Daniel R.; Lin, Nina H.

    2016-01-01

    The aging of the human immunodeficiency virus type 1 (HIV-1)–infected population obligates a focus on the interaction between aging, comorbid conditions, and HIV-1. We recruited a cohort of HIV-1infected men aged ≤35 years or ≥50 years who were receiving fully suppressive antiretroviral therapy (ART). We analyzed plasma markers of inflammation; T-cell activation, exhaustion, proliferation; and innate cellular subsets and functional capacity. Levels of lipopolysaccharide and the plasma marker of chemokine (C-C motif) ligand 2 were significantly elevated in older HIV-infected men despite comparable cellular phenotypes. Compared with similarly age-stratified uninfected subjects, older HIV-1infected adults were also more frequently in the upper quartile of soluble CD14 expression. PMID:26494772

  17. The Influence of HIV-1 Exposure and Infection on Levels of Passively Acquired Antibodies to Measles Virus in Zambian Infants

    National Research Council Canada - National Science Library

    Susana Scott; William J. Moss; Simon Cousens; Judy A. Beeler; Susette A. Audet; Nanthalile Mugala; Thomas C. Quinn; Diane E. Griffin; Felicity T. Cutts

    2007-01-01

    .... Antibodies to measles virus were measured by plaque reduction neutralization assay in HIV-1-infected, HIV-seropositive but uninfected, and HIV-seronegative Zambian infants aged 6 weeks to 9 months...

  18. The effects of low level laser therapy on both HIV-1 infected and uninfected TZM-bl cells

    CSIR Research Space (South Africa)

    Lugongolo, Masixole Y

    2017-01-01

    Full Text Available Human immunodeficiency virus (HIV-1) infection remains a major health problem despite the use of highly active antiretroviral therapy (HAART), which has greatly reduced mortality rates. Due to the unavailability of an effective vaccine and treatment...

  19. [Application progress of CRISPR/Cas9 genome editing technology in the treatment of HIV-1 infection].

    Science.gov (United States)

    Han, Yinglun; Li, Qingwei

    2016-01-01

    The goal of gene therapy is to introduce foreign genes into human target cells in a certain way to correct or compensate diseases caused by defective or abnormal genes. Therefore, gene therapy has great practical significance in studying the treatment of persistent or latent HIV-1 infection. At present, the existing methods of gene therapy have some major defects such as limited target site recognition and high frequency of off-targets. The latest research showed that the clustered regularly interspaced short palindromic repeats (CRISPR) /CRISPR-associated nuclease 9 (Cas9) system from bacteria and archaea has been successfully reformed to a targeted genome editing tool. Thus, how to achieve the goal of treating HIV-1 infection by modifying targeted HIV-1 virus genome effectively using the CRISPR/Cas9 system has become a current research focus. Here we review the latest achievements worldwide and briefly introduce applications of the CRISPR/Cas9 genome editing technology in the treatment of HIV-1 infection, including CCR5 gene editing, removal of HIV-1 virus and activation of HIV-1 virus, in order to provide reference for the prevention and treatment of HIV-1 infection.

  20. Quantification of HIV-1 viral RNA in the blood in needles used for venous puncture in HIV-infected individuals

    Directory of Open Access Journals (Sweden)

    Iris Ricardo Rossin

    2011-12-01

    Full Text Available INTRODUCTION: Occupational HIV infection among healthcare workers is an important issue in exposures involving blood and body fluids. There are few data in the literature regarding the potential and the duration of infectivity of HIV type 1 (HIV-1 in contaminated material under adverse conditions. METHODS: We quantified HIV-1 viral RNA in 25×8mm calibre hollow-bore needles, after punctures, in 25 HIV-1-infected patients selected during the sample collection. All of the patients selected were between the ages of 18 and 55. Five samples were collected from 16 patients: one sample for the immediate quantification of HIV-1 RNA in the plasma and blood samples from the interior of 4 needles to be analyzed at 0h, 6h, 24h, and 72h after collection. In nine patients, another test was carried out in the blood from one additional needle, in which HIV-1 RNA was assessed 168h after blood collection. The method used to assess HIV-1 RNA was nucleic acid sequence-based amplification. RESULTS: Up to 7 days after collection, HIV-1 RNA was detected in all of the needles. The viral RNA remained stable up to 168h, and there were no statistically significant differences among the needle samples. CONCLUSIONS: Although the infectivity of the viral material in the needles is unknown, the data indicate the need to re-evaluate the practices in cases of occupational accidents in which the source is not identified.

  1. APOBEC3G与Vif在HIV-1感染中的作用%The Roles of APOBEC3G and Vif in HIV-1 Infections

    Institute of Scientific and Technical Information of China (English)

    马寅佳; 杨怡姝; 曾毅

    2012-01-01

    Apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) proteins are cytidine deaminases that exert antiviral activity to inhibit the infection of many viruses, especially retrovintses. The antiviral activity of AP0BEC-3G( A3G) and APOBEC-3F are stronger than other family members. A3G inhibits human immunodeficiency virus (HIV) infection through cytidine deamination and non-cytidine deamination. However, the degradation of A3G by the ubiquitin- proteasome system can be antagonized by HIV-1 viral infectivity factor (Vif). The study of the interaction of A3G and Vif will be informative for its connection with HIV-1 treatments.%载脂蛋白B mRNA编辑催化多肽样(apolipoprotein B mRNA-editing catalytic polypeptide-like,APOBEC)蛋白是一组胞嘧啶脱氨基酶,具有天然的抗病毒活性,对多种病毒具有抑制作用,特别是逆转录病毒.APOBEC3蛋白能够抑制人类免疫缺陷病毒(HIV-1)的感染,其中APOBEC3G和APOBEC3F的作用最强.APOBEC3G能够通过胞嘧啶脱氨基作用和非胞嘧啶脱氨基作用抑制病毒感染.HIV-1病毒感染因子(Vif)蛋白主要经泛素-蛋白酶体途径介导APOBEC3G降解,从而拮抗其抗病毒作用.APOBEC3G和Vif之间相互作用的研究对于寻求新的抗HIV治疗靶点具有重要意义.

  2. Molecular characterisation of newly identified HIV-1 infections in Curitiba, Brazil: preponderance of clade C among males with recent infections

    Directory of Open Access Journals (Sweden)

    João Leandro de Paula Ferreira

    2008-12-01

    Full Text Available As in many areas of Brazil, the AIDS epidemic in Curitiba is relatively stable, but surveillance is important to support public policy. The molecular characteristics of HIV may be instrumental for monitoring epidemic trends. We evaluated plasma HIV-1 RNA (n = 37 from 38 cases presenting with positive serology, who were among 820 consenting volunteers visiting the downtown counselling and serology testing centre. Seroprevalence was 4.6% (CI 95% 3.2-6.3 and the estimated HIV incidence, as defined by the BED assay, was 2.86 persons/years (CI 95% 1.04-4.68. An additional set of contemporaneous, anonymous samples from a local laboratory was also analysed (n = 20. Regions of the HIV-1 polymerase (n = 57 and envelope (n = 34 were evaluated for subtyping, determination of mosaic structure, primary drug resistance mutations (pDRM, envelope V3 loop motifs and amino acid signatures related to viral tropism. HIV-1 clade B was observed in 53% of cases; HIV-1C in 30% and BC mosaics in 14%, with one F genome and one CF mosaic. Clade C infection was associated with recent infections among males (p < 0.03. Stanford surveillance pDRM was observed in 8.8% of sequences, with 7% showing high level resistance to at least one antiretroviral drug. Tropism for CXCR4 co-receptor was predicted in 18% of envelope sequences, which were exclusively among clade B genomes and cases with serological reactivity to chronic infection.

