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Sample records for acute hiv-1 infection

  1. Differences in Clinical Manifestations of Acute and Early HIV-1 Infection between HIV-1 Subtypes in African Women

    Lemonovich, Tracy L.; Watkins, Richard R.; Morrison, Charles S.; Kwok, Cynthia; Chipato, Tsungai; Musoke, Robert; Arts, Eric J; Nankya, Immaculate; Salata, Robert A.

    2015-01-01

    Little is known about the differences in clinical manifestations between women with various HIV-1 subtypes during acute (AI) and early (EI) HIV infection. In a longitudinal cohort study, clinical signs and symptoms among Uganda and Zimbabwe women with AI and EI were compared with HIV-negative controls; symptoms were assessed quarterly for 15 to 24 months. Early HIV infection was defined as the first visit during which a woman tested HIV antibody positive. Women who were HIV negative serologic...

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

    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

  3. Multiple T-cell responses are associated with better control of acute HIV-1 infection: An observational study.

    Sun, Jianping; Zhao, Yan; Peng, Yanchun; Han, Zhen; Liu, Guihai; Qin, Ling; Liu, Sai; Sun, Huanhuan; Wu, Hao; Dong, Tao; Zhang, Yonghong

    2016-07-01

    Cytotoxic T lymphocyte (CTL) responses play pivotal roles in controlling the replication of human immunodeficiency virus type 1 (HIV-1), but the correlation between CTL responses and the progression of HIV-1 infection are controversial on account of HIV immune escape mutations driven by CTL pressure were reported.The acute HIV-1-infected patients from Beijing were incorporated into our study to investigate the effects of CTL response on the progression of HIV-1 infection.A longitudinal study was performed on acute HIV-1-infected patients to clarify the kinetic of T-cell responses, the dynamic of escape mutations, as well as the correlation between effective T-cell response and the progression of HIV infection.Seven human leukocyte antigen-B51+ (HLA-B51+) individuals were screened from 105 acute HIV-1 infectors. The detailed kinetic of HLA-B51-restricted CTL responses was described through blood sampling time points including seroconversion, 3 and 6 months after HIV-1 infection in the 7 HLA-B51+ individuals, by using 16 known HLA-B51 restricted epitopes. Pol743-751 (LPPVVAKEI, LI9), Pol283-289 (TAFTIPSI, TI8), and Gag327-3459 (NANPDCKTI, NI9) were identified as 3 dominant epitopes, and ranked as starting with LI9, followed by TI8 and NI9 in the ability to induce T-cell responses. The dynamics of escape mutations in the 3 epitopes were also found with the same order as T-cell response, by using sequencing for viral clones on blood sampling at seroconversion, 3 and 6 months after HIV-1 infection.We use solid evidence to demonstrate the correlation between T-cell response and HIV-1 mutation, and postulate that multiple T-cell responses might benefit the control of HIV-1 infection, especially in acute infection phase. PMID:27472741

  4. Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection.

    Eric S Rosenberg

    Full Text Available BACKGROUND: An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099 METHODS: Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17-23 weeks after treatment discontinuation. RESULTS: Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log(10 HIV-1 RNA copies/mL, respectively. CONCLUSIONS: The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1

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

    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.

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

    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

  7. Infected Cell Killing by HIV-1 Protease Promotes NF-κB Dependent HIV-1 Replication

    Bren, Gary D.; Joe Whitman; Nathan Cummins; Brett Shepard; Rizza, Stacey A; Trushin, Sergey A.; Badley, Andrew D

    2008-01-01

    Acute HIV-1 infection of CD4 T cells often results in apoptotic death of infected cells, yet it is unclear what evolutionary advantage this offers to HIV-1. Given the independent observations that acute T cell HIV-1 infection results in (1) NF-kappaB activation, (2) caspase 8 dependent apoptosis, and that (3) caspase 8 directly activates NF-kappaB, we questioned whether these three events might be interrelated. We first show that HIV-1 infected T cell apoptosis, NF-kappaB activation, and casp...

  8. Episodes of Guillain-Barré syndrome associated with the acute phase of HIV-1 infection and with recurrence of viremia

    Castro Gleusa de

    2006-01-01

    Full Text Available We report a severe case of Guillain-Barré syndrome (GBS characterized by flaccid areflexive tetraplegia and signs of autonomic instability related to acute HIV-1 infection, and the occurrence of relapse episodes coinciding with the detection of HIV-1 RNA in blood during the phase of irregular treatment with antiretroviral agents. The patient has been asymptomatic for 3 years and has an HIV-1 load below the limit of detection. The recurrence of GBS in this case may be related to alterations of the immunologic response caused by disequilibrium in the host-HIV relationship due to the increase in HIV-1 viremia.

  9. Participation in Research Involving Novel Sampling and Study Designs to Identify Acute HIV-1 Infection among Minority Men Who Have Sex with Men

    Rodriguez, Kristina; Castor, Delivette; Mah, Timothy; Cook, Stephanie; Auguiste, Lex M.; Halkitis, Perry N.; Markowitz, Marty

    2013-01-01

    HIV-1 infection disproportionally affects African American and Latino men who have sex with men (MSM) and their inclusion in biomedical and behavioral research is critical to understanding and addressing HIV vulnerability. Using focus groups, we sought to understand the perceptions related to participating in biomedical research of acute/recent HIV-1 infection (AHI) using complex sampling and data collection methods to reach this hidden group at highest risk of acquiring and transmitting HIV....

  10. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection.

    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.

  11. Brain Invasion by CD4(+) T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice.

    Wu, Xilin; Liu, Li; Cheung, Ka-Wai; Wang, Hui; Lu, Xiaofan; Cheung, Allen Ka Loon; Liu, Wan; Huang, Xiuyan; Li, Yanlei; Chen, Zhiwei W; Chen, Samantha M Y; Zhang, Tong; Wu, Hao; Chen, Zhiwei

    2016-09-01

    Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is one of the common causes of cognitive dysfunction and morbidity among infected patients. However, to date, it remains unknown if a transmitted/founder (T/F) HIV-1 leads to neurological disorders during acute phase of infection. Since it is impossible to answer this question in humans, we studied NOD.Cg-Prkdc scid Il2rgtm1Wjl/SzJ mice (NSG) reconstituted with human PBMC (NSG-HuPBL), followed by the peritoneal challenge with the chronic HIV-1JR-FL and the T/F HIV-1BJZS7, respectively. By measuring viral load, P24 antigenemia and P24(+) cells in peripheral blood and various tissue compartments, we found that systemic infections were rapidly established in NSG-HuPBL mice by both HIV-1 strains. Although comparable peripheral viral loads were detected during acute infection, the T/F virus appeared to cause less CD4(+) T cell loss and less numbers of infected cells in different organs and tissue compartments. Both viruses, however, invaded brains with P24(+)/CD3(+) T cells detected primarily in meninges, cerebral cortex and perivascular areas. Critically, brain infections with HIV-1JR-FL but not with HIV-1BJZS7 resulted in damaged neurons together with activated microgliosis and astrocytosis as determined by significantly increased numbers of Iba1(+) microglial cells and GFAP(+) astrocytes, respectively. The increased Iba1(+) microglia was correlated positively with levels of P24 antigenemia and negatively with numbers of NeuN(+) neurons in brains of infected animals. Our findings, therefore, indicate the establishment of two useful NSG-HuPBL models, which may facilitate future investigation of mechanisms underlying HIV-1-induced microgliosis and astrocytosis. PMID:26838362

  12. Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.

    Holger B Kramer

    2010-05-01

    Full Text Available The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, beta-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA occurred as early as 5-7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha-1-antitrypsin (AAT, termed virus inhibitory peptide (VIRIP, was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.

  13. Challenges of Diagnosing Acute HIV-1 Subtype C Infection in African Women: Performance of a Clinical Algorithm and the Need for Point-of-Care Nucleic-Acid Based Testing

    Mlisana, Koleka; Sobieszczyk, Magdalena; Werner, Lise; Feinstein, Addi; van Loggerenberg, Francois; NAICKER, Nivashnee; Williamson, Carolyn; Garrett, Nigel

    2013-01-01

    Background Prompt diagnosis of acute HIV infection (AHI) benefits the individual and provides opportunities for public health intervention. The aim of this study was to describe most common signs and symptoms of AHI, correlate these with early disease progression and develop a clinical algorithm to identify acute HIV cases in resource limited setting. Methods 245 South African women at high-risk of HIV-1 were assessed for AHI and received monthly HIV-1 antibody and RNA testing. Signs and symp...

  14. 中国HIV-1急性期感染25例患者临床特点分析%The clinical characteristics of twenty-five cases of acute HIV-1 infection in China

    李宁; 郭伏平; 李冠群; 韩扬; 谢静; 李雁凌; 祝婷; 李太生

    2015-01-01

    Objective To summarize the clinical features,immunological and virological characteristics of HIV-1 infected patients in the acute phase for the sake of improving the understanding of acute HIV-1 infection and early diagnosis.Methods To retrospectively analyze the clinical manifestation and laboratory data of 25 patients with acute HIV infection,who were admitted to the Department of Infectious Diseases,Peking Union Medical College Hospital from 2006 to 2013.Results Among the total 25 patients,19 (76%) patients were sexually transmitted,including 17 (68%) of whom were homosexual.Twenty two (88%) patients presented significant symptoms.Common symptoms consisted of fever (15 patients,60%),cervical lymphoadenopathy (8 patients,32%),skin rashes (6 patients,24%),diarrhea (5 patients,20%),shortness of breath (3 patients,12%),sore throat (3 patients,12%),and cough (3 patients,12%),while only one case represented as Guillain-Barré syndrome,upper arm cellulitis,headache and vomiting,and perianal abscess.Laboratory examination indicated elevated peripheral lymphocytes (13 patients,52%),abnormal liver function (11 patients,44%),thrombocytopenia (1 patients,4%).Notably,2 patients (8%) revealed negative results of HIV antibody,who were diagnosed with positive plasma viral load.The average viral load was (4.68 ± 0.83) lg copies/ml.CD4+ T cell count was 473 (343,621) cells/μl.CD8+ T cell count was 1 296 (997,2 177) cells/pl with maximal value of 7 984 cells/μl.The CD4/CD8 ratio was 0.33 (0.22,0.53) including 24 (96%) patients with obvious inverted ratio.The positive rates of immune activation markers HLA-DR and CD38 on the surface of CD8+ T cells were (74.9 ± 16.1) % and (84.9 ± 12.5) % respectively.The viral load had a significant positive correlation with the expression of HLA-DR and CD38.Conclusions The most common symptoms of acute HIV-1 infection are fever,cervical lymphadenopathy,skin rashes and diarrhea.Significantly elevated CD8+ T

  15. Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner.

    Rajeev Mehla

    Full Text Available HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC -alpha and -delta, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC involving stress induced AMP Kinase (AMPK inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs.

  16. NKT cells in HIV-1 infection

    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.

  17. Intestinal microbiota and HIV-1 infection

    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.

  18. HIV-1 RNA quantification in CRF02_AG HIV-1 infection: too easy to make mistakes.

    Tatarelli, Paola; Taramasso, Lucia; Di Biagio, Antonio; Sticchi, Laura; Nigro, Nicola; Barresi, Renata; Viscoli, Claudio; Bruzzone, Bianca

    2016-04-01

    The number of patients newly infected by HIV-1 non-B subtypes and circulating recombinant forms (CRFs) is increasing worldwide, including in the western countries. We report on a primary HIV-1 infection in a Caucasian patient. A routine quantitative assay (Nuclisens EasyQ HIV-1 2.0, BioMérieux SA) showed 6,700 HIV-1 RNA copies/ml. A combined antiretroviral therapy (cART) consistent with low baseline HIV-1 RNA was started. Few days later, the analysis performed with REGA HIV-1 Subtyping Tool - Version 3.0 attributed the HIV-1 sequence to the CRF02_AG recombinant form. Therefore, a second real-time PCR assay was performed, using the Versant HIV-1 RNA 1.0 Assay (kPCR) (Siemens HealthCare Diagnostics) which revealed a HIV-1 RNA of 230,000 copies/ml. Consequently, the ongoing cART was potentiated. This case suggests that the wide genetic variability of HIV-1 subtypes may affect the capability of the commonly used assays to detect and accurately quantify HIV-1 RNA in non-B subtypes and CRFs. In presence of CRFs different commercial HIV-1 RNA tests should be performed to find the most reliable for viral load quantification at the diagnosis, because it influences the choice of cART, and during the follow-up. Indeed, international guidelines for HIV-1 infection management suggest to monitor patient' HIV-RNA with the same assay over the course of treatment. As different commercial tests can be performed in the same laboratory with considerable difficulty, the laboratory should select an assay that is suitable not only for the more prevalent strain, but also for less frequent ones that, nevertheless, can occur. Then, knowing and investigating the spread of non-B strains has essential clinical and laboratory implications. PMID:27196556

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

    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. PMID:26650729

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

    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. PMID:27199430

  1. N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression

    Tirumuru, Nagaraja; Zhao, Boxuan Simen; Lu, Wuxun; Lu, Zhike; He, Chuan; Wu, Li

    2016-01-01

    The internal N6-methyladenosine (m6A) methylation of eukaryotic nuclear RNA controls post-transcriptional gene expression, which is regulated by methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers) in cells. The YTH domain family proteins (YTHDF1–3) bind to m6A-modified cellular RNAs and affect RNA metabolism and processing. Here, we show that YTHDF1–3 proteins recognize m6A-modified HIV-1 RNA and inhibit HIV-1 infection in cell lines and primary CD4+ T-cells. We further mapped the YTHDF1–3 binding sites in HIV-1 RNA from infected cells. We found that the overexpression of YTHDF proteins in cells inhibited HIV-1 infection mainly by decreasing HIV-1 reverse transcription, while knockdown of YTHDF1–3 in cells had the opposite effects. Moreover, silencing the m6A writers decreased HIV-1 Gag protein expression in virus-producing cells, while silencing the m6A erasers increased Gag expression. Our findings suggest an important role of m6A modification of HIV-1 RNA in viral infection and HIV-1 protein synthesis. DOI: http://dx.doi.org/10.7554/eLife.15528.001 PMID:27371828

  2. Purinergic Receptors: Key Mediators of HIV-1 Infection and Inflammation

    Swartz, Talia H.; Dubyak, George R.; Chen, Benjamin K.

    2015-01-01

    Human immunodeficiency virus type 1 (HIV-1) causes a chronic infection that afflicts more than 30 million individuals worldwide. While the infection can be suppressed with potent antiretroviral therapies, individuals infected with HIV-1 have elevated levels of inflammation as indicated by increased T cell activation, soluble biomarkers, and associated morbidity and mortality. A single mechanism linking HIV-1 pathogenesis to this inflammation has yet to be identified. Purinergic receptors are ...

  3. Neutralizing antibodies in slowly progressing HIV-1 infection

    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 indi...

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

    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. PMID:27049645

  5. Cyclophilin B enhances HIV-1 infection.

    DeBoer, Jason; Madson, Christian J; Belshan, Michael

    2016-02-01

    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. PMID:26774171

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

    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

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

    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.

  8. Prevalence and Correlates of Helminth Co-infection in Kenyan HIV-1 Infected Adults

    Walson, Judd L; Stewart, Barclay T; Sangaré, Laura; Mbogo, Loice W.; Otieno, Phelgona A.; Piper, Benjamin K. S.; Richardson, Barbra A.; John-Stewart, Grace

    2010-01-01

    Background Deworming HIV-1 infected individuals may delay HIV-1 disease progression. It is important to determine the prevalence and correlates of HIV-1/helminth co-infection in helminth-endemic areas. Methods HIV-1 infected individuals (CD4>250 cells/ul) were screened for helminth infection at ten sites in Kenya. Prevalence and correlates of helminth infection were determined. A subset of individuals with soil-transmitted helminth infection was re-evaluated 12 weeks following albendazole the...

  9. Schistosomiasis and HIV-1 infection in rural Zimbabwe

    Kallestrup, Per; Zinyama, Rutendo; Gomo, Exnevia; Butterworth, Anthony E; van Dam, Govert J; Erikstrup, Christian; Ullum, Henrik

    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 ...

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

    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.

  11. Hematological Predictors of Increased Severe Anemia in Kenyan Children Co-infected with Plasmodium falciparum and HIV-1

    Davenport, Gregory C.; Ouma, Collins; Hittner, James B; Were, Tom; Ouma, Yamo; Ong'echa, John M.; PERKINS, Douglas J.

    2010-01-01

    Malaria and HIV-1 are co-endemic in many developing countries, with anemia being the most common pediatric hematological manifestation of each disease. Anemia is also one of the primary causes of mortality in children mono-infected with either malaria or HIV-1. Although our previous results showed HIV-1(+) children with acute Plasmodium falciparum malaria [Pf(+)] have more profound anemia, potential causes of severe anemia in co-infected children remain unknown. As such, children with P. falc...

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

    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.

  13. Short Communication: Circulating Plasma HIV-1 Viral Protein R in Dual HIV-1/Tuberculosis Infection

    Toossi, Zahra; Liu, Shigou; Wu, Mianda; Mayanja-Kizza, Harriet; Hirsch, Christina S.

    2014-01-01

    Circulating free HIV-1 viral protein R (Vpr) is found in up to one third of subjects with HIV-1 infection. Free Vpr presumably shares some of the immunopathogenic effects of cell-associated Vpr. Here we assessed Vpr in plasma and pleural fluid from HIV/tuberculosis (TB) dually infected subjects with pleural TB and from plasma of patients with pulmonary HIV/TB. Vpr was assessed by western blot analysis. In plasma from HIV/TB subjects with pulmonary TB free Vpr could be detected in 47%. Only on...

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

    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.

  15. HIV-1 Envelope Induces Memory B Cell Responses That Correlate with Plasma Antibody Levels after Envelope gp120 Protein Vaccination or HIV-1 Infection1

    Bonsignori, Mattia; Moody, M. Anthony; Parks, Robert J.; Holl, T. Matt; Kelsoe, Garnett; Hicks, Charles B.; Vandergrift, Nathan; Tomaras, Georgia D.; Haynes, Barton F.

    2009-01-01

    Successful vaccines (i.e., tetanus and diphtheria) can induce long-lived Ab levels that are maintained by bone marrow plasma cells and plasma Ab levels do not correlate with numbers of blood memory B cells. Destruction of CD4+ T cells early in HIV-1 acute infection may result in insufficient induction of neutralizing Ab responses; thus, an HIV-1 vaccine should elicit high levels of durable Abs by long-lived plasma cells to be protective. We asked if HIV-1 envelope-specific memory responses we...

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

    Arendrup, M; Olofsson, S; Nielsen, Jens Ole; Hansen, J E

    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...... 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...

  17. HIV-1 Vpr Protein Induces Proteasomal Degradation of Chromatin-associated Class I HDACs to Overcome Latent Infection of Macrophages.

    Romani, Bizhan; Baygloo, Nima Shaykh; Hamidi-Fard, Mojtaba; Aghasadeghi, Mohammad Reza; Allahbakhshi, Elham

    2016-02-01

    Mechanisms underlying HIV-1 latency remain among the most crucial questions that need to be answered to adopt strategies for purging the latent viral reservoirs. Here we show that HIV-1 accessory protein Vpr induces depletion of class I HDACs, including HDAC1, 2, 3, and 8, to overcome latency in macrophages. We found that Vpr binds and depletes chromatin-associated class I HDACs through a VprBP-dependent mechanism, with HDAC3 as the most affected class I HDAC. De novo expression of Vpr in infected macrophages induced depletion of HDAC1 and 3 on the HIV-1 LTR that was associated with hyperacetylation of histones on the HIV-1 LTR. As a result of hyperacetylation of histones on HIV-1 promotor, the virus established an active promotor and this contributed to the acute infection of macrophages. Collectively, HIV-1 Vpr down-regulates class I HDACs on chromatin to counteract latent infections of macrophages. PMID:26679995

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

    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....

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

    Pérez-Losada Marcos; Orsega Susan; Metcalf Julia A; Hirschfeld Steven; Imamichi Hiromi; Tazi Loubna; Posada David; Lane H Clifford; Crandall Keith A

    2011-01-01

    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 ...

  20. Protein methylation is required to maintain optimal HIV-1 infectivity

    Piller Sabine C; Warrilow David; Apolloni Ann; Bodetti Tracey J; Hitchen Eleanor M; Willemsen Nicole M; Harrich David

    2006-01-01

    Abstract Background: Protein methylation is recognized as a major protein modification pathway regulating diverse cellular events such as protein trafficking, transcription, and signal transduction. More recently, protein arginine methyltransferase activity has been shown to regulate HIV-1 transcription via Tat. In this study, adenosine periodate (AdOx) was used to globally inhibit protein methyltransferase activity so that the effect of protein methylation on HIV-1 infectivity could be asses...

  1. Cytokine expression during syphilis infection in HIV-1-infected individuals

    Knudsen, Andreas; Benfield, Thomas; Kofoed, Kristian

    2009-01-01

    BACKGROUND: Little is known about cytokine responses to syphilis infection in HIV-1-infected individuals. METHODS: We retrospectively identified patients with HIV-1 and Treponema pallidum coinfection. Plasma samples from before, during, and after coinfection were analyzed for interleukin (IL)-2, IL......-4, IL-6, IL-8, IL-10, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha. RESULTS: Thirty-six patients were included. IL-10 levels increased significantly in patients with primary or secondary stage syphilis from a median of 12.8 pg/mL [interquartile range (IQR), 11.0-27.8] before...... infection to 46.7 pg/mL (IQR, 28.4-78.9) at the time of diagnosis (P = 0.027) and decreased to 13.0 pg/mL (IQR, 6.2-19.4) after treatment of syphilis (P <0.001). TNF-alpha levels showed no significant change from before to during syphilis in patients with primary or secondary stage syphilis (median 3.9 pg...

  2. Contribution of immunological and virological factors to extremely severe primary HIV-1 infection

    Dalmau, Judith; Puertas, Maria Carmen; Azuara, Marta; Mariño, Ana; Frahm, Nicole; Mothe, Beatriz; Izquierdo-Useros, Nuria; Buzón, Maria José; Paredes, Roger; Matas, Lourdes; Allen, Todd M.; Brander, Christian; Rodrigo, Carlos; Clotet, Bonaventura; Martinez-Picado, Javier

    2009-01-01

    Background During acute HIV infection, high viral loads and the induction of host immune responses typically coincide with the onset of clinical symptoms. However, clinically severe presentations during acute HIV-1 infection, including AIDS-defining symptoms, are unusual. Methods Virus isolates were tested for clade, drug susceptibility, coreceptor usage, and growth rate for two cases of clinically severe sexual transmission. HLA genotype was determined, and HIV-1-specific CTL responses to an overlapping peptide set spanning the entire HIV clade A and clade B proteome were assayed. Results The virus isolated from the two unrelated cases of severe primary HIV-1 infection showed R5/X4 dual/mixed tropism, belonged to clade B and CRF02-AG, and were highly replicative in peripheral blood mononuclear cell culture. Impaired humoral responses were paralleled by a profound absence of HIV-1-specific CTL responses to the entire viral proteome in the two study cases. One case for which the virus source was available, showed a remarkable HLA similarity between the transmission pair as all 4 HLA-A and -B alleles were HLA supertype-matched between the subjects involved in the transmission case. Conclusions The data suggest that concurrence of viral and host factors contribute to the clinical severity of primary HIV-1 infection and that subjects infected with highly replicative dual tropic viruses are more prone to develop AIDS-defining symptoms during acute infection if they are unable to mount humoral and cellular HIV-1-specific immune responses. Concordant HLA supertypes might facilitate the preferential transmission of HLA-adapted viral variants, further accelerating disease progression. PMID:19093810

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

    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...... 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...... 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...

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

    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 125I iodination procedure

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

    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.

  6. Flail arm–like syndrome associated with HIV-1 infection

    Nalini, A.; Desai, Anita; Mahato, Simendra Kumar

    2009-01-01

    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. PMID:20142861

  7. Protein methylation is required to maintain optimal HIV-1 infectivity

    Piller Sabine C

    2006-12-01

    Full Text Available Abstract Background: Protein methylation is recognized as a major protein modification pathway regulating diverse cellular events such as protein trafficking, transcription, and signal transduction. More recently, protein arginine methyltransferase activity has been shown to regulate HIV-1 transcription via Tat. In this study, adenosine periodate (AdOx was used to globally inhibit protein methyltransferase activity so that the effect of protein methylation on HIV-1 infectivity could be assessed. Results: Two cell culture models were used: HIV-1-infected CEM T-cells and HEK293T cells transfected with a proviral DNA plasmid. In both models, AdOx treatment of cells increased the levels of virion in culture supernatant. However, these viruses had increased levels of unprocessed or partially processed Gag-Pol, significantly increased diameter, and displayed reduced infectivity in a MAGI X4 assay. AdOx reduced infectivity equally in both dividing and non-dividing cells. However, infectivity was further reduced if Vpr was deleted suggesting virion proteins, other than Vpr, were affected by protein methylation. Endogenous reverse transcription was not inhibited in AdOx-treated HIV-1, and infectivity could be restored by pseudotyping HIV with VSV-G envelope protein. These experiments suggest that AdOx affects an early event between receptor binding and uncoating, but not reverse transcription. Conclusion: Overall, we have shown for the first time that protein methylation contributes towards maximal virus infectivity. Furthermore, our results also indicate that protein methylation regulates HIV-1 infectivity in a complex manner most likely involving the methylation of multiple viral or cellular proteins and/or multiple steps of replication.

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

    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...

  9. Differentially-Expressed Pseudogenes in HIV-1 Infection

    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.

  10. Neuroimaging studies of the aging HIV-1-infected brain

    Holt, John L.; Kraft-Terry, Stephanie D.; Chang, Linda

    2012-01-01

    Highly active antiretroviral therapy (HAART) has increased life expectancy among HIV-infected individuals, and by 2015, at least half of all HIV-infected individuals will be over 50 years of age. Neurodegenerative processes associated with aging may be facilitated by HIV-1 infection, resulting in premature brain aging. This review will highlight brain abnormalities in HIV patients in the setting of aging, focusing on recent neuroimaging studies of the structural, physiological, functional and...

  11. Neurologic Complications in Treated HIV-1 Infection.

    Bhatia, Nisha S; Chow, Felicia C

    2016-07-01

    Effective combination antiretroviral therapy has transformed HIV infection into a chronic disease, with HIV-infected individuals living longer and reaching older age. Neurological disease remains common in treated HIV, however, due in part to ongoing inflammation and immune activation that persist in chronic infection. In this review, we highlight recent developments in our understanding of several clinically relevant neurologic complications that can occur in HIV infection despite treatment, including HIV-associated neurocognitive disorders, symptomatic CSF escape, cerebrovascular disease, and peripheral neuropathy. PMID:27170369

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

    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.)

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

    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.)

  14. Impact of HIV-1, HIV-2 and HIV-1+2 dual infection on the outcome of tuberculosis

    Wejse, C; Patsche, C B; Kühle, A;

    2014-01-01

    BACKGROUND: HIV-1 infection has been shown to impact the outcome of patients with tuberculosis (TB), but data regarding the impact of HIV-2 on TB outcomes are limited. The aim of this study was to assess the impact of HIV types on mortality among TB patients in Guinea-Bissau and to examine the...... predictive ability of the TBscoreII, a clinical score used to assess disease severity. METHODS: In a prospective follow-up study, we examined the prevalence of HIV-1, HIV-2, and HIV-1+2 co-infection in TB patients in Guinea-Bissau, and the impact on outcomes at 12 months of follow-up. We included all adult...... seventy-nine patients were HIV-infected: 241 had HIV-1, 93 had HIV-2, and 45 were HIV-1+2 dual infected. The HIV type-associated risk of TB was 6-fold higher for HIV-1, 7-fold higher for HIV-1+2 dual infection, and 2-fold higher for HIV-2 compared with the HIV-uninfected. Of the patients included, 144 (11...

  15. Challenges of diagnosing acute HIV-1 subtype C infection in African women: performance of a clinical algorithm and the need for point-of-care nucleic-acid based testing.

    Koleka Mlisana

    Full Text Available BACKGROUND: Prompt diagnosis of acute HIV infection (AHI benefits the individual and provides opportunities for public health intervention. The aim of this study was to describe most common signs and symptoms of AHI, correlate these with early disease progression and develop a clinical algorithm to identify acute HIV cases in resource limited setting. METHODS: 245 South African women at high-risk of HIV-1 were assessed for AHI and received monthly HIV-1 antibody and RNA testing. Signs and symptoms at first HIV-positive visit were compared to HIV-negative visits. Logistic regression identified clinical predictors of AHI. A model-based score was assigned to each predictor to create a risk score for every woman. RESULTS: Twenty-eight women seroconverted after a total of 390 person-years of follow-up with an HIV incidence of 7.2/100 person-years (95%CI 4.5-9.8. Fifty-seven percent reported ≥1 sign or symptom at the AHI visit. Factors predictive of AHI included age <25 years (OR = 3.2; 1.4-7.1, rash (OR = 6.1; 2.4-15.4, sore throat (OR = 2.7; 1.0-7.6, weight loss (OR = 4.4; 1.5-13.4, genital ulcers (OR = 8.0; 1.6-39.5 and vaginal discharge (OR = 5.4; 1.6-18.4. A risk score of 2 correctly predicted AHI in 50.0% of cases. The number of signs and symptoms correlated with higher HIV-1 RNA at diagnosis (r = 0.63; p<0.001. CONCLUSIONS: Accurate recognition of signs and symptoms of AHI is critical for early diagnosis of HIV infection. Our algorithm may assist in risk-stratifying individuals for AHI, especially in resource-limited settings where there is no routine testing for AHI. Independent validation of the algorithm on another cohort is needed to assess its utility further. Point-of-care antigen or viral load technology is required, however, to detect asymptomatic, antibody negative cases enabling early interventions and prevention of transmission.

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

    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.

  17. Impact of HIV-1, HIV-2, and HIV-1+2 dual infection on the outcome of tuberculosis

    C. Wejse; C.B. Patsche; Kühle, A.; F.J.V. Bamba; Mendes, M. S.; G. Lemvik; V.F. Gomes; F. Rudolf

    2015-01-01

    Background: HIV-1 infection has been shown to impact the outcome of patients with tuberculosis (TB), but data regarding the impact of HIV-2 on TB outcomes are limited. The aim of this study was to assess the impact of HIV types on mortality among TB patients in Guinea-Bissau and to examine the predictive ability of the TBscoreII, a clinical score used to assess disease severity. Methods: In a prospective follow-up study, we examined the prevalence of HIV-1, HIV-2, and HIV-1+2 co-infection ...

  18. Predictors of impaired HDL function in HIV-1 infected compared to uninfected individuals

    Kelesidis, Theodoros

    2016-01-01

    Objective: HDL function rather than absolute level may be a more accurate indicator for cardiovascular disease (CVD) but it is unclear what drives HDL dysfunction in HIV-1 infection. The objective of this study is to identify factors that may contribute to HDL dysfunction in chronic HIV-1 infection. Design: Retrospective study of HIV-1 infected males with low overall CVD risk and healthy males with no known CVD risk matched by race to the HIV-1 infected participants. Methods: We related para...

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

    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.

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

    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.

  1. Characteristics, Immunological Response & Treatment Outcomes of HIV-2 Compared with HIV-1 & Dual Infections (HIV 1/2) in Mumbai

    Chiara, Montaldo; Rony, Zachariah; Homa, Mansoor; Bhanumati, Varghese; Ladomirska, Joanna; Manzi, M.; Wilson, N; Alaka, Deshpande; Harries, A. D.

    2010-01-01

    Background & objectives: Information available on HIV-2 and dual infection (HIV-1/2) is limited. This study was carried out among HIV positive individuals in an urban referral clinic in Khar, Mumbai, India, to report on relative proportions of HIV-1, HIV-2 and HIV-1/2 and baseline characteristics, response to and outcomes on antiretroviral treatment (ART). Methods: Retrospective analysis of programme data (May 2006-May 2009) at Khar HIV/AIDS clinic at Mumbai, India was done. Three test algori...

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

    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

  3. Characterization of Antiviral Activity of Benzamide Derivative AH0109 against HIV-1 Infection

    Chen, Liyu; Ao, Zhujun; Jayappa, Kallesh Danappa; Kobinger, Gary; Liu, ShuiPing; Wu, Guojun; Wainberg, Mark A.; Yao, Xiaojian

    2013-01-01

    In the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an 50% effective concentration of 0.7 μM in HIV-1-susceptible CD...

  4. Dendritic cells exposed to MVA-based HIV-1 vaccine induce highly functional HIV-1-specific CD8(+ T cell responses in HIV-1-infected individuals.

    Núria Climent

    Full Text Available Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B in human monocyte-derived dendritic cells (MDDC and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α. MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8(+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8(+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4(+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B.

  5. The Achilles Heel of the Trojan Horse Model of HIV-1 trans-Infection

    Marielle Cavrois; Jason Neidleman; Greene, Warner C.

    2008-01-01

    To ensure their survival, microbial pathogens have evolved diverse strategies to subvert host immune defenses. The human retrovirus HIV-1 has been proposed to hijack the natural endocytic function of dendritic cells (DCs) to infect interacting CD4 T cells in a process termed trans-infection. Although DCs can be directly infected by certain strains of HIV-1, productive infection of DCs is not required during trans-infection; instead, DCs capture and internalize infectious HIV-1 virions in vesi...

  6. Selective elimination of HIV-1-infected cells by Env-directed, HIV-1-based virus-like particles

    We recently showed that both replicating and resting cells cultivated with ganciclovir (GCV) were killed when challenged with vesicular stomatitis virus G glycoprotein pseudotyped HIV-1-based virus-like particles (VLPs) carrying the Nef7 (i.e., an HIV-1 Nef mutant incorporating in virions at high levels)/herpes simplex virus-1 thymidine kinase (HSV-TK) fusion product. On this basis, a novel anti-HIV therapeutic approach based on Nef7/TK VLPs expressing X4 or R5 HIV cell receptor complexes has been attempted. We here report that (CD4-CXCR4) and (CD4-CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains, respectively. Importantly, the delivery of the VLP-associated Nef7/TK led to cell death upon GCV treatment. Of interest, VLPs were effective also against non-replicating, HIV-1-infected primary human monocyte-derived macrophages. HIV-targeted VLPs represent a promising candidate for the treatment of persistently HIV-1-infected cells that are part of virus reservoirs resistant to HAART therapies

  7. AMYLOID BETA ACCUMULATION IN HIV-1-INFECTED BRAIN: THE ROLE OF THE BLOOD BRAIN BARRIER

    András, Ibolya E.; Toborek, Michal

    2012-01-01

    In recent years we face an increase in the aging of the HIV-1-infected population, which is not only due to effective antiretroviral therapy but also to new infections among older people. Even with the use of the antiretroviral therapy, HIV-associated neurocognitive disorders represent an increasing problem as the HIV-1-infected population ages. Increased amyloid beta (Aβ) deposition is characteristic of HIV-1-infected brains, and it has been hypothesized that brain vascular dysfunction contr...

  8. P24 antigen detection, viral isolation, DNA-PCR and in vitro antibody production for the diagnosis of HIV-1 latent infection in heterosexual women at high risk for HIV-1 infection.

    M. Di Stefano; J.R. Fiore; M. Chironna; G. Buccoliero; Romanelli, C.; La Grasta, L; QUARTO, M.; Angarano, G.; Pastore, G.

    1995-01-01

    INTRODUCTION--The report of the existence of at-risk seronegative subjects, latently infected with HIV-1 and producing "in vitro" HIV-1 specific antibodies, prompted the authors to evaluate extensively twenty-five heterosexual HIV-1 seronegative women at high risk for HIV-1 infection. MATERIAL AND METHODS--The capability of peripheral blood mononuclear cells from such subjects to produce "in vitro" HIV-1 specific antibodies after pokeweed-mitogen stimulation, was studied. Silent HIV-1 infecti...

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

    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.

  10. HTLV-1/-2 and HIV-1 co-infections: retroviral interference on host immune status

    Pilotti, Elisabetta; Bianchi, Maria V.; De Maria, Andrea; Bozzano, Federica; Romanelli, Maria G.; Bertazzoni, Umberto; Casoli, Claudio

    2013-01-01

    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 HT...

  11. Evaluation of the Aptima(®) HIV-1 Quant Dx assay for HIV-1 RNA viral load detection and quantitation in plasma of HIV-1-infected individuals: A comparison with Abbott RealTime HIV-1 assay.