  3. Inter-laboratory assessment of a prototype multiplex kit for determination of recent HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Kelly A Curtis

    Full Text Available BACKGROUND: Accurate and reliable laboratory-based assays are needed for estimating HIV-1 incidence from cross-sectional samples. We recently described the development of a customized, HIV-1-specific Bio-Plex assay that allows for the measurement of HIV-specific antibody levels and avidity to multiple analytes for improved HIV-1 incidence estimates. METHODS: To assess intra- and inter-laboratory assay performance, prototype multiplex kits were developed and evaluated by three distinct laboratories. Longitudinal seroconversion specimens were tested in parallel by each laboratory and kit performance was compared to that of an in-house assay. Additionally, the ability of the kit to distinguish recent from long-term HIV-1 infection, as compared to the in-house assay, was determined by comparing the reactivity of known recent (infected 12 months drug naïve specimens. RESULTS: Although the range of reactivity for each analyte varied between the prototype kit and in-house assay, a measurable distinction in reactivity between recent and long-term specimens was observed with both assays in all three laboratories. Additionally, kit performance was consistent between all three laboratories. The intra-assay coefficient of variation (CV, between sample replicates for all laboratories, ranged from 0.5% to 6.1%. The inter-laboratory CVs ranged from 8.5% to 21.3% for gp160-avidity index (a and gp120-normalized mean fluorescent intensity (MFI value (n, respectively. CONCLUSION: We demonstrate the feasibility of producing a multiplex kit for measuring HIV antibody levels and avidity, with the potential for improved incidence estimates based on multi-analyte algorithms. The availability of a commercial kit will facilitate the transfer of technology among diverse laboratories for widespread assay use.

  4. Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms.

    Directory of Open Access Journals (Sweden)

    Michael S Harper

    Full Text Available HIV-1 is transmitted primarily across mucosal surfaces and rapidly spreads within the intestinal mucosa during acute infection. The type I interferons (IFNs likely serve as a first line of defense, but the relative expression and antiviral properties of the 12 IFNα subtypes against HIV-1 infection of mucosal tissues remain unknown. Here, we evaluated the expression of all IFNα subtypes in HIV-1-exposed plasmacytoid dendritic cells by next-generation sequencing. We then determined the relative antiviral potency of each IFNα subtype ex vivo using the human intestinal Lamina Propria Aggregate Culture model. IFNα subtype transcripts from the centromeric half of the IFNA gene complex were highly expressed in pDCs following HIV-1 exposure. There was an inverse relationship between IFNA subtype expression and potency. IFNα8, IFNα6 and IFNα14 were the most potent in restricting HIV-1 infection. IFNα2, the clinically-approved subtype, and IFNα1 were both highly expressed but exhibited relatively weak antiviral activity. The relative potencies correlated with binding affinity to the type I IFN receptor and the induction levels of HIV-1 restriction factors Mx2 and Tetherin/BST-2 but not APOBEC3G, F and D. However, despite the lack of APOBEC3 transcriptional induction, the higher relative potency of IFNα8 and IFNα14 correlated with stronger inhibition of virion infectivity, which is linked to deaminase-independent APOBEC3 restriction activity. By contrast, both potent (IFNα8 and weak (IFNα1 subtypes significantly induced HIV-1 GG-to-AG hypermutation. The results unravel non-redundant functions of the IFNα subtypes against HIV-1 infection, with strong implications for HIV-1 mucosal immunity, viral evolution and IFNα-based functional cure strategies.

  5. Global Stability of an HIV-1 Infection Model with General Incidence Rate and Distributed Delays.

    Science.gov (United States)

    Ndongo, Abdoul Samba; Talibi Alaoui, Hamad

    2014-01-01

    In this work an HIV-1 infection model with nonlinear incidence rate and distributed intracellular delays and with humoral immunity is investigated. The disease transmission function is assumed to be governed by general incidence rate f(T, V)V. The intracellular delays describe the time between viral entry into a target cell and the production of new virus particles and the time between infection of a cell and the emission of viral particle. Lyapunov functionals are constructed and LaSalle invariant principle for delay differential equation is used to establish the global asymptotic stability of the infection-free equilibrium, infected equilibrium without B cells response, and infected equilibrium with B cells response. The results obtained show that the global dynamics of the system depend on both the properties of the general incidence function and the value of certain threshold parameters R 0 and R 1 which depends on the delays.

  6. Global Stability of an HIV-1 Infection Model with General Incidence Rate and Distributed Delays

    Science.gov (United States)

    2014-01-01

    In this work an HIV-1 infection model with nonlinear incidence rate and distributed intracellular delays and with humoral immunity is investigated. The disease transmission function is assumed to be governed by general incidence rate f(T, V)V. The intracellular delays describe the time between viral entry into a target cell and the production of new virus particles and the time between infection of a cell and the emission of viral particle. Lyapunov functionals are constructed and LaSalle invariant principle for delay differential equation is used to establish the global asymptotic stability of the infection-free equilibrium, infected equilibrium without B cells response, and infected equilibrium with B cells response. The results obtained show that the global dynamics of the system depend on both the properties of the general incidence function and the value of certain threshold parameters R 0 and R 1 which depends on the delays. PMID:27355007

  7. Reduced CD4 T cell activation and in vitro susceptibility to HIV-1 infection in exposed uninfected Central Africans

    Directory of Open Access Journals (Sweden)

    Fontanet Arnaud

    2006-06-01

    Full Text Available Abstract Background Environmentally driven immune activation was suggested to contribute to high rates of HIV-1 infection in Africa. We report here a study of immune activation markers and susceptibility to HIV-1 infection in vitro of forty-five highly exposed uninfected partners (EUs of HIV-1 infected individuals in Central African Republic, in comparison with forty-four low-risk blood donors (UCs. Results Analysis of T lymphocyte subsets and activation markers in whole blood showed that the absolute values and the percentage of HLA-DR+CD4 T cells and of CCR5+CD4 T cells were lower in the EUs than in the UCs (p = 0.0001. Mutations in the CCR5 coding region were not found in either group. Susceptibility to in vitro infection of unstimulated peripheral blood mononuclear cells, prior of PHA activation, was decreased in EUs compared to UCs, either using a CXCR4-tropic or a CCR5-tropic HIV-1 strain (p = 0.02 and p = 0.05, respectively. Levels of MIP-1β, but not of MIP-1α or RANTES, in the supernatants of PHA-activated PBMC, were higher in the EUs than in the UCs (p = 0.007. Conclusion We found low levels of CD4 T cell activation and reduced PBMC susceptibility to HIV-1 infection in Central African EUs, indicating that both may contribute to the resistance to HIV-1 infection.

  8. Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

    Institute of Scientific and Technical Information of China (English)

    Chang; Li; Wei; Jin; Tao; Du; Biao; Wu; Yalan; Liu; Robin; J; Shattock; Qinxue; Hu

    2014-01-01

    HIV-1 envelope glycoprotein is reported to interact with α4β7, an integrin mediating the homing of lymphocytes to gut-associated lymphoid tissue, but the significance of α4β7 in HIV-1 infection remains controversial. Here, using HIV-1 strain Ba L, the gp120 of which was previously shown to be capable of interacting with α4β7, we demonstrated that α4β7 can mediate the binding of whole HIV-1 virions to α4β7-expressing transfectants. We further constructed a cell line stably expressing α4β7 and confirmed the α4β7-mediated HIV-1 binding. In primary lymphocytes with activated α4β7 expression, we also observed significant virus binding which can be inhibited by an anti-α4β7 antibody. Moreover, we investigated the impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells. In α4β7-activated CD4+ T cells, both anti-α4β7 antibodies and introduction of shorthairpin RNAs specifically targeting α4β7 resulted in a decreased HIV-1 infection. Our findings indicate that α4β7 may serve as an attachment factor at least for some HIV-1 strains. The established approach provides a promising means for the investigation of other viral strains to understand the potential roles of α4β7 in HIV-1 infection.

  9. Evaluation of Cervical Mucosa in Transmission Bottleneck during Acute HIV-1 Infection Using a Cervical Tissue-Based Organ Culture

    Science.gov (United States)

    Shen, Chengli; Ding, Ming; Ratner, Deena; Montelaro, Ronald C.; Chen, Yue; Gupta, Phalguni

    2012-01-01

    Background Although there are different strains of HIV-1 in a chronically infected individual, only one or limited virus strains are successfully transmitted to a new individual. The reason for this “transmission bottleneck” is as yet unknown. Methodology/Principal Findings A human cervical explant model was used to measure HIV-1 transmission efficiency of viral strains from chronic infections, and transmitter/founder variants. We also evaluated the genetic characteristics of HIV-1 variants in the inoculums compared to those transmitted across the cervical mucosa. Eight different HIV-1 isolates were used in this study, six chronic isolates and two transmitter/founder viruses. The transmission efficiency of the chronic and transmitter/founder virus isolates and the viral diversity of chronic isolates before and after viral transmission were assessed. The results indicate that transmitter/founder viruses did not display higher transmission efficiency than chronic HIV-1 isolates. Furthermore, no evidence for a difference in diversity was found between the inoculums and transmitted virus strains. Phylogenetic analysis indicated that the sequences of variants in the inoculums and those present in transmitted virus intermingled irrespective of co-receptor usage. In addition, the inoculum and transmitted variants had a similar pairwise distance distribution. Conclusion There was no selection of a single or limited number of viral variants during HIV-1 transmission across the cervical mucosa in the organ culture model, indicating that the cervical mucosa alone may not produce the transmission bottleneck of HIV-1 infection observed in vivo. PMID:22412886

  10. Microfluidic Chip-based Nucleic Acid Testing using Gingival Crevicular Fluid as a New Technique for Detecting HIV-1 Infection

    Directory of Open Access Journals (Sweden)

    Alex Willyandre

    2013-05-01

    Full Text Available Transmission of HIV-1 infection by individuals in window period who are tested negative in conventional HIV-1 detection would pose the community with serious problems. Several diagnostic tools require specific labora-tory equipment, perfect timing of diagnosis, antibody to HIV-1, and invasive technique to get sample for examination, until high amount of time to process the sample as well as accessibility of remote areas. Many attempts have been made to solve those problems to come to a new detection technique. This review aims to give information about the current development technique for detection of HIV infection. Microfluidic Chip-based Nucleic Acid Testing is currently introduced for detection of HIV-1 infection. This review also cover the possible usage of gingival crevicular fluid as sample specimen that could be taken noninvasively from the individual.DOI: 10.14693/jdi.v18i2.63

  11. Hepatitis C virus NS3/4A quasispecies diversity in acute hepatitis C infection in HIV-1 co-infected patients.

    Science.gov (United States)

    Nevot, M; Boesecke, C; Parera, M; Andrés, C; Franco, S; Revollo, B; Ingiliz, P; Tural, C; Clotet, B; Rockstroh, J K; Martinez, M A

    2014-06-01

    The growing number of cases of acute hepatitis C (AHC) infections among human immunodeficiency virus type 1 (HIV-1)-positive men who have sex with men (MSM) in the last 10 years has promoted the search for predictors of AHC clearance as well as for epidemiological networks of viral transmission. We characterized the diversity and catalytic efficiency of HCV NS3/4A protease quasispecies in AHC patients coinfected with HIV-1. Plasma samples obtained at HCV diagnosis from 18 MSM HIV-coinfected patients with AHC were studied. Five HCV monoinfected patient samples with AHC were also investigated. An average of 39 clones from each sample was analysed. The catalytic efficiency of the dominant quasispecies (i.e. the most abundant) from each quasispecies was also assayed for mitochondrial antiviral signalling protein (MAVS) cleavage. Phylogenetic analysis identified two clusters of patients with highly related viruses, suggesting a common source of HCV infection. None of the 18 MSM HIV-coinfected patients spontaneously cleared HCV, although 78% of the treated patients achieved a sustained virological response after early treatment with pegylated interferon (pegIFN) plus ribavirin (RBV). The synonymous-nonsynonymous (ds/dn) mutation ratio, a marker of selective pressure, was higher in AHC compared to 26 HIV-1-infected men with genotype 1a chronic hepatitis C (CHC) (P < 0.0001). NS3/4A proteases from AHC patients also exhibited higher catalytic efficiency compared to CHC patients (P < 0.0001). No differences were found when ds/dn mutation ratios and NS3/4A protease catalytic efficiencies from AHC HIV-coinfected patients were compared with AHC monoinfected patients. The presence of epidemiological networks of HCV transmission was confirmed among HIV-1-positive MSM. In addition, substantial genetic diversity was demonstrated in AHC. NS3/4A protease efficiency cleaving MAVS may be associated with virus transmission and response to pegIFN/RBV treatment.

  12. High resolution human leukocyte antigen class I allele frequencies and HIV-1 infection associations in Chinese Han and Uyghur cohorts.

    Directory of Open Access Journals (Sweden)

    Yanhou Liu

    Full Text Available BACKGROUND: Host immunogenetic factors such as HLA class I polymorphism are important to HIV-1 infection risk and AIDS progression. Previous studies using high-resolution HLA class I profile data of Chinese populations appeared insufficient to provide information for HIV-1 vaccine development and clinical trial design. Here we reported HLA class I association with HIV-1 susceptibility in a Chinese Han and a Chinese Uyghur cohort. METHODOLOGY/PRINCIPAL FINDINGS: Our cohort included 327 Han and 161 Uyghur ethnic individuals. Each cohort included HIV-1 seropositive and HIV-1 seronegative subjects. Four-digit HLA class I typing was performed by sequencing-based typing and high-resolution PCR-sequence specific primer. We compared the HLA class I allele and inferred haplotype frequencies between HIV-1 seropositive and seronegative groups. A neighbor-joining tree between our cohorts and other populations was constructed based on allele frequencies of HLA-A and HLA-B loci. We identified 58 HLA-A, 75 HLA-B, and 32 HLA-Cw distinct alleles from our cohort and no novel alleles. The frequency of HLA-B*5201 and A*0301 was significantly higher in the Han HIV-1 negative group. The frequency of HLA-B*5101 was significantly higher in the Uyghur HIV-1 negative group. We observed statistically significant increases in expectation-maximization (EM algorithm predicted haplotype frequencies of HLA-A*0201-B*5101 in the Uyghur HIV-1 negative group, and of Cw*0304-B*4001 in the Han HIV-1 negative group. The B62s supertype frequency was found to be significantly higher in the Han HIV-1 negative group than in the Han HIV-1 positive group. CONCLUSIONS: At the four-digit level, several HLA class I alleles and haplotypes were associated with lower HIV-1 susceptibility. Homogeneity of HLA class I and Bw4/Bw6 heterozygosity were not associated with HIV-1 susceptibility in our cohort. These observations contribute to the Chinese HLA database and could prove useful in the

  13. Differential effects of sex in a West African cohort of HIV-1, HIV-2 and HIV-1/2 dually infected patients: men are worse off.

    Science.gov (United States)

    Jespersen, Sanne; Hønge, Bo Langhoff; Esbjörnsson, Joakim; Medina, Candida; da Silva Té, David; Correira, Faustino Gomes; Laursen, Alex Lund; Østergaard, Lars; Andersen, Andreas; Aaby, Peter; Erikstrup, Christian; Wejse, Christian

    2016-02-01

    Several studies have reported conflicting effects of sex on HIV-1 infection. We describe differences in baseline characteristics and assess the impact of sex on HIV progression among patients at a clinic with many HIV-2 and HIV-1/2 dually infected patients. This study utilised a retrospective cohort of treatment-naïve adults at the largest HIV clinic in Guinea-Bissau from 6 June 2005 to 1 December 2013. Baseline characteristics were assessed and the patients followed until death, transfer, loss to follow-up, or 1 June 2014. We estimated the time from the first clinic visit until initiation of ART, death or loss to follow-up using Cox proportional hazard models. A total of 5694 patients were included in the study, 3702 women (65%) and 1992 men (35%). Women were more likely than men to be infected with HIV-2 (19% vs. 15%, P < 0.01) or dually infected with HIV-1/2 (11% vs. 9%, P = 0.02). For all HIV types, women were younger (median 35 vs. 40 years), less likely to have schooling (55% vs. 77%) or to be married (46% vs. 67%), and had higher baseline CD4 cell counts (median 214 vs. 178 cells/μl). Men had a higher age-adjusted mortality rate (hazard rate ratio (HRR) 1.29, 95% confidence interval (CI) 1.09-1.52) and were more often lost to follow-up (HRR 1.27, 95% CI 1.17-1.39). Significant differences exist between HIV-infected men and women regardless of HIV type. Men seek treatment at a later stage and, despite better socio-economic status, have higher mortality and loss to follow-up than women. © 2015 John Wiley & Sons Ltd.