    Amendola, Alessandra; Pisciotta, Maria; Aleo, Loredana; Ferraioli, Valeria; Angeletti, Claudio; Capobianchi, Maria Rosaria

    2016-09-01

    The Hologic Aptima(®) HIV-1 Quant Dx assay (Aptima HIV) is a real-time transcription-mediated amplification method CE-approved for use in diagnosis and monitoring of HIV-1 infection. The analytical performance of this new assay was compared to the FDA-approved Abbott RealTime HIV-1 (RealTime). The evaluation was performed using 220 clinical plasma samples, the WHO 3rd HIV-1 International Standard, and the QCMD HIV-1 RNA EQA. Concordance on qualitative results, correlation between quantitative results, accuracy, and reproducibility of viral load data were analyzed. The ability to measure HIV-1 subtypes was assessed on the second WHO International Reference Preparation Panel for HIV-1 Subtypes. With clinical samples, inter-assay agreement for qualitative results was high (91.8%) with Cohen's kappa statistic equal to 0.836. For samples with quantitative results in both assays (n = 93), Lin's concordance correlation coefficient was 0.980 (P R(2)  > 0.970) and showed higher sensitivity compared to RealTime being able to detect HIV-1 RNA in 10 out of 10 replicates containing down to 7 cp/ml (20 IU/ml). Reproducibility was very high, even at low HIV-1 RNA values. The Aptima HIV was able to detect and accurately quantify all the main HIV-1 subtypes in both reference panels and clinical samples. Besides excellent performance, Aptima HIV shows full automation, ease of use, and improved workflow compared to RealTime. J. Med. Virol. 88:1535-1544, 2016. © 2016 Wiley Periodicals, Inc. PMID:26864171

  12. β-catenin/TCF-4 signaling regulates susceptibility of macrophages and resistance of monocytes to HIV-1 productive infection

    Aljawai, Yosra; Richards, Maureen H.; Seaton, Melanie S.; Narasipura, Srinivas D.; Al-Harthi, Lena

    2014-01-01

    Cells of the monocyte/macrophage lineage are an important target for HIV-1 infection. They are often at anatomical sites linked to HIV-1 transmission and are an important vehicle for disseminating HIV-1 throughout the body, including the central nervous system. Monocytes do not support extensive productive HIV-1 replication, but they become more susceptible to HIV-1 infection as they differentiate into macrophages. The mechanisms guiding susceptibility of HIV-1 replication in monocytes versus...

  13. HIV-1 vaccine design: Learning from natural infection

    T.L.G.M. van den Kerkhof

    2016-01-01

    Het humane immuundeficiëntie virus type 1 (hiv-1) is het virus dat aids veroorzaakt. Er is nog steeds geen bescherming tegen een hiv-1 infectie en de beëindiging van de wereldwijde epidemie kan waarschijnlijk alleen worden bereikt met behulp van een vaccin. Een hiv-1 vaccin zal bescherming moeten bi

  14. Specific elimination of HIV-1 infected cells using Tat/Rev-dependent circuit

    Perdigão, Pedro Ricardo Lucas, 1987-

    2011-01-01

    Tese de mestrado. Biologia (Biologia Molecular e Genética). Universidade de Lisboa, Faculdade de Ciências, 2011 Despite the success of antiretroviral cocktails, a cure for HIV-1 remains elusive. This is mainly due to the existence of persistent cellular reservoirs infected with non-transcriptional, latent HIV-1. An effective treatment against HIV-1 would target both active and latent HIV-1-infected cells, and eliminate them without harming non-infected cells. In order to achieve this, we h...

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

    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.

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

    Susan Morrison; Grace John-Stewart; John J Egessa; Sezi Mubezi; Sylvia Kusemererwa; Dennis K Bii; Nulu Bulya; Francis Mugume; Campbell, James D.; Jonathan Wangisi; Bukusi, Elizabeth A.; Connie Celum; Baeten, Jared M.

    2015-01-01

    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.

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

    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.

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

    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

  19. HIV-1 vaccine design: Learning from natural infection

    Kerkhof, van den, T.L.G.M.

    2016-01-01

    Het humane immuundeficiëntie virus type 1 (hiv-1) is het virus dat aids veroorzaakt. Er is nog steeds geen bescherming tegen een hiv-1 infectie en de beëindiging van de wereldwijde epidemie kan waarschijnlijk alleen worden bereikt met behulp van een vaccin. Een hiv-1 vaccin zal bescherming moeten bieden tegen de verschillende subtypes die wereldwijd voorkomen. Ongeveer 10-30% van de hiv-1 geïnfecteerde patiënten ontwikkelen zogenoemde "breed-neutraliserende" antistoffen. Alhoewel deze antisto...

  20. HIV-1 vaccine design: Learning from natural infection

    Schuitemaker, J.; Sanders, R W; Kerkhof, van den, T.L.G.M.

    2016-01-01

    Het humane immuundeficiëntie virus type 1 (hiv-1) is het virus dat aids veroorzaakt. Er is nog steeds geen bescherming tegen een hiv-1 infectie en de beëindiging van de wereldwijde epidemie kan waarschijnlijk alleen worden bereikt met behulp van een vaccin. Een hiv-1 vaccin zal bescherming moeten bieden tegen de verschillende subtypes die wereldwijd voorkomen. Ongeveer 10-30% van de hiv-1 geïnfecteerde patiënten ontwikkelen zogenoemde “breed-neutraliserende” antistoffen. Alhoewel deze antisto...

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

    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.

  2. Primary HIV-1 Infection Among Infants in sub-Saharan Africa: HPTN 024.

    Read, Jennifer S.; Mwatha, Anthony; Richardson, Barbra; Valentine, Megan; Emel, Lynda; Manji, Karim; Hoffman, Irving; Sharma, Usha; Goldenberg, Robert L.; Taha, Taha E.

    2009-01-01

    Our objectives were to assess clinical signs and diagnoses associated with primary HIV-1 infection among infants. We analyzed data from a clinical trial (HIV Prevention Trials Network Protocol 024) in sub-Saharan Africa. Study visits were conducted at birth, at 4-6 weeks, and at 3, 6, 9, and 12 months. The study population comprised live born, singleton, first-born infants of HIV-1-infected women with negative HIV-1 RNA assays who were still breastfeeding at 4-6 weeks. Of 1317 HIV-1-exposed i...

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

    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.

  4. Discordance between Frequency of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon-Producing CD4+ T Cells and HIV-1-Specific Lymphoproliferation in HIV-1-Infected Subjects with Active Viral Replication

    Palmer, B. E.; Boritz, E; Blyveis, N.; Wilson, C C

    2002-01-01

    One hallmark of uncontrolled, chronic human immunodeficiency virus type 1 (HIV-1) infection is the absence of strong HIV-1-specific, CD4+ T-cell-proliferative responses, yet the mechanism underlying this T helper (Th)-cell defect remains controversial. To better understand the impact of HIV-1 replication on Th-cell function, we compared the frequency of CD4+ Th-cell responses based on production of gamma interferon to lymphoproliferative responses directed against HIV-1 proteins in HIV-1-infe...

  5. Outcome and reinfection after Staphylococcus aureus bacteraemia in individuals with and without HIV-1 infection: a case–control study

    Stammler Jaliff, Bianca; Dahl-Knudsen, Jenny; Petersen, Andreas; Skov, Robert; Benfield, Thomas

    2014-01-01

    Objectives Individuals infected with HIV-1 are at an increased risk of Staphylococcus aureus bacteraemia (SAB). The aim of this study was to investigate mortality rate and risk of reinfection associated with SAB in HIV-1-infected individuals compared to individuals without HIV-1 infection. Setting University hospital treating a third of the estimated 5000 individuals with HIV infection in Denmark. Participants HIV-1-infected (n=82) and sex-matched and age-matched uninfected (n=163) individual...

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

    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.

  7. APOBEC3H polymorphisms and susceptibility to HIV-1 infection in an Indian population.

    Naruse, Taeko K; Sakurai, Daisuke; Ohtani, Hitoshi; Sharma, Gaurav; Sharma, Surendra K; Vajpayee, Madhu; Mehra, Narinder K; Kaur, Gurvinder; Kimura, Akinori

    2016-03-01

    Human APOBEC3H (A3H) is a member of APOBEC cytidine deaminase family intensively constraining the HIV-1 replication. A3H is known to be polymorphic with different protein stability and anti-HIV-1 activity in vitro. We recently reported that A3H haplotypes composed of two functional polymorphisms, rs139292 (N15del) and rs139297 (G105R), were associated with the susceptibility to HIV-1 infection in Japanese. To confirm the association of A3H and HIV-1 infection in another ethnic group, a total of 241 HIV-1-infected Indian individuals and ethnic-matched 286 healthy controls were analyzed for the A3H polymorphisms. The frequency of 15del allele was high in the HIV-1-infected subjects as compared with the controls (0.477 vs 0.402, odds ratio (OR)=1.36, P=0.014). Haplotype analysis showed that the frequencies of 15del-105R was high (0.475 vs 0.400, OR=1.36, permutation P=0.037) in the HIV-1-infected subjects, confirming the association of A3H polymorphisms with the susceptibility to HIV-1 infection. PMID:26559750

  8. Epigenetics of μ-Opioid receptors: Intersection with HIV-1 infection of the Central Nervous System

    Regan, Patrick M.; Dave, Rajnish S.; Datta, Prasun K.; Khalili, Kamel

    2012-01-01

    The abuse of intravenous drugs, such as heroin, has become a major public health concern due to the increased risk of HIV-1 infection. Opioids such as heroin were originally identified and subsequently abused for their analgesic effects. However, many investigations have found additional effects of opioids, including regulation of the immune system. As such, chronic opioid abuse has been shown to promote HIV-1 pathogenesis and facilitate HIV-1-associated neurocognitive dysfunction. Clinical o...

  9. Multiple roles of the capsid protein in the early steps of HIV-1 infection.

    Fassati, A.

    2012-01-01

    The early steps of HIV-1 infection starting after virus entry into cells up to integration of its genome into host chromosomes are poorly understood. From seminal work showing that HIV-1 and oncoretroviruses follow different steps in the early stages post-entry, significant advances have been made in recent years and an important role for the HIV-1 capsid (CA) protein, the constituent of the viral core, has emerged. CA appears to orchestrate several events, such as virus uncoating, recognitio...

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

    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.

  11. Emergence of HIV-1 drug resistance mutations among antiretroviral-naïve HIV-1-infected patients after rapid scaling up of antiretroviral therapy in Thailand

    Sungkanuparph Somnuek

    2012-03-01

    Full Text Available Abstract Background After rapid scaling up of antiretroviral therapy in HIV-1-infected patients, the data of primary HIV-1 drug resistance in Thailand is still limited. This study aims to determine the prevalence and associated factors of primary HIV-1 drug resistance in Thailand. Methods A prospective observational study was conducted among antiretroviral-naïve HIV-1-infected Thai patients from 2007 to 2010. HIV-1 subtypes and mutations were assayed by sequencing a region of HIV-1 pol gene. Surveillance drug resistance mutations recommended by the World Health Organization for surveillance of transmitted HIV-1 drug resistance in 2009 were used in all analyses. Primary HIV-1 drug resistance was defined as the presence of one or more surveillance drug resistance mutations. Results Of 466 patients with a mean age of 38.8 years, 58.6% were males. Risks of HIV-1 infection included heterosexual (77.7%, homosexual (16.7%, and intravenous drug use (5.6%. Median (IQR CD4 cell count and HIV-1 RNA were 176 (42-317 cells/mm3 and 68,600 (19,515-220,330 copies/mL, respectively. HIV-1 subtypes were CRF01_AE (86.9%, B (8.6 and other recombinants (4.5%. The prevalence of primary HIV-1 drug resistance was 4.9%; most of these (73.9% had surveillance drug resistance mutations to only one class of antiretroviral drugs. The prevalence of patients with NRTI, NNRTI, and PI surveillance drug resistance mutations was 1.9%, 2.8% and 1.7%, respectively. From logistic regression analysis, there was no factor significantly associated with primary HIV-1 drug resistance. There was a trend toward higher prevalence in females [odds ratio 2.18; 95% confidence interval 0.896-5.304; p = 0.086]. Conclusions There is a significant emergence of primary HIV-1 drug resistance in Thailand after rapid scaling up of antiretroviral therapy. Although HIV-1 genotyping prior to antiretroviral therapy initiation is not routinely recommended in Thailand, our results raise concerns about the

  12. Cognitive Performance in Men and Women Infected with HIV-1

    José María Faílde Garrido

    2013-01-01

    Full Text Available Introduction. Very few studies have examined the neuropsychological performance of HIV-positive women, and even fewer have attempted a comparison of cognitive functioning by gender. The aim of this study was to describe the nature of the neuropsychological performance of HIV seropositive patients by gender. Methods. A clinical sample made up of 151 subjects was recruited to participate in this study. All of the subjects underwent the same assessment process, consisting of a neuropsychological evaluation and an interview to gather sociodemographic, toxicological, and clinical data. Results and Discussion. Despite the fact that men obtained higher scores in visual memory, attention/psychomotor speed, and abstract reasoning/verbal intelligence, these differences were not statistically significant. In contrast, significant differences were found depending on subjects’ serological status. Seropositive participants’ neuropsychological performance was significantly lower than that of the seronegative participants in all of the areas assessed as follows: (1 visual memory; (2 attention/psychomotor speed; (3 abstract reasoning/verbal intelligence; (4 verbal memory for texts; (5 verbal memory for digits and words. Conclusions. The results from this study reveal no significant gender differences in the cognitive performance of patients infected with HIV-1.

  13. Pulmonary Tuberculosis in Humanized Mice Infected with HIV-1

    Nusbaum, Rebecca J.; Calderon, Veronica E.; Huante, Matthew B.; Sutjita, Putri; Vijayakumar, Sudhamathi; Lancaster, Katrina L.; Hunter, Robert L.; Actor, Jeffrey K.; Cirillo, Jeffrey D.; Aronson, Judith; Gelman, Benjamin B.; Lisinicchia, Joshua G.; Valbuena, Gustavo; Endsley, Janice J.

    2016-01-01

    Co-infection with HIV increases the morbidity and mortality associated with tuberculosis due to multiple factors including a poorly understood microbial synergy. We developed a novel small animal model of co-infection in the humanized mouse to investigate how HIV infection disrupts pulmonary containment of Mtb. Following dual infection, HIV-infected cells were localized to sites of Mtb-driven inflammation and mycobacterial replication in the lung. Consistent with disease in human subjects, we observed increased mycobacterial burden, loss of granuloma structure, and increased progression of TB disease, due to HIV co-infection. Importantly, we observed an HIV-dependent pro-inflammatory cytokine signature (IL-1β, IL-6, TNFα, and IL-8), neutrophil accumulation, and greater lung pathology in the Mtb-co-infected lung. These results suggest that in the early stages of acute co-infection in the humanized mouse, infection with HIV exacerbates the pro-inflammatory response to pulmonary Mtb, leading to poorly formed granulomas, more severe lung pathology, and increased mycobacterial burden and dissemination. PMID:26908312

  14. The CsA washout assay to detect HIV-1 uncoating in infected cells

    Hulme, Amy E.; Hope, Thomas J.

    2014-01-01

    Uncoating is an early step of HIV-1 replication in which the viral capsid disassembles by p24 capsid (p24CA) protein dissociating from the viral complex. Although uncoating is required for HIV-1 replication, many questions remain about the mechanism of this process as well as its impact on other steps in viral replication. Here we describe a recently developed assay to study the process of uncoating in HIV-1 infected cells. The CsA washout assay is a cell based assay that utilizes the HIV-1 r...

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

    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.

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

    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.

  17. Estimating time since infection in early homogeneous HIV-1 samples using a poisson model

    Perelson Alan S

    2010-10-01

    Full Text Available Abstract Background The occurrence of a genetic bottleneck in HIV sexual or mother-to-infant transmission has been well documented. This results in a majority of new infections being homogeneous, i.e., initiated by a single genetic strain. Early after infection, prior to the onset of the host immune response, the viral population grows exponentially. In this simple setting, an approach for estimating evolutionary and demographic parameters based on comparison of diversity measures is a feasible alternative to the existing Bayesian methods (e.g., BEAST, which are instead based on the simulation of genealogies. Results We have devised a web tool that analyzes genetic diversity in acutely infected HIV-1 patients by comparing it to a model of neutral growth. More specifically, we consider a homogeneous infection (i.e., initiated by a unique genetic strain prior to the onset of host-induced selection, where we can assume a random accumulation of mutations. Previously, we have shown that such a model successfully describes about 80% of sexual HIV-1 transmissions provided the samples are drawn early enough in the infection. Violation of the model is an indicator of either heterogeneous infections or the initiation of selection. Conclusions When the underlying assumptions of our model (homogeneous infection prior to selection and fast exponential growth are met, we are under a very particular scenario for which we can use a forward approach (instead of backwards in time as provided by coalescent methods. This allows for more computationally efficient methods to derive the time since the most recent common ancestor. Furthermore, the tool performs statistical tests on the Hamming distance frequency distribution, and outputs summary statistics (mean of the best fitting Poisson distribution, goodness of fit p-value, etc. The tool runs within minutes and can readily accommodate the tens of thousands of sequences generated through new ultradeep pyrosequencing

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

    Rickabaugh, Tammy M; Baxter, Ruth M; Sehl, Mary; Sinsheimer, Janet S; Hultin, Patricia M; Hultin, Lance E; Quach, Austin; Martínez-Maza, Otoniel; Horvath, Steve; Vilain, Eric; Jamieson, Beth D

    2015-01-01

    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, pnetwork 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 are similar to age-associated patterns and suggest that general aging

  19. Clinical presentation and opportunistic infections in HIV-1, HIV-2 and HIV-1/2 dual seropositive patients in Guinea-Bissau

    Sørensen, Allan; Jespersen, Sanne; Katzenstein, Terese L;

    2016-01-01

    BACKGROUND: Better understanding of HIV-2 infection is likely to affect the patient care in areas where HIV-2 is prevalent. In this study, we aimed to characterize the clinical presentations among HIV-1, HIV-2 and HIV-1/2 dual seropositive patients. METHODS: In a cross-sectional study, newly...... diagnosed HIV patients attending the HIV outpatient clinic at Hospital Nacional Simão Mendes in Guinea-Bissau were enrolled. Demographical and clinical data were collected and compared between HIV-1, HIV-2 and HIV-1/2 dual seropositive patients. RESULTS: A total of 169 patients (76% HIV-1, 17% HIV-2 and 6......% HIV 1/2) were included in the study between 21 March 2012 and 14 December 2012. HIV-1 seropositive patients were younger than HIV-2 and HIV-1/2 seropositive patients, but no difference in sex was observed. Patients with HIV-1 and HIV-1/2 had a lower baseline CD4 cell count than HIV-2 seropositive...

  20. Multiple roles of the capsid protein in the early steps of HIV-1 infection.

    Fassati, Ariberto

    2012-12-01

    The early steps of HIV-1 infection starting after virus entry into cells up to integration of its genome into host chromosomes are poorly understood. From seminal work showing that HIV-1 and oncoretroviruses follow different steps in the early stages post-entry, significant advances have been made in recent years and an important role for the HIV-1 capsid (CA) protein, the constituent of the viral core, has emerged. CA appears to orchestrate several events, such as virus uncoating, recognition by restriction factors and the innate immune system. It also plays a role in nuclear import and integration of HIV-1 and has become a novel target for antiretroviral drugs. Here we describe the different functions of CA and how they may be integrated into one or more coherent models that illuminate the early events in HIV-1 infection and their relations with the host cell. PMID:23041358

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

    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.

  2. HIV-1 infection, but not syphilis or HBV infection, is a strong risk factor for anorectal condyloma in Asian population: A prospective colonoscopy screening study

    Takeshi Nishijima

    2015-08-01

    Conclusions: HIV-1 infection, but not syphilis or HBV infection, was identified as a strong risk for anorectal condyloma. Anal HPV 16/18 was highly prevalent in patients with HIV-1 infection, especially in those with condyloma.

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

    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.

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

    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.