  14. Independent evolution of Fc- and Fab-mediated HIV-1-specific antiviral antibody activity following acute infection

    Science.gov (United States)

    Dugast, Anne-Sophie; Stamatatos, Leonidas; Tonelli, Andrew; Suscovich, Todd J.; Licht, Anna F.; Mikell, Iliyana; Ackerman, Margaret E.; Streeck, Hendrik; Klasse, P.J.; Moore, John P.; Alter, Galit

    2014-01-01

    Fc-related antibody activities, such as antibody-dependent cellular cytotoxicity (ADCC), or more broadly, antibody-mediated cellular viral inhibition (ADCVI), play a role in curbing early SIV viral replication, are enriched in human long-term infected non-progressors, and could potentially contribute to protection from infection. However, little is known about the mechanism by which such humoral immune responses are naturally induced following infection. Here we focused on the early evolution of the functional antibody response, largely driven by the Fc portion of the antibody, in the context of the evolving binding and neutralizing antibody response, which is driven mainly by the antibody binding fragment (Fab). We show that ADCVI/ADCC-inducing responses in humans are rapidly generated following acute HIV-1 infection, peak at approximately 6 months post-infection, but decay rapidly in the setting of persistent immune activation, as Fab-related activities persistently increase. Moreover, the loss of Fc activity occurred in synchrony with a loss of HIV-specific IgG3 responses. Our data strongly suggest that Fc- and Fab-related antibody functions are modulated in a distinct manner following acute HIV infection. Vaccination strategies intended to optimally induce both sets of antiviral antibody activities may, therefore, require a fine-tuning of the inflammatory response. PMID:25043633

  15. Variations in the Biological Functions of HIV-1 Clade C Envelope in a SHIV-Infected Rhesus Macaque during Disease Progression.

    Directory of Open Access Journals (Sweden)

    For Yue Tso

    Full Text Available A better understanding of how the biological functions of the HIV-1 envelope (Env changes during disease progression may aid the design of an efficacious anti-HIV-1 vaccine. Although studies from patient had provided some insights on this issue, the differences in the study cohorts and methodology had make it difficult to reach a consensus of the variations in the HIV-1 Env functions during disease progression. To this end, an animal model that can be infected under controlled environment and reflect the disease course of HIV-1 infection in human will be beneficial. Such an animal model was previously demonstrated by the infection of macaque with SHIV, expressing HIV-1 clade C Env V1-V5 region. By using this model, we examined the changes in biological functions of Env in the infected animal over the entire disease course. Our data showed an increase in the neutralization resistance phenotype over time and coincided with the decrease in the net charges of the V1-V5 region. Infection of PBMC with provirus expressing various Env clones, isolated from the infected animal over time, showed a surprisingly better replicative fitness for viruses expressing the Env from early time point. Biotinylation and ELISA data also indicated a decrease of cell-surface-associated Env and virion-associated gp120 content with disease progression. This decrease did not affect the CD4-binding capability of Env, but were positively correlated with the decrease of Env fusion ability. Interestingly, some of these changes in biological functions reverted to the pre-AIDS level during advance AIDS. These data suggested a dynamic relationship between the Env V1-V5 region with the host immune pressure. The observed changes of biological functions in this setting might reflect and predict those occurring during natural disease progression in human.

  16. Systemic Immune Activation Profiles of HIV-1 Subtype C-Infected Children and Their Mothers

    Directory of Open Access Journals (Sweden)

    Tinyiko G. Makhubele

    2016-01-01

    Full Text Available Little is known about immune activation profiles of children infected with HIV-1 subtype C. The current study compared levels of selected circulating biomarkers of immune activation in HIV-1 subtype C-infected untreated mothers and their children with those of healthy controls. Multiplex bead array, ELISA, and immunonephelometric procedures were used to measure soluble CD14 (sCD14, beta-2 microglobulin (β2M, CRP, MIG, IP-10, and transforming growth factor beta 1 (TGF-β1. Levels of all 6 biomarkers were significantly elevated in the HIV-infected mothers and, with the exception of MIG, in their children (P<0.01–P<0.0001. The effects of antiretroviral therapy (ART and maternal smoking on these biomarkers were also assessed. With the exception of TGF-β1, which was unchanged in the children 12 months after therapy, initiation of ART was accompanied by decreases in the other biomarkers. Regression analysis revealed that although most biomarkers were apparently unaffected by smoking, exposure of children to maternal smoking was associated with a significant increase in IP-10. These findings demonstrate that biomarkers of immune activation are elevated in HIV-infected children pre-ART and decline, with the exception of TGF-β1, after therapy. Although preliminary, elevation of IP-10 in smoke-exposed infants is consistent with a higher level of immune activation in this group.

  17. Antiviral activity of derivatized dextrans on HIV-1 infection of primary macrophages and blood lymphocytes.

    Science.gov (United States)

    Seddiki, N; Mbemba, E; Letourneur, D; Ylisastigui, L; Benjouad, A; Saffar, L; Gluckman, J C; Jozefonvicz, J; Gattegno, L

    1997-11-28

    The present study demonstrates at the molecular level that dextran derivatives carboxymethyl dextran benzylamine (CMDB) and carboxymethyl dextran benzylamine sulfonate (CMDBS), characterized by a statistical distribution of anionic carboxylic groups, hydrophobic benzylamide units, and/or sulfonate moieties, interact with HIV-1 LAI gp120 and V3 consensus clades B domain. Only limited interaction was observed with carboxy-methyl dextran (CMD) or dextran (D) under the same conditions. CMDBS and CMDB (1 microM) strongly inhibited HIV-1 infection of primary macrophages and primary CD4+ lymphocytes by macrophage-tropic and T lymphocyte-tropic strains, respectively, while D or CMD had more limited effects on M-tropic infection of primary macrophages and exert no inhibitory effect on M- or T-tropic infection of primary lymphocytes. CMDBS and CMDB (1 microM) had limited but significant effect on oligomerized soluble recombinant gp120 binding to primary macrophages while they clearly inhibit (> 50%) such binding to primary lymphocytes. In conclusion, the inhibitory effect of CMDB and the CMDBS, is observed for HIV M- and T-tropic strain infections of primary lymphocytes and macrophages which indicates that these compounds interfere with steps of HIV replicative cycle which neither depend on the virus nor on the cell.

  18. Impact of gender on response to highly active antiretroviral therapy in HIV-1 infected patients

    DEFF Research Database (Denmark)

    Thorsteinsson, Kristina; Ladelund, Steen; Jensen-Fangel, Søren;

    2012-01-01

    ABSTRACT: BACKGROUND: Impact of gender on time to initiation, response to and risk of modification of highly active antiretroviral therapy (HAART) in HIV-1 infected individuals is still controversial. METHODS: From a nationwide cohort of Danish HIV infected individuals we identified all heterosex......ABSTRACT: BACKGROUND: Impact of gender on time to initiation, response to and risk of modification of highly active antiretroviral therapy (HAART) in HIV-1 infected individuals is still controversial. METHODS: From a nationwide cohort of Danish HIV infected individuals we identified all...... counts (adjusted p=0.21). We observed no delay in time to initiation of HAART in women compared to men (HR 0.91, 95% CI 0.79-1.06). There were no gender differences in risk of treatment modification of the original HAART regimen during the first year of therapy for either toxicity (IRR 0.97 95% CI 0.......66-1.44) or other/unknown reasons (IRR 1.18 95% CI 0.76-1.82). Finally, CD4 counts and the risk of having a detectable viral load at 1, 3 and 6 years did not differ between genders. CONCLUSIONS: In a setting with free access to healthcare and HAART, gender does neither affect time from eligibility to HAART...