  5. The X awakens: multifactorial ramifications of sex-specific differences in HIV-1 infection.

    Hagen, Sven; Altfeld, Marcus

    2016-01-01

    Sex-specific differences have been described for a variety of infectious and autoimmune diseases. In HIV-1 infection women present with significantly lower viral loads during early infection, but during chronic infection women progress faster to AIDS for the same amount of viral replication. Recent studies have shown that sex differences during HIV-1 infection might also include the size of the latent viral reservoir, which represents a major obstacle towards a cure for HIV-1. Here we review different immunological and virological aspects that can be influenced by sex hormones and sex-specific genetic factors and their contribution to viral replication, as well as the creation and maintenance of the HIV-1 reservoir. PMID:27482439

  6. Plasma plasminogen activator inhibitor-1 predicts myocardial infarction in HIV-1-infected individuals

    Knudsen, Andreas; Katzenstein, Terese L; Benfield, Thomas;

    2014-01-01

    (PAI-1) were measured using a Luminex assay in plasma samples from routine visits both 12 and 2 months prior to the case patient's MI. RESULTS: The two groups had similar HIV characteristics and traditional cardiovascular risk factors. In univariate analysis, PAI-1 levels were associated with MI......OBJECTIVES: Biomarkers of endothelial dysfunction, inflammation and coagulation are associated with atherosclerosis and cardiovascular disease, but their association and possible predictive value remain controversial among HIV-1-infected individuals. We sought to investigate the association of...... seven biomarkers with first-time myocardial infarction (MI) in an HIV-1-infected population. DESIGN: A matched case-control study of 54 cases and 54 controls. METHODS: We compared 54 HIV-1-infected patients with verified first-time MI and 54 HIV-1-infected controls matched for age, duration of...

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

    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.

  8. The achilles heel of the trojan horse model of HIV-1 trans-infection.

    Marielle Cavrois

    2008-06-01

    Full Text Available To ensure their survival, microbial pathogens have evolved diverse strategies to subvert host immune defenses. The human retrovirus HIV-1 has been proposed to hijack the natural endocytic function of dendritic cells (DCs to infect interacting CD4 T cells in a process termed trans-infection. Although DCs can be directly infected by certain strains of HIV-1, productive infection of DCs is not required during trans-infection; instead, DCs capture and internalize infectious HIV-1 virions in vesicles for later transmission to CD4 T cells via vesicular exocytosis across the infectious synapse. This model of sequential endocytosis and exocytosis of intact HIV-1 virions has been dubbed the "Trojan horse" model of HIV-1 trans-infection. While this model gained rapid favor as a strong example of how a pathogen exploits the natural properties of its cellular host, our recent studies challenge this model by showing that the vast majority of virions transmitted in trans originate from the plasma membrane rather than from intracellular vesicles. This review traces the experimental lines of evidence that have contributed to what we view as the "rise and decline" of the Trojan horse model of HIV-1 trans-infection.

  9. Production of Interferons and β-Chemokines by Placental Trophoblasts of HIV-1-Infected Women

    Reuben, James M.; Shearer, William T; Mary Paul; Claudia Kozinetz; Stanley Cron; Popek, Edwina J; Hunter Hammill; Bang-Ning Lee

    2001-01-01

    Objective: The mechanism whereby the placental cells of a human immunodeficiency virus (HIV)-1-infected mother protect the fetus from HIV-1 infection is unclear. Interferons (IFNs) inhibit the replication of viruses by acting at various stages of the life cycle and may play a role in protecting against vertical transmission of HIV-1. In addition the β-chemokines RANTES (regulated on activation T cell expressed and secreted), macrophage inflammatory protein-1-α (MIP-1α), and MIP-1β can block H...

  10. Defining the HLA class I-associated viral antigen repertoire from HIV-1-infected human cells

    Ternette, Nicola; Yang, Hongbing; Partridge, Thomas;

    2016-01-01

    Recognition and eradication of infected cells by cytotoxic T lymphocytes is a key defense mechanism against intracellular pathogens. High-throughput definition of HLA class I-associated immunopeptidomes by mass spectrometry is an increasingly important analytical tool to advance our understanding...... time the identification of 75 HIV-1-derived peptides bound to HLA class I complexes that were purified directly from HIV-1-infected human primary CD4+ T cells and the C8166 human T-cell line. Importantly, one-third of eluted HIV-1 peptides had not been previously known to be presented by HLA class I...

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

    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.

  12. Brief Report: Macrophage Activation in HIV-2-Infected Patients Is Less Affected by Antiretroviral Treatment-sCD163 in HIV-1, HIV-2, and HIV-1/2 Dually Infected Patients.

    Hønge, Bo L; Andersen, Morten N; Jespersen, Sanne; Medina, Candida; Correira, Faustino G; Jakobsen, Martin R; Laursen, Alex; Erikstrup, Christian; Møller, Holger J; Wejse, Christian

    2016-07-01

    The course of disease among HIV-2, HIV-1, and HIV-1/2 dually infected patients is different. We investigated the macrophage activation marker soluble CD163 (sCD163) dynamics in 212 HIV-1, HIV-2, and HIV-1/2 dually infected patients. There were no differences in sCD163 levels at baseline or during follow-up without antiretroviral therapy (ART). At follow-up on ART, median sCD163 levels were decreased for HIV-1-infected patients (P < 0.001), but not among HIV-2 (P = 0.093) or HIV-1/2 dually infected patients (P = 0.145). The larger decrease in sCD163 levels among HIV-1-infected patients during ART may indicate an HIV type-dependent differential effect of ART on macrophage activation during HIV infection. PMID:26825178

  13. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection

    Sharon L. Walmsley; Antela, Antonio; Clumeck, Nathan; Duiculescu, Dan; Eberhard, Andrea; Gutiérrez, Felix; Hocqueloux, Laurent; Maggiolo, Franco; Sandkovsky, Uriel; Granier, Catherine; Pappa, Keith; Wynne, Brian; Min, Sherene; Nichols, Garrett; SINGLE Investigators, for the

    2013-01-01

    Background: Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen. Methods: We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection a...

  14. Role of IL-7 in immune activation during HIV-1 infection

    Sammicheli, Stefano

    2011-01-01

    Viral replication, lymphopenia and microbial translocation at the mucosal surfaces lead to a chronic state of immune activation during HIV-1 infection. Chronic immune activation is believed to impact on the functionality of cell types that are not the main target for virus replication, including CD8+T cells, B cells and NK cells. In this thesis two main aspects of the pathogenesis of HIV-1 infection were studied: 1) how viral replication and disease progression affect the homeo...

  15. Selection dramatically reduces effective population size in HIV-1 infection

    Mittler John E

    2008-05-01

    Full Text Available Abstract Background In HIV-1 evolution, a 100–100,000 fold discrepancy between census size and effective population size (Ne has been noted. Although it is well known that selection can reduce Ne, high in vivo mutation and recombination rates complicate attempts to quantify the effects of selection on HIV-1 effective size. Results We use the inbreeding coefficient and the variance in allele frequency at a linked neutral locus to estimate the reduction in Ne due to selection in the presence of mutation and recombination. With biologically realistic mutation rates, the reduction in Ne due to selection is determined by the strength of selection, i.e., the stronger the selection, the greater the reduction. However, the dependence of Ne on selection can break down if recombination rates are very high (e.g., r ≥ 0.1. With biologically likely recombination rates, our model suggests that recurrent selective sweeps similar to those observed in vivo can reduce within-host HIV-1 effective population sizes by a factor of 300 or more. Conclusion Although other factors, such as unequal viral reproduction rates and limited migration between tissue compartments contribute to reductions in Ne, our model suggests that recurrent selection plays a significant role in reducing HIV-1 effective population sizes in vivo.

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

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

    2008-01-01

    recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients...

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

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

    2008-01-01

    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......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...... 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...

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

    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...

  19. Oral epithelial cells are susceptible to cell-free and cell-associated HIV-1 infection in vitro

    Epithelial cells lining the oral cavity are exposed to HIV-1 through breast-feeding and oral-genital contact. Genital secretions and breast milk of HIV-1-infected subjects contain both cell-free and cell-associated virus. To determine if oral epithelial cells can be infected with HIV-1 we exposed gingival keratinocytes and adenoid epithelial cells to cell-free virus and HIV-1-infected peripheral blood mononuclear cells and monocytes. Using primary isolates we determined that gingival keratinocytes are susceptible to HIV-1 infection via cell-free CD4-independent infection only. R5 but not X4 viral strains were capable of infecting the keratinocytes. Further, infected cells were able to release infectious virus. In addition, primary epithelial cells isolated from adenoids were also susceptible to infection; both cell-free and cell-associated virus infected these cells. These data have potential implications in the transmission of HIV-1 in the oral cavity

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

    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.

  1. nef gene sequence variation among HIV-1-infected African children

    Chakraborty, R.; Reiniš, Milan; Rostron, T.; Philpott, S.; Dong, T.; D'Agostino, A.; Musoke, R.; de Silva, E.; Stumpf, M.; Weiser, B.; Burger, H.; Rowland-Jones, S.L.

    2006-01-01

    Roč. 7, č. 2 (2006), s. 75-84. ISSN 1464-2662 Grant ostatní: Fogarty International Center, NIH(US) 3D43TW00915; NIH(US) RO1 AI 42555 Institutional research plan: CEZ:AV0Z50520514 Keywords : HIV-1 nef gene * non-clade B * Kenya Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.674, year: 2006

  2. TRIM5 and the Regulation of HIV-1 Infectivity

    Jeremy Luban

    2012-01-01

    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 un...

  3. TRIM5 and the Regulation of HIV-1 Infectivity

    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.

  4. TRIM5 and the Regulation of HIV-1 Infectivity.

    Luban, Jeremy

    2012-01-01

    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. PMID:22701176

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

    Hoffmann, Matthias; Pantazis, Nikos; Martin, Genevieve E; Hickling, Stephen; Hurst, Jacob; Meyerowitz, Jodi; Willberg, Christian B; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Babiker, Abdel; Weber, Jonathan; Nwokolo, Nneka; Fox, Julie; Fidler, Sarah; Phillips, Rodney; Frater, John

    2016-07-01

    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 approaches. PMID:27415828

  6. Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

    Holmes, Derek; Jiang, Qi; Zhang, Liguo; Su, Lishan

    2008-01-01

    FoxP3+CD4+CD25+ regulatory T (Treg) cells are implicated in a number of pathologic processes including elevated levels in cancers and infectious diseases, and reduced levels in autoimmune diseases. Treg cells are activated to modulate immune responses to avoid over-reactive immunity. However, conflicting findings are reported regarding relative levels of Treg cells during HIV-1 infection and disease progression. The role of Treg cells in HIV-1 diseases (aberrant immune activation) is poorly u...

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

    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

  8. Steady increase in cellular HIV-1 load during the asymptomatic phase of untreated infection despite stable plasma viremia

    A.O. Pasternak; S. Jurriaans; M. Bakker; B. Berkhout; V.V. Lukashov

    2010-01-01

    Objective: To compare the dynamics of HIV-1 molecular markers in peripheral blood mononuclear cells (PBMCs) and in plasma during the asymptomatic phase of untreated HIV-1 infection. Design and methods: Using seminested real-time PCR assays, we measured the levels of HIV-1 proviral (pr) DNA, unsplice

  9. Characterization of mannose-binding lectin plasma levels and genetic polymorphisms in HIV-1-infected individuals

    Antonio Carlos Rosário Vallinoto

    2011-02-01

    Full Text Available INTRODUCTION: The present study investigated the association between mannose-binding lectin (MBL gene polymorphism and serum levels with infection by HIV-1. METHODS: Blood samples (5mL were collected from 97 HIV-1-infected individuals resident in Belém, State of Pará, Brazil, who attended the Special Outpatient Unit for Infections and Parasitic Diseases (URE-DIPE. CD4+ T-lymphocyte count and plasma viral load were quantified. A 349bp fragment of exon 1 of the MBL was amplified via PCR, using genomic DNA extracted from controls and HIV-1-infected individuals, following established protocols. MBL plasma levels of the patients were quantified using an enzyme immunoassay kit. RESULTS: Two alleles were observed: MBL*O, with a frequency of 26.3% in HIV-1-infected individuals; and the wild allele MBL*A (73.7%. Similar frequencies were observed in the control group (p > 0.05. Genotype frequencies were distributed according to the Hardy-Weinberg equilibrium in both groups. Mean MBL plasma levels varied by genotype, with statistically significant differences between the AA and AO (p 0.05. CONCLUSIONS: The results of this study do not support the hypothesis that MBL gene polymorphism or low plasma MBL concentrations might have a direct influence on HIV-1 infection, although a broader study involving a large number of patients is needed.

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

    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

  11. Drug resistance mutation of HIV-1 in HIV/AIDS patients infected by blood transfusion

    Xin-li LU

    2013-03-01

    Full Text Available Objective  To study the characteristic of HIV-1 gene mutation in HIV/AIDS patients infected by blood transfusion, and analyze the resistance to anti-HIV drugs. Methods  Plasma samples were collected from 37 HIV/AIDS patients infected by blood transfusion for extraction of HIV-1 RNA. The gene fragments of HIV pol domain were amplified by RT-PCR and nested-PCR , and the electrophoresis positive products were sequenced. The sequencing result was landed to the website http:// HIV-1db.stanford.edu to analyze the drug resistance mutations. Results  Drug resistance mutations were found in 20 patients, including 19 cases of virological or immunological failure. Mutation of gene locus V32AV of protease inhibitors (PIs occurred in 3 patients during the treatment, but it did not cause the drug resistance of PIs. Mutation of the coding regions of reverse transcriptase was found in 23 patients, including M184V, TAMs, Q151M complexus, K103N, Y181C and so on. Of the 23 patients mentioned above, the HIV-1 gene mutation induced the resistance to reverse transcriptase inhibitors (RTIs in 20 patients, and the mutation rate of RTIs was 54.05% (20/37. Conclusion  The drug resistance rate of HIV-1 in patients infected by blood transfusion may be high for antiviral therapy, so the drug resistance of HIV-1 should be monitored and treatment plan should be adjusted timely.

  12. Dendritic Cells from HIV Controllers Have Low Susceptibility to HIV-1 Infection In Vitro but High Capacity to Capture HIV-1 Particles.

    Hamimi, Chiraz; David, Annie; Versmisse, Pierre; Weiss, Laurence; Bruel, Timothée; Zucman, David; Appay, Victor; Moris, Arnaud; Ungeheuer, Marie-Noëlle; Lascoux-Combe, Caroline; Barré-Sinoussi, Françoise; Muller-Trutwin, Michaela; Boufassa, Faroudy; Lambotte, Olivier; Pancino, Gianfranco; Sáez-Cirión, Asier

    2016-01-01

    HIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs. We found that monocyte derived dendritic cells (MDDCs) from HICs are less permissive to HIV-1 infection than cells from healthy donors. In contrast MDDCs from HICs are particularly efficient at capturing HIV-1 particles when compared to cells from healthy donors or HIV-1 patients with suppressed viral load on antiretroviral treatment. MDDCs from HICs expressed on their surface high levels of syndecan-3, DC-SIGN and MMR, which could cooperate to facilitate HIV-1 capture. The combination of low susceptibility to HIV-1 infection but enhanced capacity to capture particles might allow MDDCs from HICs to preserve their function from the deleterious effect of infection while facilitating induction of HIV-specific CD8+ T cells by cross-presentation in a context of low viremia. PMID:27505169

  13. Differential effects of sex in a West African cohort of HIV-1, HIV-2 and HIV-1/2 dually infected patients

    Jespersen, Sanne; Hønge, Bo Langhoff; Esbjörnsson, Joakim;

    2016-01-01

    OBJECTIVES: 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. METHODS: This study utilised...... visit until initiation of ART, death or loss to follow-up using Cox proportional hazard models. RESULTS: 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...

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

    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.

  15. HIV-1 infected patients with suppressed plasma viremia on treatment have pro-inflammatory HDL

    Navab Kaveh

    2011-02-01

    Full Text Available Abstract Background The role of pro-inflammatory lipids in systemic immune activation in HIV infection remains largely unknown. We hypothesized that HIV-1-infected persons on antiretroviral therapy would have pro-inflammatory high density lipoprotein (HDL, and that an apoA-1 mimetic peptide might reverse the inflammatory properties of HDL in these persons. Methods Plasma was obtained from 10 HIV-1-infected individuals on combination antiretroviral therapy with suppressed viremia and was incubated with the apoA-I mimetic peptide L-4F or sham-treated prior to isolation of HDL. The HDL that was isolated from each sample was tested for its ability to inhibit LDL-induced MCP-1 production in cultures of human aortic endothelial cells. Results We found in a small pilot study of HIV-1-infected individuals with suppressed viremia on combination antiretroviral therapy that oxidative stress and inflammation in HIV-1 are associated with a marked reduction of HDL antioxidant/anti-inflammatory activities. In vitro, these abnormalities were significantly improved by treatment with the apoA-1 mimetic peptide, 4F. Conclusions These preliminary observations suggest that the anti-inflammatory properties of HDL are defective in HIV-1-infected persons despite treatment that is considered to be virologically successful.

  16. APOBEC3G Variants and Protection against HIV-1 Infection in Burkina Faso.

    Tegwinde Rebeca Compaore

    Full Text Available Studies on host factors, particularly the APOBEC3G gene, have previously found an association with AIDS progression in some populations and against some HIV-1 strains but not others. Our study had two main objectives: firstly, to screen a population from Burkina Faso for three variants of APOBEC3G previously described, and secondly to analyze the effect of these three variants and their haplotypes on HIV-1 infection with Circulating Recombinant Forms (CRFs present in Burkina Faso. This case control study involved 708 seropositive and seronegative individuals. Genotyping was done by the TaqMan allelic discrimination method. Minor allele frequencies of rs6001417 (p<0.05, rs8177832 (P<0.05, and rs35228531 (P<0.001 were higher in seronegative subjects. The rs6001417 and rs8177832 SNPs were associated with HIV-1 infection in an additive model (P<0.01. Furthermore the SNP rs35228531 was also associated with HIV-1 infection in a dominant model (P<0.001. Odds ratio analysis of genotypes and alleles of the different APOBEC3G variants showed that there is a strong association between the minor genetic variants, genotype of the three SNPs, and HIV-1 status. Haplotype analysis demonstrated that rs6001417, rs8177832, and rs35228531 are in linkage disequilibrium. The haplotype GGT from the rs6001417, rs8177832 and rs35228531 respectively has a protective effect OR = 0.54 [0.43-0.68] with P<0.001. There was also associations between the haplotypes GGC OR = 1.6 [1.1;-2.3] P<0.05, and CGC OR = 5.21 [2.4-11.3] P<0.001, which increase the risk of infection by HIV-1 from almost two (2 to five (5 fold. This study demonstrates an association of rs6001417, rs8177832, and rs35228531 of APOBEC3G with HIV-1 infection in a population from Burkina Faso.