  19. Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Schunter Marco

    2012-06-01

    Full Text Available Abstract Background Infection with HIV-1 results in marked immunologic insults and structural damage to the intestinal mucosa, including compromised barrier function. While the development of highly active antiretroviral therapy (HAART has been a major advancement in the treatment of HIV-1 infection, the need for novel complementary interventions to help restore intestinal structural and functional integrity remains unmet. Known properties of pre-, pro-, and synbiotics suggest that they may be useful tools in achieving this goal. Methods This was a 4-week parallel, placebo-controlled, randomized pilot trial in HIV-infected women on antiretroviral therapy. A synbiotic formulation (Synbiotic 2000® containing 4 strains of probiotic bacteria (1010 each plus 4 nondigestible, fermentable dietary fibers (2.5 g each was provided each day, versus a fiber-only placebo formulation. The primary outcome was bacterial translocation. Secondary outcomes included the levels of supplemented bacteria in stool, the activation phenotype of peripheral T-cells and monocytes, and plasma levels of C-reactive protein and soluble CD14. Results Microbial translocation, as measured by plasma bacterial 16S ribosomal DNA concentration, was not altered by synbiotic treatment. In contrast, the synbiotic formulation resulted in significantly elevated levels of supplemented probiotic bacterial strains in stool, including L. plantarum and P. pentosaceus, with the colonization of these two species being positively correlated with each other. T-cell activation phenotype of peripheral blood lymphocytes showed modest changes in response to synbiotic exposure, with HLA-DR expression slightly elevated on a minor population of CD4+ T-cells which lack expression of HLA-DR or PD-1. In addition, CD38 expression on CD8+ T-cells was slightly lower in the fiber-only group. Plasma levels of soluble CD14 and C-reactive protein were unaffected by synbiotic treatment in this study. Conclusions

  20. Association of single nucleotide polymorphisms in the lens epithelium-derived growth factor (LEDGF/p75) with HIV-1 infection outcomes in Brazilian HIV-1+ individuals.

    Science.gov (United States)

    Passaes, Caroline Pereira Bittencourt; Cardoso, Cynthia Chester; Caetano, Diogo Gama; Teixeira, Sylvia Lopes Maia; Guimarães, Monick Lindenmeyer; Campos, Dayse Pereira; Veloso, Valdilea Gonçalves; Babic, Dunja Z; Stevenson, Mario; Moraes, Milton Ozório; Morgado, Mariza Gonçalves

    2014-01-01

    The lens epithelium-derived growth factor p75 (LEDGF/p75), coded by the PSIP1 gene, is an important host co-factor that interacts with HIV-1 integrase to target integration of viral cDNA into active genes. The aim of this study was to investigate the association of SNPs in the PSIP1 gene with disease outcome in HIV-1 infected patients. We performed a genetic association study in a cohort of 171 HIV-1 seropositive Brazilian individuals classified as rapid progressors (RP, n = 69), typical progressors (TP, n = 79) and long-term nonprogressors (LTNP, n = 23). The exonic SNP rs61744944 and 9 tag SNPs were genotyped. A group of 192 healthy subjects was analyzed to determine the frequency of SNPs and haplotypes in the general population. Linkage disequilibrium (LD) analyses indicated that the SNPs analyzed were not in high LD (r2<0.8). Logistic regression models suggested that patients carrying the T allele rs61744944 (472L) were more likely to develop a LTNP phenotype (OR = 4.98; p = 0.05) as compared to TP group. The same trend was observed when LTNPs were compared to the RP group (OR = 3.26). Results of haplotype analyses reinforced this association, since the OR values obtained for the haplotype carrying allele T at rs61744944 also reflected an association with LTNP status (OR = 6.05; p = 0.08 and OR = 3.44; p = 0.12 for comparisons to TP and RP, respectively). The rare missense variations Ile436Ser and Thr473Ile were not identified in the patients enrolled in this study. Gene expression analyses showed lower LEDGF/p75 mRNA levels in peripheral blood mononuclear cells obtained from HIV-1 infected individuals. However, these levels were not influenced by any of the SNPs investigated. In spite of the limited number of LTNPs, these data suggest that the PSIP1 gene could be associated with the outcome of HIV-1 infection. Further analyses of this gene may guide the identification of causative variants to help predict disease course.

  1. New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection.

    Science.gov (United States)

    Garcia-Perez, Javier; Rueda, Patricia; Staropoli, Isabelle; Kellenberger, Esther; Alcami, Jose; Arenzana-Seisdedos, Fernando; Lagane, Bernard

    2011-02-18

    CC chemokine receptor 5 (CCR5) is a G-protein-coupled receptor for the chemokines CCL3, -4, and -5 and a coreceptor for entry of R5-tropic strains of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T-cells. We investigated the mechanisms whereby nonpeptidic, low molecular weight CCR5 ligands block HIV-1 entry and infection. Displacement binding assays and dissociation kinetics demonstrated that two of these molecules, i.e. TAK779 and maraviroc (MVC), inhibit CCL3 and the HIV-1 envelope glycoprotein gp120 binding to CCR5 by a noncompetitive and allosteric mechanism, supporting the view that they bind to regions of CCR5 distinct from the gp120- and CCL3-binding sites. We observed that TAK779 and MVC are full and weak inverse agonists for CCR5, respectively, indicating that they stabilize distinct CCR5 conformations with impaired abilities to activate G-proteins. Dissociation of [(125)I]CCL3 from CCR5 was accelerated by TAK779, to a lesser extent by MVC, and by GTP analogs, suggesting that inverse agonism contributes to allosteric inhibition of the chemokine binding to CCR5. TAK779 and MVC also promote dissociation of [(35)S]gp120 from CCR5 with an efficiency that correlates with their ability to act as inverse agonists. Displacement experiments revealed that affinities of MVC and TAK779 for the [(35)S]gp120-binding receptors are in the same range (IC(50) ∼6.4 versus 22 nm), although we found that MVC is 100-fold more potent than TAK779 for inhibiting HIV infection. This suggests that allosteric CCR5 inhibitors not only act by blocking gp120 binding but also alter distinct steps of CCR5 usage in the course of HIV infection.

  2. Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature.

    Directory of Open Access Journals (Sweden)

    Amanda K Steele

    Full Text Available Systemic inflammation is a characteristic of both HIV-1 infection and aging ("inflammaging". Intestinal epithelial barrier damage (IEBD and microbial translocation (MT contribute to HIV-associated inflammation, but their impact on inflammaging remains unclear.Plasma biomarkers for IEBD (iFABP, MT (LPS, sCD14, T-cell activation (sCD27, and inflammation (hsCRP, IL-6 were measured in 88 HIV-1 uninfected (HIV(neg and 83 treated, HIV-1-infected (HIV(pos adults from 20-100 years old.Age positively correlated with iFABP (r = 0.284, p = 0.008, sCD14 (r = 0.646, p = <0.0001 and LPS (r = 0.421, p = 0.0002 levels in HIV(neg but not HIV(pos subjects. Age also correlated with sCD27, hsCRP, and IL-6 levels regardless of HIV status. Middle-aged HIV(pos subjects had elevated plasma biomarker levels similar to or greater than those of elderly HIV(neg subjects with the exception of sCD14. Clustering analysis described an inflammaging phenotype (IP based on iFABP, sCD14, sCD27, and hsCRP levels in HIV(neg subjects over 60 years of age. The IP in HIV(neg subjects was used to develop a classification model that was applied to HIV(pos subjects to determine whether HIV(pos subjects under 60 years of age were IP+. HIV(pos IP+ subjects were similar in age to IP- subjects but had a greater risk of cardiovascular disease (CVD based on Framingham risk score (p =  0.01.We describe a novel IP that incorporates biomarkers of IEBD, MT, immune activation as well as inflammation. Application of this novel IP in HIV-infected subjects identified a group at higher risk of CVD.