  17. Macrophage Inflammatory Protein-3 Alpha (MIP-3α)/CCL20 in HIV-1-Infected Individuals

    Aziz, Najib; Detels, Roger; Chang, L Cindy; Butch, Anthony W

    2016-01-01

    Objective Uncontrolled HIV infection progresses to the depletion of systemic and mucosal CD4 and AIDS. Early HIV infection may be associated with increases in the concentration of MIP-3α in the blood and gut fluids. MIP-3α/CCL20 is the only chemokine known to interact with CCR6 receptors which are expressed on immature dendritic cells and both effector and memory CD8+ and CD4+ T cells. The role and prognostic value of blood levels of MIP-3α in HIV-infected individuals has yet to be described. Methods We determined the serum levels of MIP-3α, and IFN-γ, in 167 HIV-1-infected and 27 HIV-1-uninfected men participating in the Multicenter AIDS Cohort Study (MACS). The blood biomarkers were measured using enzyme-linked immunosorbent assays (ELISA) and the cell phenotypes using flow cytometry. Results Median serum levels of MIP-3α in HIV-1-infected and uninfected men was significantly different (pabsolute number of CD4+ T cell (p=0.01) and were positively correlated with CD38 molecules on CD8+ T cells (p=0.0002) and with serum levels of IFN-γ (0.006). Conclusion Serum levels of MIP-3α concomitantly increase with plasma levels of IFN-γ, CD38 expression on CD8+ T cells, and decreased of absolute CD4+ T cells in HIV-1-infected men. A higher blood level of MIP-3α may be representation of locally high level of MIP-3α and more recruitment of immature dendritic cell at site of infection. Involvement of CCR6/CCL20 axis and epithelial cells at the recto-colonel level may enhance sexual transmission of HIV-1 in MSM and may be useful as a prognostic marker in HIV-1-infection and AIDS.

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

    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.

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

    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.

  20. No relationship between gastric pH, small bowel bacterial colonisation, and diarrhoea in HIV-1 infected patients

    Wilcox, C; Waites, K; SMITH, P., CUBAS, M., CORRIN, J., TAPIA, J., DE PEDRO, I., RUIZ COBO, J., PEREDA ROSALES, E.M.

    1999-01-01

    Background/Aims—Conclusive studies of small bowel bacterial overgrowth in patients with HIV-1 infection are limited. The relation was therefore determined between the quantity and species of bacteria in the proximal small intestine of HIV-1 infected patients and the presence of diarrhoea, gastric acidity, severity of immune deficiency, and clinical outcome. 
Methods—Bacteria in the duodenal fluids obtained endoscopically from 32 HIV-1 infected patients, 21 of whom had dia...

  1. Association between active GB virus-C (hepatitis G) infection and HIV-1 disease in Uganda.

    Yirrell, D L; Wright, E; Shafer, L A; Campbell, E; Van der Paal, L; Kaleebu, P; Grosskurth, H; Whitworth, J A

    2007-04-01

    Although not linked to a disease, GB virus-C viraemia has been associated with an improved prognosis in HIV-1-co-infected individuals. Most studies have been conducted on men (men who have sex with men or injection drug users) infected with HIV-1 subtype B, whereas here we report on both male and female subjects from rural Uganda, predominantly infected via the heterosexual route with HIV-1 subtypes A and D. In a longitudinal study of 272 participants, 47 were GBV-C positive and 181 negative, as determined by reverse transcription-polymerase chain reaction, in both of two plasma samples taken a median of 5.0 years apart. The remainder either acquired (25) or cleared (19) infection. Multilevel regression analyses and Cox survival analyses revealed that participants chronically infected with GBV-C had a slower decline in CD4(+) T cells (P<0.001) and increased survival time (P=0.041) compared with GBV-C RNA-negative, HIV-positive adults. We show that the association between active GBV-C co-infection and improved survival of HIV-1-infected adults is not restricted to HIV subtype B, but is also observed in both males and females infected with HIV subtypes A and D. PMID:17509174

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

    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

  3. The growth of human HIV-1 infected U937 cells in immune-deprived mice.

    Chernukhin, I V; Chepurnov, A A; Gaidul, K V

    1995-01-01

    We report in vivo growth of human promonocytic cells infected with HIV-1 presented in new mouse model. Cloned U937 cells chronically infected with HIV-1 were grafted in (CBA*C57B1/6)F1 mice deprived of immunity by thymectomia and total body irradiation with subsequent marrow reconstitution. Nine weeks after cell inoculation, HIV-1-positive cells were found only in mice that received an additional single dose of cyclophosphamide (100 mg/kg bw) prior to transplantation, whereas, in mice without further immune deprivation, the complete elimination of cells bearing viral antigen occurred already on the seventh day after transplantation. The approach described may be suitable for in vivo development of antiviral drugs against latent infection in macrophage-like cells which represent a serious problem in therapy of AIDS in humans. PMID:8562863

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

    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

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

    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.

  6. Off-label use of maraviroc in HIV-1-infected paediatric patients in clinical practice.

    Palladino, Claudia; Gómez, María Luisa Navarro; Soler-Palacín, Pere; González-Tomé, María Isabel; De Ory, Santiago J; Espiau, María; Hoyos, Santiago Pérez; León-Leal, Juan Antonio; Méndez, María; Moreno-Pérez, David; Guasch, Claudia Fortuny; Sierra, Antoni Mur; Guruceta, Itziar Pocheville; Guillén, Santiago Moreno; Briz, Verónica

    2015-10-23

    Maraviroc (MVC) is not approved for HIV-1-infected paediatric patients. This is the first assessment of the use of MVC-based salvage therapy in vertically HIV-1-infected paediatric patients in clinical settings. The results suggest that MVC-based salvage therapy is useful in children and adolescents with extensive resistance profile leading to maintained virological suppression in up to 88% of the patients with CCR5-tropic virus. The likelihood of treatment success might increase when MVC is combined with other active drugs. PMID:26544580

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

    Bonifati, Serena; Daly, Michele B; St Gelais, Corine; Kim, Sun Hee; Hollenbaugh, Joseph A; Shepard, Caitlin; Kennedy, Edward M; Kim, Dong-Hyun; Schinazi, Raymond F; Kim, Baek; Wu, Li

    2016-08-01

    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 G1/G0 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. PMID:27183329

  8. polymorphism Analysis of Resistance Genes in Chinese Populations with HIV-1 Infection

    冯铁建; 王福生; 王晓辉; 陈琳; 金磊; 侯静; 李良成; 施红; 洪卫国; 王业东

    2001-01-01

    Objective: To analyze the genotypes of CCR5 △ 32,CCR2b-64I and SDF 1-3`A and mutation frequencies of allelic genes in Chinese populations infected with HIV-1.Methods: Genome DNA from peripheral blood mononuclear cells (PBMCs) of 78 HIV-1 infectors was amplified by polymerase chain reaction (PCR). CCR5, CCR2b and SDF1 gene fragments were obtained from restrictive fragment length polymorphism (RFLP) and/or CCR/△32, CCR5m303,CCR2b-64I and SDF1-3' A allelic genes' mutational frequencies were sequenced directly from PCR products.Results: None of CCR5△32, CCR5m303 gene mutation were found in 78 subjects with HIV-1 infection. The allelic gene mutation frequencies of CCR2b-64I and SDF1-3'A corresponding to 14.9-34.0% and 17.6-38.2% of 95% CI, were 22.79% and 26.92% respectively. Their colony distribution conformed to the Hardy-Weinberg equilibrium.Conclusion: The HIV-1 infections found at present are all susceptible population of CCR5△32 and CCR5m303. The polymorphism and frequencies of CCR5△32, CCR5m303,CCR2b-64I and SDFI-3'A alleles from Chinese HIV-1 infected population were disclosed in this study for the first time, which is of significance for studying the genetic resistance to susceptibility to HIV-1 infection as well as AIDS disease progression.

  9. HIV-1 diversity in infected individuals in Suzhou and Suqian, China.

    Qin, Chenhao; Zhang, Ping; Zhu, Weiguang; Hao, Fangyuan; Gu, Aiping; Fen, Ping; Zhu, Xueming; Du, Hong

    2016-01-01

    Jiangsu is one province with severe HIV-1 epidemic in China. However, the molecular epidemiological characterizations of HIV-1 in many cities of Jiangsu remain unclear. A molecular epidemiological investigation was performed based on 38 HIV-positive samples collected from Suzhou and Suqian during 2011-2013. Five HIV-1 genomic fragments, p17, pol, vif-vpr, vpr-env, and C2V3 were amplified and sequenced from these samples. HIV-1 group M subtype of each sample was determined by phylogenetic analyses with the standard reference sequences. Among these infected individuals, 81.6 % (31/38) self-reported to be infected via sexual contacts, including 50.0 % (19/38) via heterosexual contact and 31.6 % (12/38) via homosexual contact. Among 34 samples with available pol or vif-env sequence, 19 (55.9 %) CRF01_AE, 7 (20.6 %) CRF07_BC, 3 (8.8 %) CRF08_BC, and 5 (14.7 %) inter-subtype recombinants were identified. No pure B, B' and C subtypes were found in this cohort. The five recombinants contain one B/C, three CRF01/B and one CRF01/B/C recombinants. These results suggest that CRF01_AE was the most predominant HIV-1 group M subtype and CRF01_AE-involved recombinants were the major recombinant forms. Comparison showed that there was no obvious difference in HIV-1 group M subtype distribution between Jiangsu (including Suzhou and Suqian) and the surrounding provinces (e.g., Shanghai, Anhui, and Shandong). CRF01_AE and CRF07_BC were the top two predominant HIV-1 genotypes in Jiangsu, and less and/or no pure subtype B and C was currently circulating here. We predicted that more CRF01/CRF07 recombinants, but fewer B/C recombinants will be generated in Jiangsu in future. PMID:27386334

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

    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.

  11. Dermatomyositis associated with HIV-1 infection in a Nigerian adult female: a case report

    Ogoina, D; A. Umar; Obiako, OR

    2012-01-01

    Human immunodeficiency virus (HIV) infection has been implicated as a trigger for various autoimmune diseases, one of which is dermatomyositis. This is a very rare autoimmune disease characterised by myopathy, typical cutaneous signs and variable systemic manifestations. To our knowledge, the association of this rare disease with HIV infection has not been previously reported in Nigeria. We therefore decided to report the case of a 40 year old HIV-1 infected Nigerian female who presented to u...

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

    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 ...

  13. Care and management of the infant of the HIV-1-infected mother.

    Paintsil, Elijah; Andiman, Warren A

    2007-04-01

    Mother-to-child transmission of the human immunodeficiency virus continues to be a major global health problem. The pediatric HIV-1 epidemic is fueled by HIV-1 infection in women of childbearing age with vertical transmission in utero or at the time of birth. In resource-rich countries, the birth of an infected child is a sentinel health event signaling a chain of missed opportunities and barriers to prevention. Because the fate and ultimate HIV-infection status of the baby is inextricably linked to the infection status of the mother and her general state of well-being, we provide in this review: 1) background and state-of-the-art management guidelines for optimum maternal care; 2) strategies to minimize the risk of vertical transmission of HIV; and 3) recommendations for managing infants born to HIV-infected women. These are discussed under four case scenarios that obstetric and pediatric providers frequently encounter in their practices. PMID:17462496

  14. Prevalence of prediabetes in HIV-1 infected adults receiving antiretroviral therapy in Addis Ababa, Ethiopia.

    Hagos Amare Gebreyesus

    2015-02-01

    Full Text Available Background: Prediabetes is a substantial risk factor for developing type-2 diabetes mellitus and its sequel, which include heart disease, stroke, nephropathy and retinopathy. Apart from the genetic and lifestyle risk factors, antiretroviral drugs aggravate the predisposition. Thus, detecting this condition can allow for the provision of better care for HIV-1-infected patients. Objective: The aim of the study was to determine the prevalence of prediabetes in HIV-1 infected patients on antiretroviral therapy. Method: A cross sectional study was conducted in HIV-1 infected patients enrolled in ART program in a tertiary hospital ART clinic in Addis Ababa. A total of 134 subjects taking HAART were included in the study. 61 (45.5% were males and 73(54.5% were females. The age of the participants range from 20-69 with a median of 40 years. The median duration of HAART intake was 58 months. The prevalence of prediabetes was found to be 22.4%. Among the total study subjects, 19.4% of them had overweight. 50.5% of males and 41% females had a WHR of ≥0.90 and ≥0.85, respectively indicating a high prevalence of central obesity and future risk of cardiovascular problem among this group. Conclusion: Pre-diabetes is common in HIV-1-infected patients receiving ART; putting this group at substantial risk of developing type 2 diabetes and cardiovascular disease.

  15. The cyclosporin A washout assay to detect HIV-1 uncoating in infected cells.

    Hulme, Amy E; Hope, Thomas J

    2014-01-01

    Uncoating is an early step of HIV-1 replication in which the viral capsid disassembles by p24 capsid (p24(CA)) protein dissociating from the viral complex. Although uncoating is required for HIV-1 replication, many questions remain about the mechanism of this process as well as its impact on other steps in viral replication. Here we describe a recently developed assay to study the process of uncoating in HIV-1-infected cells. The CsA washout assay is a cell-based assay that utilizes the HIV-1 restriction factor TRIM-CypA to detect and inhibit infection of coated viral complexes. Owl monkey kidney (OMK) cells are infected with a GFP reporter virus and TRIM-CypA restriction is switched on at various times postinfection allowing the kinetics of uncoating to be monitored in infected cells. This assay also can be used to examine the effect of different viral or cellular factors on the process of uncoating. PMID:24158812

  16. HIV-1-infected macrophages induce astrogliosis by SDF-1α and matrix metalloproteinases

    Brain macrophages/microglia and astrocytes are known to be involved in the pathogenesis of HIV-1-associated dementia (HAD). To clarify their interaction and contribution to the pathogenesis, HIV-1-infected or uninfected macrophages were used as a model of brain macrophages/microglia, and their effects on human astrocytes in vitro were examined. The culture supernatants of HIV-1-infected or uninfected macrophages induced significant astrocyte proliferation, which was annihilated with a neutralizing antibody to stromal cell-derived factor (SDF)-1α or a matrix metalloproteinase (MMP) inhibitor. In these astrocytes, CXCR4, MMP, and tissue inhibitors of matrix metalloproteinase mRNA expression and SDF-1α production were significantly up-regulated. The supernatants of infected macrophages were always more effective than those of uninfected cells. Moreover, the enhanced production of SDF-1α was suppressed by the MMP inhibitor. These results indicate that the activated and HIV-1-infected macrophages can indirectly induce astrocyte proliferation through up-regulating SDF-1α and MMP production, which implies a mechanism of astrogliosis in HAD

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

    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.

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

    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...

  19. Soluble urokinase receptor levels in plasma during 5 years of highly active antiretroviral therapy in HIV-1-infected patients

    Ostrowski, Sisse R; Katzenstein, Terese L; Piironen, Timo;

    2004-01-01

    High blood levels of the soluble urokinase receptor (suPAR) strongly predict increased mortality in human immunodeficiency virus-1 (HIV-1)-infected patients. This study investigated the plasma concentration of suPAR in 29 treatment-naive HIV-1-infected patients during 5 years treatment with highl...

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

    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

  1. Raltegravir: The evidence of its therapeutic value in HIV-1 infection

    Kavya Ramkumar

    2009-07-01

    Full Text Available Kavya Ramkumar, Nouri NeamatiDepartment of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USAIntroduction: The antiretroviral treatment paradigm for human immunodeficiency virus-1 (HIV-1 infection has undergone a significant change with the addition of a new class of therapeutic agents targeting HIV-1 integrase (IN. IN inhibitors prevent the integration of viral DNA into the human genome and terminate the viral life cycle. As the first member of this new class of anti-HIV drugs, raltegravir has shown promising results in the clinic. Aims: To review the emerging evidence for the use of the IN inhibitor raltegravir in the treatment of HIV-1 infection.Evidence review: Strong evidence shows that raltegravir is effective in reducing the viral load to less than 50 copies/mL and increasing CD4 cell count in treatment-experienced patients with triple-drug class-resistant HIV-1 infection. Substantial evidence also indicates that while raltegravir is able to achieve treatment response in patients with drug-resistant HIV-1, it is susceptible to development of resistance. Raltegravir should be used with at least one other active drug. In addition to its use in salvage therapy upon failure of first-line antiretroviral treatment, a raltegravir-based treatment regimen may also be effective as initial therapy. Substantial evidence also shows that raltegravir-based treatment regimen is well tolerated with minimal clinically severe adverse events and toxicities. Modeling studies suggest a cost-effectiveness of US$21,339 per quality-adjusted life year gained with raltegravir use, though further direct evidence on quality of life and cost-effectiveness is needed. Place in therapy: Raltegravir shows significant and sustained virologic and immunologic response in combination with other antiretrovirals in treatment-experienced HIV-1 infected patients who show evidence of viral replication or multidrug

  2. Identification of Capsid Mutations That Alter the Rate of HIV-1 Uncoating in Infected Cells

    Hulme, Amy E.; Kelley, Z; Okocha, Eneniziaogochukwu A.; Hope, Thomas J.

    2014-01-01

    After viral fusion with the cell membrane, the conical capsid of HIV-1 disassembles by a process called uncoating. We recently utilized the cyclosporine (CsA) washout assay, in which TRIM-CypA-mediated restriction of viral replication is used to detect the state of the viral capsid, to study the kinetics of uncoating in HIV-1-infected cells. Here we have extended this analysis to examine the effects of p24 capsid protein (p24CA) mutations and cellular environment on the kinetics of uncoating ...

  3. Guillain Barre syndrome in an HIV-1-infected patient after the beginning of combined antiretroviral therapy: an immune reconstitution inflammatory syndrome?

    Fantauzzi, Alessandra; Digiulio, Maria Anna; Cavallari, Eugenio Nelson; d'Ettorre, Gabriella; Vullo, Vincenzo; Mezzaroma, Ivano

    2014-01-01

    HIV-1-associated Guillan-Barre syndrome (hGBS) is an ascendant progressive polyradiculoneuropathy described throughout the course of the viral disease, mainly associated with the acute retroviral syndrome. HGBS is occasionally described in severely immunocompromised subjects in the context of the immune reconstitution inflammatory syndrome. The case described occurred soon after the start of a combined antiretroviral treatment in an HIV-1 infected patient with ulcerative colitis in the absence of severe immunosuppression. This manifestation may be interpreted as an uncommon appearance of an immune reconstitution syndrome in the presence of a predisposing autoimmune pathology. PMID:24531178

  4. FOXP3 Inhibits HIV-1 Infection of CD4 T-cells via Inhibition of LTR Transcriptional Activity

    Selliah, Nithianandan; Zhang, Mingce; White, Sara; Zoltick, Philip; Sawaya, Bassel E.; Finkel, Terri H.; Cron, Randy Q

    2008-01-01

    FOXP3 is a necessary transcription factor for the development and function of CD4+ regulatory T-cells (Tregs). The role of Tregs in HIV-1 infection remains unclear. Here, we show expression of FOXP3 in primary human CD4 T-cells significantly inhibits HIV-1 infection. Since FOXP3 inhibits NFAT activity, and NFAT proteins contribute to HIV-1 transcription, we explore a transcriptional repressive function of HIV-1 LTR by FOXP3. Over-expression of FOXP3 in primary CD4 T-cells inhibits wild-type H...

  5. Cerebrovascular disease in children with HIV-1 infection.

    Hammond, Charles K; Eley, Brian; Wieselthaler, Nicky; Ndondo, Alvin; Wilmshurst, Jo M

    2016-05-01

    An estimated 3.2 million children worldwide have human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) has resulted in prolonged survival, leading to an increase in complications previously recognized in adults. Children with HIV infection have increased risk of cerebrovascular disease from multiple aetiologies including HIV-associated vasculopathy, opportunistic vasculitis, cardioembolism or coagulopathy, all of which may be secondary to the infection. Prevalence of cerebrovascular disease in HIV-infected children is underestimated because of limited neuroimaging in low and middle income countries, silent events without overt motor manifestations, and mislabeling as HIV encephalopathy for non-motor manifestations such as behavioural and cognitive difficulties. No management guidelines for cerebrovascular disease in HIV-infected children exist but common practices target risk factors for stroke in low and middle income countries. Where capacity permits, screening for opportunistic infections, vasculitis, coagulopathy and cardioembolism is important. Optimising virological suppression, correction of anaemia, control of seizures and aspirin prophylaxis are management priorities. Neurosurgical interventions may have a role. PMID:26890389

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

    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

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

    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.

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

    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.

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

    Cimbro, Raffaello; Peterson, Francis C; Liu, Qingbo; Guzzo, Christina; Zhang, Peng; Miao, Huiyi; Van Ryk, Donald; Ambroggio, Xavier; Hurt, Darrell E; De Gioia, Luca; Volkman, Brian F; Dolan, Michael A; Lusso, Paolo

    2016-08-01

    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. PMID:27389109

  10. Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) infections in alcoholics.

    Prakash, Om; Mason, Andrew; Luftig, Ronald B; Bautista, Abraham P

    2002-07-01

    Approximately 400,000 individuals in the United States are co-infected with hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) and it is likely that almost one in two of these subjects consumes alcohol. The majority of these patients suffer an accelerated course of liver disease as manifested by the onset of cirrhosis within 5 to 10 years of developing HCV infection, as well as an increased risk of developing hepatocellular carcinoma (HCC). It is thought that chronic alcohol abuse mediates liver damage as a result of increased production of free radicals and proinflammatory cytokines. In the setting of chronic HCV infection, alcohol ingestion has an additional effect of diminishing immune clearance and increasing viral burden to hasten the onset of cirrhosis and HCC. Likewise, chronic HCV and HIV-1 co-infection results in a net increase in HCV burden; higher prevalence rates of HCV transmission to sexual partners and offspring, as well as an accelerated progression to end stage liver disease as compared to individuals with HCV infection alone. Thus, the synergistic effects of alcohol abuse and HIV-1 greatly impact on the morbidity and mortality for patients with HCV coinfection. Ultimately, this cumulative disease process will require far more aggressive management with abstinence and counseling for alcohol abuse; highly active antiretroviral therapy (HAART) for HIV infection and combination anti-viral therapy for HCV infection to stem the rapid progression to end stage liver disease. PMID:12086918

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

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

    2008-01-01

    Despite undetectable viral load in conventional assays, probably all human immunodeficiency virus (HIV)-1 infected patients have residual viraemia (RV) detectable by ultra-sensitive assays. To study this issue, this study investigated virologic and immunologic consequences of RV in highly active......-count, CD4+HLA-DR+, CD8+HLA-DR+CD38+, CD4+CD45RA-CD45RO+, CD8+CD45RA-CD45RO+, CD4+CD45RA+CD62L+, CD8+CD45RA+CD62L+ T cells, IgG or IgM. In conclusion, RV was associated with increased blood levels of soluble immune activation markers in HAART-treated HIV-1-infected patients. The finding that RV was...... 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...

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

    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.

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

    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.

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

    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

  15. Primary drug resistance at diagnosis of HIV-1 infection: a Portuguese cohort

    Nuno Rocha Pereira; Raquel Duro; Carmela Piñero; Cristóvão Figueiredo; Ana Sofia Santos; Jorge Soares; Rosário Serrão; António Sarmento

    2014-01-01

    Introduction: Presence of viral mutations conferring resistance to antiretroviral drugs has potential impact on success of antiretroviral therapy (ART). The aim of this study was to describe the prevalence of resistance-associated mutations in HIV-infected patients without prior ART in a Portuguese cohort. Materials and Methods: Retrospective single-centre study of patients newly diagnosed with HIV-1 infection between 2006 and 2012. Resistance genotyping was obtained with HIV TRUGENE® and Vir...

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

    Dharan, Adarsh; Talley, Sarah; Tripathi, Abhishek; Mamede, João I; Majetschak, Matthias; Hope, Thomas J; Campbell, Edward M

    2016-06-01

    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. PMID:27327622

  17. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia.

    Dillon, S M; Lee, E J; Kotter, C V; Austin, G L; Dong, Z; Hecht, D K; Gianella, S; Siewe, B; Smith, D M; Landay, A L; Robertson, C E; Frank, D N; Wilson, C C

    2014-07-01

    Human immunodeficiency virus-1 (HIV-1) infection disrupts the intestinal immune system, leading to microbial translocation and systemic immune activation. We investigated the impact of HIV-1 infection on the intestinal microbiome and its association with mucosal T-cell and dendritic cell (DC) frequency and activation, as well as with levels of systemic T-cell activation, inflammation, and microbial translocation. Bacterial 16S ribosomal DNA sequencing was performed on colon biopsies and fecal samples from subjects with chronic, untreated HIV-1 infection and uninfected control subjects. Colon biopsies of HIV-1-infected subjects had increased abundances of Proteobacteria and decreased abundances of Firmicutes compared with uninfected donors. Furthermore at the genus level, a significant increase in Prevotella and decrease in Bacteroides was observed in HIV-1-infected subjects, indicating a disruption in the Bacteroidetes bacterial community structure. This HIV-1-associated increase in Prevotella abundance was associated with increased numbers of activated colonic T cells and myeloid DCs. Principal coordinates analysis demonstrated an HIV-1-related change in the microbiome that was associated with increased mucosal cellular immune activation, microbial translocation, and blood T-cell activation. These observations suggest that an important relationship exists between altered mucosal bacterial communities and intestinal inflammation during chronic HIV-1 infection. PMID:24399150

  18. Hiv-1 Drug Resistance Among Newly Hiv-1 Infected Individuals Attending Tertiary Referral Center in Chennai, India

    Hussain Syed Iqbal

    2011-01-01

    Full Text Available Context: In the era of free HAART, accessibility and availability of ARV has been dramatically increased in India. However, rates of treatment literacy and adherence appear to be sub-optimal. Therefore, it is essential to monitor the extent of primary drug resistance in such settings. Materials and Methods: Between July and October 2006, 18 anti-retroviral-naοve individuals were identified as recent infected by the BED-Capture enzyme immunoassay in a VCTC clinic in Chennai. Specimens from these individuals were subjected to genotypic drug resistance testing. Phylogenetic trees were generated using MEGA for Windows version 4.0 using neighbor-joining method. The significant differences in polymorphic mutation frequencies between the study specimens and established subtype C-specific polymorphisms were examined using the Chi-square test. Results: Amino acid substitution (K103N and V106MV at drug resistance positions occurred in two (11% isolates, conferring high-level resistance to the non-nucleoside reverse-transcriptase inhibitors nevirapine (NVP, efavirenz (EFV, delavirdine (DLV and notably extensive genetic variations were observed. K122E (94.4% and K49R/KR (11.1% polymorphisms identified in this study have not been previously described in established subtype-C specific polymorphisms. The rate of polymorphisms showed marked difference at the locations V60, D121, V35, and D123 (P < 0.0001. All the sequences showed maximum homology with Indian HIV-1 subtype C reference strain C.IN.95IN21068. Conclusions: The finding of resistance to NNRTIs is of public health importance. There is an urgent need to establish surveillance for primary drug resistance in large scale. Further studies are required to determine the phenotype impact of newer polymorphic mutations in relation to drug resistance and viral fitness.

  19. HIV-1 Nef Inhibits Ruffles, Induces Filopodia, and Modulates Migration of Infected Lymphocytes▿

    Nobile, Cinzia; Rudnicka, Dominika; Hasan, Milena; Aulner, Nathalie; Porrot, Françoise; Machu, Christophe; Renaud, Olivier; Prévost, Marie-Christine; Hivroz, Claire; Schwartz, Olivier; Sol-Foulon, Nathalie

    2010-01-01

    The HIV-1 Nef protein is a pathogenic factor modulating the behavior of infected cells. Nef induces actin cytoskeleton changes and impairs cell migration toward chemokines. We further characterized the morphology, cytoskeleton dynamics, and motility of HIV-1-infected lymphocytes. By using scanning electron microscopy, confocal immunofluorescence microscopy, and ImageStream technology, which combines flow cytometry and automated imaging, we report that HIV-1 induces a characteristic remodeling of the actin cytoskeleton. In infected lymphocytes, ruffle formation is inhibited, whereas long, thin filopodium-like protrusions are induced. Cells infected with HIV with nef deleted display a normal phenotype, and Nef expression alone, in the absence of other viral proteins, induces morphological changes. We also used an innovative imaging system to immobilize and visualize living individual cells in suspension. When combined with confocal “axial tomography,” this technique greatly enhances three-dimensional optical resolution. With this technique, we confirmed the induction of long filopodium-like structures in unfixed Nef-expressing lymphocytes. The cytoskeleton reorganization induced by Nef is associated with an important impairment of cell movements. The adhesion and spreading of infected cells to fibronectin, their spontaneous motility, and their migration toward chemokines (CXCL12, CCL3, and CCL19) were all significantly decreased. Therefore, Nef induces complex effects on the lymphocyte actin cytoskeleton and cellular morphology, which likely impacts the capacity of infected cells to circulate and to encounter and communicate with bystander cells. PMID:20015995

  20. Activation and lysis of human CD4 cells latently infected with HIV-1.

    Pegu, Amarendra; Asokan, Mangaiarkarasi; Wu, Lan; Wang, Keyun; Hataye, Jason; Casazza, Joseph P; Guo, Xiaoti; Shi, Wei; Georgiev, Ivelin; Zhou, Tongqing; Chen, Xuejun; O'Dell, Sijy; Todd, John-Paul; Kwong, Peter D; Rao, Srinivas S; Yang, Zhi-yong; Koup, Richard A; Mascola, John R; Nabel, Gary J

    2015-01-01

    The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. Here we report an approach to reduce the viral reservoir by activating dormant viral gene expression and directing T lymphocytes to lyse previously latent, HIV-1-infected cells. An immunomodulatory protein was created that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. It further stimulates CD8 T-cell effector function and redirects T cells to lyse these previously latent-infected cells through recognition of newly expressed Env. This immunomodulatory protein could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. PMID:26485194

  1. Studies on the allostimulatory function of dendritic cells from HCV-HIV-1 co-infected patients

    Justin STEBBING; Brian GAZZARD; Steve PATTERSON; Simon PORTSMOUTH; Claire THOMAS; Robert GLASSMAN; Adrian WILDFIRE; Frances GOTCH; Mark BOWER; Mark NELSON

    2004-01-01

    There is increasing recognition of the potential morbidity and mortality associated with HIV-1 and hepatitis C (HCV)co-infection. HIV appears to adversely affect HCV disease while the reciprocal effect of HCV on HIV remains controversial.We therefore studied the effect of co-infection on dendritic cell function versus HIV infection alone, as previous work has shown that HCV impairs dendritic cell (DC) function. HIV-1 positive individuals with HCV were matched for CD4count, HIV- 1 RNA viral load and therapy, to HIV- 1 positive patients without HCV. Monocyte-derived DC were generated and mixed leukocyte reactions were performed. We assessed allostimulatory capacity with and without administration of exogenous Thl cytokines, using thymidine uptake and cell division analyses with the vital dye CFSE. We found that monocyte-derived DC from co-infected individuals showed no significant differences in allostimulatory capacity to ex vivo generated DC from HIV-1 infected individuals without HCV. Unlike the situation with HCV infection alone, this impairment was not reversed by increasing concentrations of either interleukin-2 or -12. Monocyte-derived DC from HIV-1 and HCV co-infected individuals have a similar allostimulatory capacity to DC from matched patients with HIV-1alone. These findings are compatible with results of prior clinical studies that found no evidence that HCV co-infection altered HIV disease progression and has implications for immunotherapeutic approaches in co-infected individuals.

  2. Low dose rectal inoculation of rhesus macaques by SIV SME660 or SIV MAC251 recapitulates human mucosal infection by HIV-1

    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.

  3. Cytokine therapies in HIV-1 infection: present and future.

    Pett, Sarah L; Kelleher, Anthony D

    2003-06-01

    Since the introduction of highly active antiretroviral therapy (HAART), HIV-related deaths have declined dramatically in the developed world. However, HAART is neither able to eradicate the virus nor are its immunomodulatory effects sufficient to effect complete control of the virus. In addition, the long-term use of HAART is complicated by drug-related toxicities and compliance issues, both of which impact upon the development of viral resistance. The failure of structured treatment interruption strategies in those with chronic HIV-infection combined with the above limitations, has prompted renewed interest in immunotherapy. Cytokines and therapeutic vaccination have been proposed as HAART-adjunctive and HAART-sparing treatments in HIV-infection, and the current and future role of cytokine therapy in this disease will be the subject of this review. PMID:15482104

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

    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

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

    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....

  6. APOBEC3G Variants and Protection against HIV-1 Infection in Burkina Faso.

    Compaore, Tegwinde Rebeca; Soubeiga, Serge Theophile; Ouattara, Abdoul Karim; Obiri-Yeboah, Dorcas; Tchelougou, Damehan; Maiga, Mamoudou; Assih, Maleki; Bisseye, Cyrille; Bakouan, Didier; Compaore, Issaka Pierre; Dembele, Augustine; Martinson, Jeremy; Simpore, Jacques

    2016-01-01

    Studies on host factors, particularly the APOBEC3G gene, have previously found an association with AIDS progression in some populations and against some HIV-1 strains but not others. Our study had two main objectives: firstly, to screen a population from Burkina Faso for three variants of APOBEC3G previously described, and secondly to analyze the effect of these three variants and their haplotypes on HIV-1 infection with Circulating Recombinant Forms (CRFs) present in Burkina Faso. This case control study involved 708 seropositive and seronegative individuals. Genotyping was done by the TaqMan allelic discrimination method. Minor allele frequencies of rs6001417 (pratio analysis of genotypes and alleles of the different APOBEC3G variants showed that there is a strong association between the minor genetic variants, genotype of the three SNPs, and HIV-1 status. Haplotype analysis demonstrated that rs6001417, rs8177832, and rs35228531 are in linkage disequilibrium. The haplotype GGT from the rs6001417, rs8177832 and rs35228531 respectively has a protective effect OR = 0.54 [0.43-0.68] with P<0.001. There was also associations between the haplotypes GGC OR = 1.6 [1.1;-2.3] P<0.05, and CGC OR = 5.21 [2.4-11.3] P<0.001, which increase the risk of infection by HIV-1 from almost two (2) to five (5) fold. This study demonstrates an association of rs6001417, rs8177832, and rs35228531 of APOBEC3G with HIV-1 infection in a population from Burkina Faso. PMID:26741797

  7. Chronic renal failure among HIV-1-infected patients

    Mocroft, Amanda; Kirk, Ole; Gatell, Jose;

    2007-01-01

    BACKGROUND: The role of exposure to antiretrovirals in chronic renal failure (CRF) is not well understood. Glomerular filtration rates (GFR) are estimated using the Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) equations. METHODS: Baseline was arbitrarily defined as the first...... recorded GFR; patients with two consecutive GFR determine odds ratio (OR) of CRF at baseline. ART exposure (yes/no or cumulative exposure) prior to baseline was included in multivariate models (adjusted for region...... of Europe, age, prior AIDS, CD4 cell count nadir, viral load, hypertension and use of nephrotoxic anti-infective therapy). RESULTS: Using CG, the median GFR at baseline (n = 4474) was 94.4 (interquartile range, 80.5-109.3); 158 patients (3.5%) had CRF. Patients with CRF were older (median, 61.9 versus 43...

  8. Mortality attributable to smoking among HIV-1-infected individuals

    Helleberg, Marie; Afzal, Shoaib; Kronborg, Gitte;

    2013-01-01

    population-attributable risk of death associated with smoking was 61.5% among HIV patients and 34.2% among controls.Conclusions. In a setting where HIV care is well organized and antiretroviral therapy is free of charge, HIV-infected smokers lose more life-years to smoking than to HIV. The excess mortality......Background. We assessed mortality attributable to smoking among patients with human immunodeficiency virus (HIV).Methods. We estimated mortality rates (MRs), mortality rate ratios (MRRs), life expectancies, life-years lost, and population-attributable risk of death associated with smoking and with...... of smokers is tripled and the population-attributable risk of death associated with smoking is doubled among HIV patients compared to the background population....

  9. Large Isoform of Mammalian Relative of DnaJ is a Major Determinant of Human Susceptibility to HIV-1 Infection

    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.

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

    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.

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

    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.

  12. Biophysical characterization of V3-lipopeptide liposomes influencing HIV-1 infectivity

    The V3-loop of the HIV-1 gp120 alters host cell immune function and modulates infectivity. We investigated biophysical parameters of liposome constructs with embedded lipopeptides from the principle neutralizing domain of the V3-loop and their influence on viral infectivity. Dynamic light scattering measurements showed liposome supramolecular structures with hydrodynamic radius of the order of 900 and 1300 nm for plain and V3-lipopeptide liposomes. Electron paramagnetic resonance measurements showed almost identical local microenvironment. The difference in liposome hydrodynamic radius was attributed to the fluctuating ionic environment of the V3-lipopeptide liposomes. In vitro HIV-1 infectivity assays showed that plain liposomes reduced virus production in all cell cultures, probably due to the hydrophobic nature of the aggregates. Liposomes carrying V3-lipopeptides with different cationic potentials restored and even enhanced infectivity (p < 0.05). These results highlight the need for elucidation of the involvement of lipid bilayers as dynamic components in supramolecular structures and in HIV-1 fusion mechanisms

  13. Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors of ribonucleotide reductase.

    Rawson, Jonathan M O; Roth, Megan E; Xie, Jiashu; Daly, Michele B; Clouser, Christine L; Landman, Sean R; Reilly, Cavan S; Bonnac, Laurent; Kim, Baek; Patterson, Steven E; Mansky, Louis M

    2016-06-01

    Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2'-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5-aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity. PMID:27117260

  14. 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

    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.