  3. Short Communication: Failures in Detecting HTLV-1 and HTLV-2 in Patients Infected with HIV-1.

    Science.gov (United States)

    Campos, Karoline Rodrigues; Gonçalves, Maria Gisele; Caterino-de-Araujo, Adele

    2017-04-01

    Changes in retrovirus acquisition/transmission behaviors have been reported in Brazil, with a concerning increase in HIV-1-infected individuals aged 15-39 years. In São Paulo, HIV-1/HTLV-1 and HIV-1/HTLV-2 coinfections have been associated with intravenous drug use and failure to detect HTLV-1/2 (human T cell lymphotropic virus types 1 and 2) with immunosuppression and the use of highly active antiretroviral therapy (HAART). Negative results for HTLV serologic [western blotting (WB)] and molecular [real-time PCR pol (qPCR)] confirmatory assays have been reported, whereas the best sensitivity has been found for INNO-LIA (LIA). In this study, we expand our previous data by analyzing a group of young patients (n = 1,383; median age 35.6 years) who recently acquired HIV by sexual contact, the majority of whom were HAART naïve, and comparing the performances of four HTLV confirmatory assays: LIA, WB, qPCR, and PCR-RFLP (tax). We confirmed HTLV infection in 58 (4.2%) blood samples: 29 HTLV-1, 24 HTLV-2, 1 HTLV-1+HTLV-2, and 4 HTLV. LIA, WB, qPCR, and PCR-RFLP sensitivities were 94.8%, 82.8%, 79.2%, and 74.5%, respectively. Associations of HTLV infection with female gender (OR = 2.28, 1.31-4.00) and age >40 years (p < .0001) were detected. The results confirm the low sensitivities of molecular assays and the best performance of LIA in detecting HTLV-1/2 in such patients. We hypothesize that the negative PCR results are due to the presence of defective provirus and/or low proviral load circulating in such patients, with inconclusive WB coinciding with the seroconversion period. Corroborating the associations obtained, repeated exposure is required for HTLV sexual transmission/acquisition, which is more efficient from male to female.

  4. Activation of HIV-1 from latent infection via synergy of RUNX1 inhibitor Ro5-3335 and SAHA.

    Directory of Open Access Journals (Sweden)

    Zachary Klase

    2014-03-01

    Full Text Available A major barrier to the elimination of HIV-1 infection is the presence of a pool of long-lived, latently infected CD4+ memory T-cells. The search for treatments to re-activate latent HIV to aid in clearance is hindered by the incomplete understanding of the mechanisms that lead to transcriptional silencing of viral gene expression in host cells. Here we identify a previously unknown role for RUNX1 in HIV-1 transcriptional latency. The RUNX proteins, in combination with the co-factor CBF-β, are critical transcriptional regulators in T-cells. RUNX1 strongly modulates CD4 expression and contributes to CD4+ T-cell function. We show that RUNX1 can bind DNA sequences within the HIV-1 LTR and that this binding represses transcription. Using patient samples we show a negative correlation between RUNX1 expression and viral load. Furthermore, we find that pharmacologic inhibition of RUNX1 by a small molecule inhibitor, Ro5-3335, synergizes with the histone deacetylase (HDAC inhibitor SAHA (Vorinostat to enhance the activation of latent HIV-1 in both cell lines and PBMCs from patients. Our findings indicate that RUNX1 and CBF-β cooperate in cells to modulate HIV-1 replication, identifying for the first time RUNX1 as a cellular factor involved in HIV-1 latency. This work highlights the therapeutic potential of inhibitors of RUNX1 to re-activate virus and aid in clearance of HIV-1.

  5. Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy.

    Science.gov (United States)

    Imamichi, Hiromi; Dewar, Robin L; Adelsberger, Joseph W; Rehm, Catherine A; O'Doherty, Una; Paxinos, Ellen E; Fauci, Anthony S; Lane, H Clifford

    2016-08-02

    Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5'LTR-to-3'LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of "defective" proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not "silent," but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.

  6. Activation of HIV-1 from latent infection via synergy of RUNX1 inhibitor Ro5-3335 and SAHA.

    Science.gov (United States)

    Klase, Zachary; Yedavalli, Venkat S R K; Houzet, Laurent; Perkins, Molly; Maldarelli, Frank; Brenchley, Jason; Strebel, Klaus; Liu, Paul; Jeang, Kuan-Teh

    2014-03-01

    A major barrier to the elimination of HIV-1 infection is the presence of a pool of long-lived, latently infected CD4+ memory T-cells. The search for treatments to re-activate latent HIV to aid in clearance is hindered by the incomplete understanding of the mechanisms that lead to transcriptional silencing of viral gene expression in host cells. Here we identify a previously unknown role for RUNX1 in HIV-1 transcriptional latency. The RUNX proteins, in combination with the co-factor CBF-β, are critical transcriptional regulators in T-cells. RUNX1 strongly modulates CD4 expression and contributes to CD4+ T-cell function. We show that RUNX1 can bind DNA sequences within the HIV-1 LTR and that this binding represses transcription. Using patient samples we show a negative correlation between RUNX1 expression and viral load. Furthermore, we find that pharmacologic inhibition of RUNX1 by a small molecule inhibitor, Ro5-3335, synergizes with the histone deacetylase (HDAC) inhibitor SAHA (Vorinostat) to enhance the activation of latent HIV-1 in both cell lines and PBMCs from patients. Our findings indicate that RUNX1 and CBF-β cooperate in cells to modulate HIV-1 replication, identifying for the first time RUNX1 as a cellular factor involved in HIV-1 latency. This work highlights the therapeutic potential of inhibitors of RUNX1 to re-activate virus and aid in clearance of HIV-1.

  7. Sugar-binding proteins potently inhibit dendritic cell human immunodeficiency virus type 1 (HIV-1) infection and dendritic-cell-directed HIV-1 transfer.

    Science.gov (United States)

    Turville, Stuart G; Vermeire, Kurt; Balzarini, Jan; Schols, Dominique

    2005-11-01

    Both endocytic uptake and viral fusion can lead to human immunodeficiency virus type 1 (HIV-1) transfer to CD4+ lymphocytes, either through directional regurgitation (infectious transfer in trans [I-IT]) or through de novo viral production in dendritic cells (DCs) resulting in a second-phase transfer to CD4+ lymphocytes (infectious second-phase transfer [I-SPT]). We have evaluated in immature monocyte-derived DCs both pathways of transfer with regard to their susceptibilities to being blocked by potential microbicidal compounds, including cyanovirin (CNV); the plant lectins Hippeastrum hybrid agglutinin, Galanthus nivalis agglutinin, Urtica dioica agglutinin, and Cymbidium hybrid agglutinin; and the glycan mannan. I-IT was a relatively inefficient means of viral transfer compared to I-SPT at both high and low levels of the viral inoculum. CNV was able to completely block I-IT at 15 microg/ml. All other compounds except mannan could inhibit I-IT by at least 90% when used at doses of 15 microg/ml. In contrast, efficient inhibition of I-SPT was remarkably harder to achieve, as 50% effective concentration levels for plant lectins and CNV to suppress this mode of HIV-1 transfer increased significantly. Thus, our findings indicate that I-SPT may be more elusive to targeting by antiviral drugs and stress the need for drugs affecting the pronounced inhibition of the infection of DCs by HIV-1.