  15. Ectopic expression of anti-HIV-1 shRNAs protects CD8+ T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation

    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+ T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8+ T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8+ T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24Gag in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8+ 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+ T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8+ T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8+ T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8+ T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8+ T cells from HIV-1 infection suppresses its cytopathic effect

  16. Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children

    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. Coinfection with HIV-1 alleviates iron accumulation in patients with chronic hepatitis C virus infection.

    Yuan Liu

    Full Text Available Most chronically-infected hepatitis C virus (HCV patients have increased levels of iron in the liver. Iron overload reduces sustained responses to antiviral therapy, leading to more rapid progression to liver cirrhosis and the development of hepatocellular carcinoma. However, it is still unclear how HIV-1 infection affects iron status in patients chronically infected with HCV. The present study recruited 227 patients from a village in central China. These patients were either monoinfected with HCV (n = 129 or coinfected with HCV/HIV-1 (n = 98. Healthy controls (n = 84 were also recruited from the same village. Indicators of iron status, such as serum levels of iron, ferritin, and transferrin, total iron-binding capacity (TIBC, transferrin saturation (Tfs, and hepcidin, were analyzed and compared across the three groups. The results showed that serum levels of iron (p = 0.001 and ferritin (p = 0.009 and the Tfs (p = 0.002 were significantly higher in HCV-monoinfected patients than in the healthy controls; however, there were no differences in iron levels and Tfs between HCV/HIV-1 coinfected patients and healthy controls. Additionally, although serum hepcidin levels in HCV-monoinfected and HCV/HIV-1-coinfected patients were lower (p<0.001 than those in health controls, the levels in coinfected patients were higher (p = 0.025 than those in HCV-monoinfected patients. Serum iron and ferritin levels in HCV-monoinfected patients were positively correlated with serum ALT/AST. Serum transferrin levels were negatively correlated with ALT/AST levels. The levels of iron in the serum of coinfected patients with a CD4+T-cell count <500/µl were lower than those in patients with a CD4+T-cell count ≥500/µl, whereas serum hepcidin levels showed the opposite trend. Taken together, these results suggest that coinfection with HIV-1 alleviates iron accumulation caused by chronic HCV infection. Our study indicated that determining the

  18. Frequency of class I anti-HLA alloantibodies in patients infected by HIV-1

    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.

  19. Polymorphisms in the IFNγ, IL-10, and TGFβ Genes May Be Associated with HIV-1 Infection

    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. IgM Repertoire Biodiversity is Reduced in HIV-1 Infection and Systemic Lupus Erythematosus

    Yin, Li; Hou, Wei; Liu, Li; Cai, Yunpeng; Wallet, Mark Andrew; Gardner, Brent Paul; Chang, Kaifen; Lowe, Amanda Catherine; Rodriguez, Carina Adriana; Sriaroon, Panida; Farmerie, William George; Sleasman, John William; Goodenow, Maureen Michels

    2013-01-01

    Background: HIV-1 infection or systemic lupus erythematosus (SLE) disrupt B cell homeostasis, reduce memory B cells, and impair function of IgG and IgM antibodies. Objective: To determine how disturbances in B cell populations producing polyclonal antibodies relate to the IgM repertoire, the IgM transcriptome in health and disease was explored at the complementarity determining region 3 (CDRH3) sequence level. Methods: 454-deep pyrosequencing in combination with a novel analysis pipelin...

  1. Enhanced CD4+ cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection

    CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) strains cause CD4+ T-cell loss in most infected individuals, but mechanisms underlying cytopathicity of R5 viruses are poorly understood. We investigated mechanisms contributing to R5 envelope glycoprotein (Env)-mediated cellular apoptosis by constructing a panel of retroviral vectors engineered to co-express GFP and R5 Envs derived from two HIV-1-infected subjects spanning asymptomatic (Early, E-R5 Envs) to late stages of infection (Late, L-R5 Envs). The L-R5 Envs induced significantly more cellular apoptosis than E-R5 Envs, but only in Env-expressing (GFP-positive) cells, and only in cells where CD4 and CCR5 levels were limiting. Studies with fusion-defective Env mutants showed induction of apoptosis required membrane-fusing events. Our results provide evidence for an intracellular mechanism of R5 Env-induced apoptosis of CD4+ cells that requires membrane fusion. Furthermore, they contribute to a better understanding of mechanisms involved in CD4+ T-cell loss in subjects experiencing progressive R5 HIV-1 infection.

  2. Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection.

    Joanne D Stekler

    Full Text Available OBJECTIVE: To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA but not consensus sequencing among subjects with primary HIV-1 infection. DESIGN/METHODS: Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV therapy, evaluated the time to virologic suppression (HIV-1 RNA<50 copies/mL among subjects with minority variants conferring intermediate or high-level resistance. RESULTS: Consensus sequencing and OLA detected resistance mutations in 5% and 27% of subjects, respectively, in specimens obtained a median of 30 days after infection. Median time to virologic suppression was 110 (IQR 62-147 days for 63 treated subjects without detectable mutations, 84 (IQR 56-109 days for ten subjects with minority variant mutations treated with ≥3 active ARVs, and 104 (IQR 60-162 days for nine subjects with minority variant mutations treated with <3 active ARVs (p = .9. Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with ≥3 active ARVs (aHR 1.2, 95% CI 0.6-2.4, p = .6 and subjects with minority variant mutations treated with <3 active ARVs (aHR 1.0, 95% CI 0.4-2.4, p = .9. Two subjects with drug resistance and two subjects without detectable resistance experienced virologic failure. CONCLUSIONS: Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naïve subjects with primary HIV-1 infection. Minority variants were not associated with impaired ARV response, possibly due to the small sample size. It is also possible that, with highly-potent ARVs, minority variant mutations may be relevant only at certain critical codons.

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

    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...... treated with doxycycline were the same. CONCLUSION: Syphilis was associated with a decrease in CD4 cell counts and an increase in HIV-RNA levels that both improved after treatment of syphilis....

  4. Quantification of HIV-1 viral RNA in the blood in needles used for venous puncture in HIV-infected individuals

    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.

  5. Brief Report: HIV-1 Tropism During Primary Infections in France: 1996-2014.

    Raymond, Stéphanie; Nicot, Florence; Sauné, Karine; Cazabat, Michelle; Pasquier, Christophe; Massip, Patrice; Marchou, Bruno; Delobel, Pierre; Izopet, Jacques

    2016-08-01

    HIV-1 was mainly CCR5 tropic in recent seroconverters. We analyzed the coreceptor use in 239 primary HIV-1 infections (PHIs) between 1996 and 2014 using a validated recombinant virus phenotypic entry assay. CXCR4-using viruses were detected in 8.3%, 3.8%, and 6.1% of PHIs from 1996 to 2004, 2005 to 2009, and 2010 to 2014, respectively. The presence of CXCR4-using viruses was associated with the virological failure of antiretroviral treatment initiated during PHI (odds ratio, 7.9; 95% confidence interval, 1.1 to 56.5). The phenotypic tropism assay data show that the prevalence of X4 tropic transmitted viruses was stable in this French cohort of PHIs between 1996 and 2014. PMID:26959188

  6. Evidence for biphasic uncoating during HIV-1 infection from a novel imaging assay

    Xu, Hongzhan; Franks, Tamera; Gibson, Gregory; Huber, Kelly; Rahm, Nadia; De Castillia, Caterina Strambio; Luban, Jeremy; Aiken, Christopher; Watkins, Simon; Sluis-Cremer, Nicolas; Ambrose, Zandrea

    2013-01-01

    Background Uncoating of the HIV-1 core plays a critical role during early post-fusion stages of infection but is poorly understood. Microscopy-based assays are unable to easily distinguish between intact and partially uncoated viral cores. Results In this study, we used 5-ethynyl uridine (EU) to label viral-associated RNA during HIV production. At early time points after infection with EU-labeled virions, the viral-associated RNA was stained with an EU-specific dye and was detected by confoca...

  7. Lipidomic dataset of plasma from patients infected with wild type and nef-deficient HIV-1 strain

    Peter Meikle; Hann Low; Churchill, Melissa J.; Michael Bukrinsky; Dmitri Sviridov

    2015-01-01

    Previous in vitro and in vivo studies demonstrated that HIV protein nef plays a key role in impairing cellular and systemic cholesterol metabolism in HIV disease, but clinical support for these findings is lacking. Here we present the data of comparative lipidomic analysis (330 lipid species) of plasma samples from HIV-negative subjects, patients infected with WT HIV-1 strain and patients infected with nef-deficient strain of HIV-1. We determine which effects of HIV on plasma lipidome are exp...

  8. Molecular Epidemiology and Transmission Dynamics of Recent and Long-Term HIV-1 Infections in Rural Western Kenya

    Zeh, Clement; Inzaule, Seth C.; Ondoa, Pascale; Nafisa, Lillian G.; Kasembeli, Alex; Otieno, Fredrick; Vandenhoudt, Hilde; Amornkul, Pauli N.; Mills, Lisa A.; John N. Nkengasong

    2016-01-01

    Objective To identify unique characteristics of recent versus established HIV infections and describe sexual transmission networks, we characterized circulating HIV-1 strains from two randomly selected populations of ART-naïve participants in rural western Kenya. Methods Recent HIV infections were identified by the HIV-1 subtype B, E and D, immunoglobulin G capture immunoassay (IgG BED-CEIA) and BioRad avidity assays. Genotypic and phylogenetic analyses were performed on the pol gene to ident...

  9. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection.

    Lynch, Rebecca M; Boritz, Eli; Coates, Emily E; DeZure, Adam; Madden, Patrick; Costner, Pamela; Enama, Mary E; Plummer, Sarah; Holman, Lasonji; Hendel, Cynthia S; Gordon, Ingelise; Casazza, Joseph; Conan-Cibotti, Michelle; Migueles, Stephen A; Tressler, Randall; Bailer, Robert T; McDermott, Adrian; Narpala, Sandeep; O'Dell, Sijy; Wolf, Gideon; Lifson, Jeffrey D; Freemire, Brandie A; Gorelick, Robert J; Pandey, Janardan P; Mohan, Sarumathi; Chomont, Nicolas; Fromentin, Remi; Chun, Tae-Wook; Fauci, Anthony S; Schwartz, Richard M; Koup, Richard A; Douek, Daniel C; Hu, Zonghui; Capparelli, Edmund; Graham, Barney S; Mascola, John R; Ledgerwood, Julie E

    2015-12-23

    Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression. PMID:26702094

  10. Inter-laboratory assessment of a prototype multiplex kit for determination of recent HIV-1 infection.

    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.

  11. Inhibition of highly productive HIV-1 infection in T cells, primary human macrophages, microglia, and astrocytes by Sargassum fusiforme

    Veille Jean-Claude

    2006-05-01

    Full Text Available Abstract Background The high rate of HIV-1 mutation and increasing resistance to currently available antiretroviral (ART therapies highlight the need for new antiviral agents. Products derived from natural sources have been shown to inhibit HIV-1 replication during various stages of the virus life cycle, and therefore represent a potential source of novel therapeutic agents. To expand our arsenal of therapeutics against HIV-1 infection, we investigated aqueous extract from Sargassum fusiforme (S. fusiforme for ability to inhibit HIV-1 infection in the periphery, in T cells and human macrophages, and for ability to inhibit in the central nervous system (CNS, in microglia and astrocytes. Results S. fusiforme extract blocked HIV-1 infection and replication by over 90% in T cells, human macrophages and microglia, and it also inhibited pseudotyped HIV-1 (VSV/NL4-3 infection in human astrocytes by over 70%. Inhibition was mediated against both CXCR4 (X4 and CCR5 (R5-tropic HIV-1, was dose dependant and long lasting, did not inhibit cell growth or viability, was not toxic to cells, and was comparable to inhibition by the nucleoside analogue 2', 3'-didoxycytidine (ddC. S. fusiforme treatment blocked direct cell-to-cell infection spread. To investigate at which point of the virus life cycle this inhibition occurs, we infected T cells and CD4-negative primary human astrocytes with HIV-1 pseudotyped with envelope glycoprotein of vesicular stomatitis virus (VSV, which bypasses the HIV receptor requirements. Infection by pseudotyped HIV-1 (VSV/NL4-3 was also inhibited in a dose dependant manner, although up to 57% less, as compared to inhibition of native NL4-3, indicating post-entry interferences. Conclusion This is the first report demonstrating S. fusiforme to be a potent inhibitor of highly productive HIV-1 infection and replication in T cells, in primary human macrophages, microglia, and astrocytes. Results with VSV/NL4-3 infection, suggest inhibition

  12. Human TOP1 residues implicated in species specificity of HIV-1 infection are required for interaction with BTBD2, and RNAi of BTBD2 in old world monkey and human cells increases permissiveness to HIV-1 infection

    Cutler Mary

    2010-11-01

    Full Text Available Abstract Background Host determinants of HIV-1 viral tropism include factors from producer cells that affect the efficiency of productive infection and factors in target cells that block infection after viral entry. TRIM5α restricts HIV-1 infection at an early post-entry step through a mechanism associated with rapid disassembly of the retroviral capsid. Topoisomerase I (TOP1 appears to play a role in HIV-1 viral tropism by incorporating into or otherwise modulating virions affecting the efficiency of a post-entry step, as the expression of human TOP1 in African Green Monkey (AGM virion-producing cells increased the infectivity of progeny virions by five-fold. This infectivity enhancement required human TOP1 residues 236 and 237 as their replacement with the AGM counterpart residues abolished the infectivity enhancement. Our previous studies showed that TOP1 interacts with BTBD1 and BTBD2, two proteins which co-localize with the TRIM5α splice variant TRIM5δ in cytoplasmic bodies. Because BTBD1 and BTBD2 interact with one HIV-1 viral tropism factor, TOP1, and co-localize with a splice variant of another, we investigated the potential involvement of BTBD1 and BTBD2 in HIV-1 restriction. Results We show that the interaction of BTBD1 and BTBD2 with TOP1 requires hu-TOP1 residues 236 and 237, the same residues required to enhance the infectivity of progeny virions when hu-TOP1 is expressed in AGM producer cells. Additionally, interference with the expression of BTBD2 in AGM and human 293T target cells increased their permissiveness to HIV-1 infection two- to three-fold. Conclusions These results do not exclude the possibility that BTBD2 may modestly restrict HIV-1 infection via colocation with TRIM5 variants in cytoplasmic bodies.

  13. Dynamics of the human and viral m(6)A RNA methylomes during HIV-1 infection of T cells.

    Lichinchi, Gianluigi; Gao, Shang; Saletore, Yogesh; Gonzalez, Gwendolyn Michelle; Bansal, Vikas; Wang, Yinsheng; Mason, Christopher E; Rana, Tariq M

    2016-01-01

    N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of eukaryotic mRNA. Very little is known of the function of m(6)A in the immune system or its role in host-pathogen interactions. Here, we investigate the topology, dynamics and bidirectional influences of the viral-host RNA methylomes during HIV-1 infection of human CD4 T cells. We show that viral infection triggers a massive increase in m(6)A in both host and viral mRNAs. In HIV-1 mRNA, we identified 14 methylation peaks in coding and noncoding regions, splicing junctions and splicing regulatory sequences. We also identified a set of 56 human gene transcripts that were uniquely methylated in HIV-1-infected T cells and were enriched for functions in viral gene expression. The functional relevance of m(6)A for viral replication was demonstrated by silencing of the m(6)A writer or the eraser enzymes, which decreased or increased HIV-1 replication, respectively. Furthermore, methylation of two conserved adenosines in the stem loop II region of HIV-1 Rev response element (RRE) RNA enhanced binding of HIV-1 Rev protein to the RRE in vivo and influenced nuclear export of RNA. Our results identify a new mechanism for the control of HIV-1 replication and its interaction with the host immune system. PMID:27572442

  14. Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

    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.

  15. 趋化因子复合受体在HIV-1感染中的作用%Effect of chemokine co-receptor on HIV-1 infection

    孙利; 黄长形; 白雪帆

    2008-01-01

    趋化因子复合受体与HIV-1感染关系密切.此文简要回顾了HIV-1复合受体以及它们在病毒膜融合和HIV-1发病机制中的作用,以期为将来研究趋化因子复合受体抗HIV-1感染提供理论依据.%The chemokine co-receptor has close relations to HIV-1 infection.Binding to CD4 typically is followed by binding to either the CCR5 or CXCR4 co-receptor,which is required for fusion to proceed.The development of chemokine co-receptor may provide new tools to address this important pathogenesis question about HIV-1 infection.

  16. A novel toll-like receptor-9 agonist, MGN1703, enhances HIV-1 transcription and NK cell-mediated inhibition of HIV-1 infected autologous CD4+ T cells

    Offersen, Rasmus; Nissen, Sara Konstantin; Rasmussen, Thomas Aagaard; Østergaard, Lars Jørgen; Denton, Paul W; Søgaard, Ole Schmeltz; Tolstrup, Martin

    2016-01-01

    currently undergoing phase 3 clinical testing for the treatment of metastatic colorectal cancer) induces potent antiviral responses in immune effector cells from HIV-1-infected on suppressive antiretroviral therapy. The significant improved safety and tolerability profile of MGN1703 versus TLR9 agonists of......Toll-like receptor (TLR) agonists are potent enhancers of innate antiviral immunity and may also reverse HIV-1 latency. Therefore, TLR agonists have a potential role in the context of a 'shock and kill' approach to eradicate HIV-1. Our extensive preclinical evaluation suggests that a novel TLR9...... induced strong antiviral innate immune responses, enhanced HIV-1 transcription and boosted NK cell-mediated suppression of HIV-1 infection in autologous CD4+ T cells. These findings support clinical testing of MGN1703 in HIV-1 eradication trials. IMPORTANCE: We demonstrate, that MGN1703 (a TLR9 agonist...

  17. Microfluidic Chip-based Nucleic Acid Testing using Gingival Crevicular Fluid as a New Technique for Detecting HIV-1 Infection

    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

  18. Extensive Genetic Diversity of HIV-1 in Incident and Prevalent Infections among Malaysian Blood Donors: Multiple Introductions of HIV-1 Genotypes from Highly Prevalent Countries.