  8. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Michael Huber

    2006-11-01

    Full Text Available BACKGROUND: To explore the possibility that antibody-mediated complement lysis contributes to viremia control in HIV-1 infection, we measured the activity of patient plasma in mediating complement lysis of autologous primary virus. METHODS AND FINDINGS: Sera from two groups of patients-25 with acute HIV-1 infection and 31 with chronic infection-were used in this study. We developed a novel real-time PCR-based assay strategy that allows reliable and sensitive quantification of virus lysis by complement. Plasma derived at the time of virus isolation induced complement lysis of the autologous virus isolate in the majority of patients. Overall lysis activity against the autologous virus and the heterologous primary virus strain JR-FL was higher at chronic disease stages than during the acute phase. Most strikingly, we found that plasma virus load levels during the acute but not the chronic infection phase correlated inversely with the autologous complement lysis activity. Antibody reactivity to the envelope (Env proteins gp120 and gp41 were positively correlated with the lysis activity against JR-FL, indicating that anti-Env responses mediated complement lysis. Neutralization and complement lysis activity against autologous viruses were not associated, suggesting that complement lysis is predominantly caused by non-neutralizing antibodies. CONCLUSIONS: Collectively our data provide evidence that antibody-mediated complement virion lysis develops rapidly and is effective early in the course of infection; thus it should be considered a parameter that, in concert with other immune functions, steers viremia control in vivo.

  9. The CD16+ monocyte subset is more permissive to infection and preferentially harbors HIV-1 in vivo.

    Science.gov (United States)

    Ellery, Philip J; Tippett, Emma; Chiu, Ya-Lin; Paukovics, Geza; Cameron, Paul U; Solomon, Ajantha; Lewin, Sharon R; Gorry, Paul R; Jaworowski, Anthony; Greene, Warner C; Sonza, Secondo; Crowe, Suzanne M

    2007-05-15

    HIV-1 persists in peripheral blood monocytes in individuals receiving highly active antiretroviral therapy (HAART) with viral suppression, despite these cells being poorly susceptible to infection in vitro. Because very few monocytes harbor HIV-1 in vivo, we considered whether a subset of monocytes might be more permissive to infection. We show that a minor CD16+ monocyte subset preferentially harbors HIV-1 in infected individuals on HAART when compared with the majority of monocytes (CD14highCD16-). We confirmed this by in vitro experiments showing that CD16+ monocytes were more susceptible to CCR5-using strains of HIV-1, a finding that is associated with higher CCR5 expression on these cells. CD16+ monocytes were also more permissive to infection with a vesicular stomatitis virus G protein-pseudotyped reporter strain of HIV-1 than the majority of monocytes, suggesting that they are better able to support HIV-1 replication after entry. Consistent with this observation, high molecular mass complexes of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) were observed in CD16+ monocytes that were similar to those observed in highly permissive T cells. In contrast, CD14highCD16- monocytes contained low molecular mass active APOBEC3G, suggesting this is a mechanism of resistance to HIV-1 infection in these cells. Collectively, these data show that CD16+ monocytes are preferentially susceptible to HIV-1 entry, more permissive for replication, and constitute a continuing source of viral persistence during HAART.

  10. Fluconazole for ketoconazole-resistant oropharyngeal candidiasis in HIV-1 infected patients

    DEFF Research Database (Denmark)

    Thorsen, S; Mathiesen, Lars Reinhardt

    1990-01-01

    The efficacy of fluconazole in doses ranging from 50 to 200 mg/day in controlling oropharyngeal candidiasis was retrospectively evaluated in 16 consecutive HIV-1-infected patients. 13 patients received fluconazole due to failure of treatment with ketoconazole, and among these 11 (84%) initially...... showed complete or partial remission of oropharyngeal candidiasis. 3 (27%) of these subsequently developed failure of treatment within a median observation period of 38 days. No major toxicities were observed. Fluconazole appears promising in the therapy of ketoconazole-resistant candidiasis....

  11. Asymptotic behaviors of a cell-to-cell HIV-1 infection model perturbed by white noise

    Science.gov (United States)

    Liu, Qun

    2017-02-01

    In this paper, we analyze a mathematical model of cell-to-cell HIV-1 infection to CD4+ T cells perturbed by stochastic perturbations. First of all, we investigate that there exists a unique global positive solution of the system for any positive initial value. Then by using Lyapunov analysis methods, we study the asymptotic property of this solution. Moreover, we discuss whether there is a stationary distribution for this system and if it owns the ergodic property. Numerical simulations are presented to illustrate the theoretical results.

  12. Warfarin-induced skin necrosis in HIV-1-infected patients with tuberculosis and venous thrombosis.

    Science.gov (United States)

    Bhaijee, F; Wainwright, H; Meintjes, G; Wilkinson, R J; Todd, G; De Vries, E; Pepper, D J

    2010-06-01

    At the turn of the century, only 300 cases of warfarin-induced skin necrosis (WISN) had been reported. WISN is a rare but potentially fatal complication of warfarin therapy. There are no published reports of WISN occurring in patients with HIV-1 infection or tuberculosis (TB). We retrospectively reviewed cases of WISN presenting from April 2005 to July 2008 at a referral hospital in Cape Town, South Africa. Six cases of WISN occurred in 973 patients receiving warfarin therapy for venous thrombosis (0.62%, 95% CI 0.25 - 1.37%). All 6 cases occurred in HIV-1-infected women (median age 30 years, range 27 - 42) with microbiologically confirmed TB and venous thrombosis. All were profoundly immunosuppressed (median CD4+ count at TB diagnosis 49 cells/microl, interquartile range 23 - 170). Of the 3 patients receiving combination antiretroviral therapy, 2 had TB-IRIS (immune reconstitution inflammatory syndrome). The median interval from initiation of antituberculosis treatment to venous thrombosis was 37 days (range 0 - 150). The median duration of parallel heparin and warfarin therapy was 2 days (range 1 - 6). WISN manifested 6 days (range 4 - 8) after initiation of warfarin therapy. The international normalised ratio (INR) at WISN onset was supra-therapeutic, median 6.2 (range 3.8 - 6.6). Sites of WISN included breasts, buttocks and thighs. Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 - 37 days after WISN onset. In 4 patients, the median interval from WISN onset to death was 43 days (range 25 - 45). One of the 2 patients who survived underwent bilateral mastectomies and extensive skin grafting at a specialist centre. This is one of the largest case series of WISN. We report a novel clinical entity: WISN in HIV-1 infected patients with TB and venous thrombosis. The

  13. Leptin and adiponectin, but not IL18, are related with insulin resistance in treated HIV-1-infected patients with lipodystrophy.

    Science.gov (United States)

    Veloso, Sergi; Escoté, Xavier; Ceperuelo-Mallafré, Victòria; López-Dupla, Miguel; Peraire, Joaquim; Viladés, Consuelo; Domingo, Pere; Castro, Antoni; Olona, Montserrat; Sirvent, Joan-Josep; Leal, Manuel; Vendrell, Joan; Richart, Cristóbal; Vidal, Francesc

    2012-05-01

    Leptin, adiponectin and IL18 are adipokines related with obesity, insulin resistance and dyslipidemia in the general population. Treated HIV-1-infected patients with lipodystrophy may develop insulin resistance and proatherogenic dyslipidemia. We assessed the relationship between plasma adipokine levels, adipokine genetics, lipodystrophy and metabolic disturbances. Plasma leptin, adiponectin and IL18 levels were assessed in 446 individuals: 282 HIV-1-infected patients treated with antiretroviral drugs (132 with lipodystrophy and 150 without) and 164 uninfected controls (UC). The LEP2410A>G, LEPRQ223R, ADIPQ276G>T, ADIPOR2-Intron5A>G and IL18-607C>A polymorphisms were validated by sequencing. Leptin levels were higher in UC than in HIV-1-infected, either with or without lipodystrophy (plipodystrophy compared with those without lipodystrophy (p=0.006). In patients with lipodystrophy, leptin had a positive correlation with insulin and with HOMA-IR. Adiponectin levels were non-significantly different in UC and HIV-1-infected patients. Patients with lipodystrophy had lower adiponectin levels than non-lipodystrophy subjects (plipodystrophy, adiponectin was negatively correlated with insulin, HOMA-IR and triglycerides. Plasma IL18 levels were higher in HIV-1-infected patients compared with UC (plipodystrophy. In patients with lipodystrophy there was a negative correlation between IL18 levels and LDLc. Genetic analyses indicated no significant associations with lipodystrophy nor with insulin resistance or with lipid abnormalities. In conclusion, HIV-1-infected patients have reduced plasma leptin levels. This reduction is magnified in patients with lipodystrophy whose adiponectin levels were lower than that of non-lipodystrophy subjects. Plasma IL18 levels are increased in infected patients irrespective of the presence of lipodystrophy. The polymorphisms assessed are not associated with lipodystrophy or metabolic disturbances in treated HIV-1-infected patients.

  14. Restricted isotype, distinct variable gene usage, and high rate of gp120 specificity of HIV-1 envelope-specific B cells in colostrum compared with those in blood of HIV-1-infected, lactating African women.

    Science.gov (United States)

    Sacha, C R; Vandergrift, N; Jeffries, T L; McGuire, E; Fouda, G G; Liebl, B; Marshall, D J; Gurley, T C; Stiegel, L; Whitesides, J F; Friedman, J; Badiabo, A; Foulger, A; Yates, N L; Tomaras, G D; Kepler, T B; Liao, H X; Haynes, B F; Moody, M A; Permar, S R

    2015-03-01

    A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(∼)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination.

  15. Resilience and Life Expectations of Perinatally HIV-1 Infected Adolescents in France

    Science.gov (United States)

    Funck-Brentano, Isabelle; Assoumou, Lambert; Veber, Florence; Moshous, Despina; Frange, Pierre; Blanche, Stéphane

    2016-01-01

    Background: Resilience of perinatally HIV-infected youth in European countries is poorly studied. Life satisfaction and expectations for adulthood are rarely examined. Objective: This cross-sectional, descriptive study of a French cohort of 54 perinatally HIV-infected adolescents raised in France (age 14-20 years) aimed to (1) evaluate their psychosocial adjustment, (2) identify their expectations for adulthood and (3) delineate risk and protective factors associated with mental health, life satisfaction, and HIV-1 viral load level. Method: Medical evaluation, psychological semi-structured interview, and self-report questionnaires were used. Results: All the adolescents had been receiving Highly Active Anti-Retroviral Therapy (HAART) for 9 to 11 years and 2/3 were healthy with controlled viral load (adolescent relationships and high life satisfaction were significant protective factors for controlled viral load. Conclusion: These data indicate psychosocial resilience among perinatally HIV-1 infected adolescents with 10 years of HAART treatment. These findings demonstrate the influence of life satisfaction, parent’s life status and quality of caregiver-adolescent relationships on resilience and health outcomes in these patients. We conclude that healthcare providers should attend to these factors. PMID:27990195

  16. Resilience and Life Expectations of Perinatally HIV-1 Infected Adolescents in France.

    Science.gov (United States)

    Funck-Brentano, Isabelle; Assoumou, Lambert; Veber, Florence; Moshous, Despina; Frange, Pierre; Blanche, Stéphane

    2016-01-01

    Resilience of perinatally HIV-infected youth in European countries is poorly studied. Life satisfaction and expectations for adulthood are rarely examined. This cross-sectional, descriptive study of a French cohort of 54 perinatally HIV-infected adolescents raised in France (age 14-20 years) aimed to (1) evaluate their psychosocial adjustment, (2) identify their expectations for adulthood and (3) delineate risk and protective factors associated with mental health, life satisfaction, and HIV-1 viral load level. Medical evaluation, psychological semi-structured interview, and self-report questionnaires were used. All the adolescents had been receiving Highly Active Anti-Retroviral Therapy (HAART) for 9 to 11 years and 2/3 were healthy with controlled viral load (life satisfaction. They viewed HIV as having only minor impact on their current daily life and had positive expectations for adulthood. However, 46% exhibited psychiatric symptomatology. Multivariable analysis showed that having a deceased parent and current worries about HIV were substantial risk factors for psychiatric symptoms. Having two living parents and being satisfied with life were protective factors for mental health. Good quality of caregiver-adolescent relationships and high life satisfaction were significant protective factors for controlled viral load. These data indicate psychosocial resilience among perinatally HIV-1 infected adolescents with 10 years of HAART treatment. These findings demonstrate the influence of life satisfaction, parent's life status and quality of caregiver-adolescent relationships on resilience and health outcomes in these patients. We conclude that healthcare providers should attend to these factors.

  17. Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells

    Science.gov (United States)

    Hansen, Erik C; Ransom, Monica; Hesselberth, Jay R; Hosmane, Nina N; Capoferri, Adam A; Bruner, Katherine M; Pollack, Ross A; Zhang, Hao; Drummond, Michael Bradley; Siliciano, Janet M; Siliciano, Robert; Stivers, James T

    2016-01-01

    We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection. DOI: http://dx.doi.org/10.7554/eLife.18447.001 PMID:27644592

  18. Lack of differences in HIV-1 nef functional domains in infected chinese blood donors at different stages of disease.

    Science.gov (United States)

    Chen, Yue; Caruso, Lori; Shen, Chengli; Wu, Hao; Zhou, Yushen; Gupta, Phalguni

    2007-09-01

    HIV-1 nef regions were amplified by polymerase chain reaction and sequenced from DNA samples of five asymptomatic subjects and five AIDS patients from a cohort of HIV-1-infected Chinese plasma and blood donors. Sequence analysis revealed that regardless of the stage of disease, each patient's HIV-1 nef sequences belonged to the clade B' subtype. Although there are some differences between the sequences from different patients, no significant differences have been detected in nef nucleotide sequences or functional motifs in the deduced amino acid sequences from patients at different stages of the disease. Furthermore, the predicted binding motifs of HLA-A2 and HLA-A11 were highly conserved among patient nef sequences. These results will contribute to a better understanding of the pathogenesis of circulating HIV-1 in infected Chinese former blood donors and may have important implications in developing an epitope-based vaccine suitable for Chinese blood donors.

  19. Effect of humoral immunity on HIV-1 dynamics with virus-to-target and infected-to-target infections

    Science.gov (United States)

    Elaiw, A. M.; Raezah, A. A.; Alofi, A. S.

    2016-08-01

    We consider an HIV-1 dynamics model by incorporating (i) two routes of infection via, respectively, binding of a virus to a receptor on the surface of a target cell to start genetic reactions (virus-to-target infection), and the direct transmission from infected cells to uninfected cells through the concept of virological synapse in vivo (infected-to-target infection); (ii) two types of distributed-time delays to describe the time between the virus or infected cell contacts an uninfected CD4+ T cell and the emission of new active viruses; (iii) humoral immune response, where the HIV-1 particles are attacked by the antibodies that are produced from the B lymphocytes. The existence and stability of all steady states are completely established by two bifurcation parameters, R 0 (the basic reproduction number) and R 1 (the viral reproduction number at the chronic-infection steady state without humoral immune response). By constructing Lyapunov functionals and using LaSalle's invariance principle, we have proven that, if R 0 ≤ 1 , then the infection-free steady state is globally asymptotically stable, if R 1 ≤ 1 1 , then the chronic-infection steady state with humoral immune response is globally asymptotically stable. We have performed numerical simulations to confirm our theoretical results.

  20. Antiretroviral salvage therapy for multiclass drug-resistant HIV-1-infected patients: from clinical trials to daily clinical practice.

    Science.gov (United States)

    Imaz, Arkaitz; Falcó, Vicenç; Ribera, Esteban

    2011-01-01

    Drug resistance is one of the key problems in the management of long-term HIV-1-infected patients. Due to cross-resistance patterns within classes, broad resistance to the three original antiretroviral classes can develop in some patients, mainly those with extensive antiretroviral treatment experience and multiple treatment failures. Triple-class-resistant HIV-1 infection has been associated with a higher risk of clinical progression and death. Additionally, it increases the probability of transmission of multidrug-resistant HIV-1 strains. Over the last years, the availability of new antiretroviral agents against novel targets (integrase inhibitors and CCR5 antagonists), and new drugs within old classes (nonnucleoside reverse transcriptase inhibitors and protease inhibitors) has opened a range of new therapeutic options for patients with multiclass drug-resistant HIV-