    Chow, Wei Zhen; Bon, Abdul Hamid; Keating, Sheila; Anderios, Fread; Halim, Hazwan Abdul; Takebe, Yutaka; Kamarulzaman, Adeeba; Busch, Michael P; Tee, Kok Keng

    2016-01-01

    Transfusion-transmissible infections including HIV-1 continue to pose major risks for unsafe blood transfusions due to both window phase infections and divergent viruses that may not be detected by donor screening assays. Given the recent emergence of several HIV-1 circulating recombinant forms (CRFs) in high-risk populations in the Southeast Asia region, we investigated the genetic diversity of HIV-1 among the blood donors in Kuala Lumpur, Malaysia. A total of 211 HIV-positive plasma samples detected among 730,188 donations to the National Blood Centre between 2013 and 2014 were provided (90.5% male, median age: 27.0 years old). Recent or long-term infection status at the time of donation was determined using a limiting antigen avidity enzyme immunoassay (LAg-Avidity EIA). HIV-1 gag-pol genes were amplified and sequenced from residual plasma for 149 cases followed by genotype determination using phylogenetic and recombination analyses. Transmitted antiretroviral resistance mutations were not observed among the blood donors, among which 22.7% were classified as recent or incident infections. Major circulating HIV-1 genotypes determined by neighbour-joining phylogenetic inference included CRF01_AE at 40.9% (61/149), CRF33_01B at 21.5% (32/149), and subtype B at 10.1% (15/149). Newly-described CRFs including CRF54_01B circulated at 4.0%, CRF74_01B at 2.0%, and CRF53_01B and CRF48_01B at 0.7% each. Interestingly, unique HIV-1 genotypes including African subtype G (8.7%), CRF45_cpx (1.3%), CRF02_AG (0.7%) and CRF07_BC (0.7%) from China were detected for the first time in the country. A cluster of subtype G sequences formed a distinct founder sub-lineage within the African strains. In addition, 8.7% (13/149) of HIV-infected donors had unique recombinant forms (URFs) including CRF01_AE/B' (4.7%), B'/C (2.7%) and B'/G (1.3%) recombinants. Detailed analysis identified similar recombinant structures with shared parental strains among the B'/C and B'/G URFs, some of which

  19. High resolution human leukocyte antigen class I allele frequencies and HIV-1 infection associations in Chinese Han and Uyghur cohorts.

    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

  20. Randomized pilot trial of a synbiotic dietary supplement in chronic HIV-1 infection

    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

  1. Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature.

    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.

  2. Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway.

    Nathan L Bowers

    2014-03-01

    Full Text Available HIV-1 infection is associated with a progressive loss of T cell functional capacity and reduced responsiveness to antigenic stimuli. The mechanisms underlying T cell dysfunction in HIV-1/AIDS are not completely understood. Multiple studies have shown that binding of program death ligand 1 (PD-L1 on the surface of monocytes and dendritic cells to PD-1 on T cells negatively regulates T cell function. Here we show that neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1. PD-L1 is induced by HIV-1 virions, TLR-7/8 ligand, bacterial lipopolysaccharide (LPS, and IFNα. Neutrophil PD-L1 levels correlate with the expression of PD-1 and CD57 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils (LDNs expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs. Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS. Collectively, the accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function.

  3. Multivalent dendrimeric compounds containing carbohydrates expressed on immune cells inhibit infection by primary isolates of HIV-1

    Specific glycosphingolipids (GSL), found on the surface of target immune cells, are recognized as alternate cell surface receptors by the human immunodeficiency virus type 1 (HIV-1) external envelope glycoprotein. In this study, the globotriose and 3'-sialyllactose carbohydrate head groups found on two GSL were covalently attached to a dendrimer core to produce two types of unique multivalent carbohydrates (MVC). These MVC inhibited HIV-1 infection of T cell lines and primary peripheral blood mononuclear cells (PBMC) by T cell line-adapted viruses or primary isolates, with IC50s ranging from 0.1 to 7.4 μg/ml. Inhibition of Env-mediated membrane fusion by MVC was also observed using a dye-transfer assay. These carbohydrate compounds warrant further investigation as a potential new class of HIV-1 entry inhibitors. The data presented also shed light on the role of carbohydrate moieties in HIV-1 virus-host cell interactions. -- Research Highlights: →Multivalent carbohydrates (MVCs) inhibited infection of PBMCs by HIV-1. →MVCs inhibited infection by T cell line-adapted viruses. →MVCs inhibited infection by primary isolates of HIV-1. →MVCs inhibited Env-mediated membrane fusion.

  4. Effect of humoral immunity on HIV-1 dynamics with virus-to-target and infected-to-target infections

    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.

  5. ACYCLOVIR IS ACTIVATED INTO A HIV-1 REVERSE TRANSCRIPTASE INHIBITOR IN HERPESVIRUS-INFECTED HUMAN TISSUES

    Lisco, Andrea; Vanpouille, Christophe; Tchesnokov, Egor P.; Grivel, Jean-Charles; Biancotto, Angélique; Brichacek, Beda; Elliott, Julie; Fromentin, Emilie; Shattock, Robin; Anton, Peter; Gorelick, Robert; Balzarini, Jan; McGuigan, Christopher; Derudas, Marco; Götte, Matthias

    2008-01-01

    For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is one such drug. It is activated into a human herpesvirus (HHV) DNA polymerase inhibitor exclusively by HHV kinases and, thus, does not suppress other viruses. Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues, but not in HHV-free tissue or cell cultures. However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV activity. W...

  6. Outcome and reinfection after Staphylococcus aureus bacteraemia in individuals with and without HIV-1 infection

    Stammler Jaliff, Bianca; Dahl-Knudsen, Jenny; Petersen, Andreas;

    2014-01-01

    OBJECTIVES: Individuals infected with HIV-1 are at an increased risk of Staphylococcus aureus bacteraemia (SAB). The aim of this study was to investigate mortality rate and risk of reinfection associated with SAB in HIV-1-infected individuals compared to individuals without HIV-1 infection. SETTI...... and Pitt score predicted outcome. For patients infected with HIV, neither CD4 T-lymphocyte counts nor plasma HIV RNA levels were associated with 30-day outcome. TRIAL REGISTRATION NUMBER: The study was approved by the Danish Data Protection Agency (record no. 2007-41-1196)....... associate to mortality. During follow-up, there were 43 episodes of reinfection; in individuals with HIV infection at an incidence rate of 7.8 (95% CI 4.7 to 10.9)/100 person-years compared with 2.2 (95% CI 1.2 to 3.2)/100 person-years for individuals without HIV. In multivariate analysis, HIV status (OR 2...

  7. Modulation of the proteome of peripheral blood mononuclear cells from HIV-1 infected patients by drugs of abuse

    Jessica L. Reynolds; Supriya D Mahajan; Aalinkeel, Ravikunar; Nair, Bindukumar; Sykes, Donald E; Agosto-Mujica, Arnadri; Hsiao, Chiu Bin; Schwartz, Stanley A.

    2009-01-01

    We used proteomic analyses to assess how drug abuse modulates immunologic responses to infections with the human immunodeficiency virus type 1 (HIV-1). Two dimensional (2D) difference gel electrophoresis was utilized to determine changes in the proteome of peripheral blood mononuclear cells (PBMC) isolated from HIV-1 positive donors that occurred after treatment with cocaine or methamphetamine. Both drugs differentially regulated the expression of several functional classes of proteins. We fu...

  8. Association between invasive cancer of the cervix and HIV-1 infection in Tanzania: the need for dual screening

    Ngoma Twalib

    2008-07-01

    Full Text Available Abstract Background Cancer of the cervix is the second commonest malignancy in females worldwide and is the leading malignancy among women in Tanzania. Cancer of the cervix has been strongly associated with Human Papilloma Virus (HPV which is a sexually transmitted disease. However, the role of HIV-1 in the aetiology of cancer of the cervix is less clear. Studies suggest that HPV and HIV-1 infection are synergistic and therefore their dual occurrence may fuel increased incidence of cancer of the cervix and AIDS. We therefore conducted a study to determine the association between cancer of the cervix and HIV-1. Methods The study was carried out in Ocean Road Cancer Institute, Dar-es-salaam, Tanzania between January and March 2007. A hospital-based case control design was used to study 138 cases and 138 controls. The cases were consenting women 18 years and above with histologically confirmed squamous cell carcinoma of the cervix, while the controls were consenting non-cancer adult women attendants or visitors. The participants were counselled and tested for HIV-1 and interviewed to assess risk factors for cancer of the cervix and HIV-1. Estimation of risk was done by computing odds ratios and confidence intervals. Confounding and interaction between the factors were assessed using logistic regression. Results HIV-1 prevalence was much higher among the cases (21.0% than among the controls (11.6%. In logistic regression, HIV-1 was associated with cancer of the cervix (OR = 2.9, 95% CI = 1.4–5.9. Among the cases the mean age was lower for HIV-1 infected (44.3 years than HIV-1 uninfected women (54 years, p = 0.0001. Conclusion HIV-1 infection is associated with invasive cancer of the cervix. Resource-constrained countries with a high burden of HIV-1 and cervical cancer should adopt a high-risk approach that targets HIV-1 positive women for screening of cervical cancer initially by utilizing HIV/AIDS resources.

  9. HIV-1Infected Individuals in Antiretroviral Therapy React Specifically With Polyfunctional T-Cell Responses to Gag p24

    Brandt, Lea; Benfield, Thomas; Kronborg, Gitte;

    2013-01-01

    Still no effective HIV-1 prophylactic or therapeutic vaccines are available. However, as the proportion of HIV-1-infected individuals on antiretroviral treatment is increasing, knowledge about the residual immune response is important for the possible development of an HIV-1 vaccine....

  10. Quantitative Correlation between Infectivity and Gp120 Density on HIV-1 Virions Revealed by Optical Trapping Virometry.

    DeSantis, Michael C; Kim, Jin H; Song, Hanna; Klasse, Per Johan; Cheng, Wei

    2016-06-17

    The envelope glycoprotein (Env) gp120/gp41 is required for HIV-1 infection of host cells. Although in general it has been perceived that more Env gives rise to higher infectivity, the precise quantitative dependence of HIV-1 virion infectivity on Env density has remained unknown. Here we have developed a method to examine this dependence. This method involves 1) production of a set of single-cycle HIV-1 virions with varied density of Env on their surface, 2) site-specific labeling of Env-specific antibody Fab with a fluorophore at high efficiency, and 3) optical trapping virometry to measure the number of gp120 molecules on individual HIV-1 virions. The resulting gp120 density per virion is then correlated with the infectivity of the virions measured in cell culture. In the presence of DEAE-dextran, the polycation known to enhance HIV-1 infectivity in cell culture, virion infectivity follows gp120 density as a sigmoidal dependence and reaches an apparent plateau. This quantitative dependence can be described by a Hill equation, with a Hill coefficient of 2.4 ± 0.6. In contrast, in the absence of DEAE-dextran, virion infectivity increases monotonically with gp120 density and no saturation is observed under the experimental conditions. These results provide the first quantitative evidence that Env trimers cooperate on the virion surface to mediate productive infection by HIV-1. Moreover, as a result of the low number of Env trimers on individual virions, the number of additional Env trimers per virion that is required for the optimal infectivity will depend on the inclusion of facilitating agents during infection. PMID:27129237

  11. Prevalence and risk factors for HIV-1 infection in rural Kilimanjaro region of Tanzania: Implications for prevention and treatment

    Leyna Germana H

    2007-04-01

    Full Text Available Abstract Background Variability in stages of the HIV-1 epidemic and hence HIV-1 prevalence exists in different areas in sub-Saharan Africa. The purpose of this study was to investigate the magnitude of HIV-1 infection and identify HIV-1 risk factors that may help to develop preventive strategies in rural Kilimanjaro, Tanzania. Methods A cross-sectional study was conducted between March and May of 2005 involving all individuals aged between 15–44 years having an address in Oria Village. All eligible individuals were registered and invited to participate. Participants were interviewed regarding their demographic characteristics, sexual behaviors, and medical history. Following a pre-test counseling, participants were offered an HIV test. Results Of the 2 093 eligible individuals, 1 528 (73.0% participated. The overall age and sex adjusted HIV-1 prevalence was 5.6%. Women had 2.5 times higher prevalence (8.0% vs. 3.2% as compared to men. The age group 25–44 years, marriage, separation and low education were associated with higher risk of HIV-1 infection for both sexes. HIV-1 infection was significantly associated with >2 sexual partners in the past 12 months (women: Adjusted odds ratio [AOR], 2.5 (95%CI: 1.3–4.7, and past 5 years, [(men: AOR, 2.2 (95%CI:1.2–5.6; women: AOR, 2.5 (95%CI: 1.4–4.0], unprotected casual sex (men: AOR,1.8 95%CI: 1.2–5.8, bottled alcohol (Men: AOR, 5.9 (95%CI:1.7–20.1 and local brew (men: AOR, 3.7 (95%CI: 1.5–9.2. Other factors included treatment for genital ulcers and genital discharge in the past 1 month. Health-related complaints were more common among HIV-1 seropositive as compared to seronegative participants and predicted the presence of HIV-1 infection. Conclusion HIV-1 infection was highly prevalent in this population. As compared to our previous findings, a shift of the epidemic from a younger to an older age group and from educated to uneducated individuals was observed. Women and married or

  12. Identification of Host Micro RNAs That Differentiate HIV-1 and HIV-2 Infection Using Genome Expression Profiling Techniques.

    Devadas, Krishnakumar; Biswas, Santanu; Haleyurgirisetty, Mohan; Ragupathy, Viswanath; Wang, Xue; Lee, Sherwin; Hewlett, Indira

    2016-01-01

    While human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) share many similar traits, major differences in pathogenesis and clinical outcomes exist between the two viruses. The differential expression of host factors like microRNAs (miRNAs) in response to HIV-1 and HIV-2 infections are thought to influence the clinical outcomes presented by the two viruses. MicroRNAs are small non-coding RNA molecules which function in transcriptional and post-transcriptional regulation of gene expression. MiRNAs play a critical role in many key biological processes and could serve as putative biomarker(s) for infection. Identification of miRNAs that modulate viral life cycle, disease progression, and cellular responses to infection with HIV-1 and HIV-2 could reveal important insights into viral pathogenesis and provide new tools that could serve as prognostic markers and targets for therapeutic intervention. The aim of this study was to elucidate the differential expression profiles of host miRNAs in cells infected with HIV-1 and HIV-2 in order to identify potential differences in virus-host interactions between HIV-1 and HIV-2. Differential expression of host miRNA expression profiles was analyzed using the miRNA profiling polymerase chain reaction (PCR) arrays. Differentially expressed miRNAs were identified and their putative functional targets identified. The results indicate that hsa-miR 541-3p, hsa-miR 518f-3p, and hsa-miR 195-3p were consistently up-regulated only in HIV-1 infected cells. The expression of hsa-miR 1225-5p, hsa-miR 18a* and hsa-miR 335 were down modulated in HIV-1 and HIV-2 infected cells. Putative functional targets of these miRNAs include genes involved in signal transduction, metabolism, development and cell death. PMID:27144577

  13. Identification of Host Micro RNAs That Differentiate HIV-1 and HIV-2 Infection Using Genome Expression Profiling Techniques

    Krishnakumar Devadas

    2016-05-01

    Full Text Available While human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2 share many similar traits, major differences in pathogenesis and clinical outcomes exist between the two viruses. The differential expression of host factors like microRNAs (miRNAs in response to HIV-1 and HIV-2 infections are thought to influence the clinical outcomes presented by the two viruses. MicroRNAs are small non-coding RNA molecules which function in transcriptional and post-transcriptional regulation of gene expression. MiRNAs play a critical role in many key biological processes and could serve as putative biomarker(s for infection. Identification of miRNAs that modulate viral life cycle, disease progression, and cellular responses to infection with HIV-1 and HIV-2 could reveal important insights into viral pathogenesis and provide new tools that could serve as prognostic markers and targets for therapeutic intervention. The aim of this study was to elucidate the differential expression profiles of host miRNAs in cells infected with HIV-1 and HIV-2 in order to identify potential differences in virus-host interactions between HIV-1 and HIV-2. Differential expression of host miRNA expression profiles was analyzed using the miRNA profiling polymerase chain reaction (PCR arrays. Differentially expressed miRNAs were identified and their putative functional targets identified. The results indicate that hsa-miR 541-3p, hsa-miR 518f-3p, and hsa-miR 195-3p were consistently up-regulated only in HIV-1 infected cells. The expression of hsa-miR 1225-5p, hsa-miR 18a* and hsa-miR 335 were down modulated in HIV-1 and HIV-2 infected cells. Putative functional targets of these miRNAs include genes involved in signal transduction, metabolism, development and cell death.

  14. Comparison of Heterologous Neutralizing Antibody Responses of Human Immunodeficiency Virus Type 1 (HIV-1)- and HIV-2-Infected Senegalese Patients: Distinct Patterns of Breadth and Magnitude Distinguish HIV-1 and HIV-2 Infections▿

    Rodriguez, Shaun; Sarr, A. D.; MacNeil, A; Thakore-Meloni, S.; Gueye-Ndiaye, A.; Traore, I.; Dia, M. C.; Mboup, S.; Kanki, Phyllis Jean

    2007-01-01

    Neutralizing antibody responses against heterologous isolates in human immunodeficiency virus type 1 (HIV-1) and HIV-2 infections were compared, and their relationships with established clinical markers of progression were examined. Neutralizing responses against 7 heterologous primary isolates and 1 laboratory strain were compared between 32 untreated HIV-1-infected subjects and 35 untreated HIV-2-infected subjects using a pseudotyped reporter virus assay. The breadth of the neutralizing res...

  15. Factors secreted by human T lymphotropic virus type I (HTLV-I)-infected cells can enhance or inhibit replication of HIV-1 in HTLV-I-uninfected cells: implications for in vivo coinfection with HTLV-I and HIV-1.

    Moriuchi, H; Moriuchi, M; Fauci, A S

    1998-05-18

    It remains controversial whether human T lymphotropic virus type I (HTLV-I) coinfection leads to more rapid progression of human immunodeficiency virus (HIV) disease in dually infected individuals. To investigate whether HTLV-I infection of certain cells can modulate HIV-1 infection of surrounding cells, primary CD4(+) T cells were treated with cell-free supernatants from HTLV-I-infected MT-2 cell cultures. The primary CD4+ T cells became resistant to macrophage (M)-tropic HIV-1 but highly susceptible to T cell (T)-tropic HIV-1. The CC chemokines RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta in the MT-2 cell supernatants were identified as the major suppressive factors for M-tropic HIV-1 as well as the enhancers of T-tropic HIV-1 infection, whereas soluble Tax protein increased susceptibility to both M- and T-tropic HIV-1. The effect of Tax or CC chemokines on T-tropic HIV-1 was mediated, at least in part, by increasing HIV Env-mediated fusogenicity. Our data suggest that the net effect of HTLV-I coinfection in HIV-infected individuals favors the transition from M- to T-tropic HIV phenotype, which is generally indicative of progressive HIV disease. PMID:9584147

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

    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.

  17. HIV-1 specific antibody titers and neutralization among chronically infected patients on long-term suppressive antiretroviral therapy (ART: a cross-sectional study.

    Johannes S Gach

    Full Text Available The majority of potent and broadly neutralizing antibodies against HIV-1 have been isolated from untreated patients with acute or chronic infection. To assess the extent of HIV-1 specific antibody response and neutralization after many years of virologic suppression from potent combination ART, we examined antibody binding titers and neutralization of 51 patients with chronic HIV-1 infection on suppressive ART for at least three years. In this cross-sectional analysis, we found high antibody titers against gp120, gp41, and the membrane proximal external region (MPER in 59%, 43%, and 27% of patients, respectively. We observed significantly higher endpoint binding titers for gp120 and gp41 for patients with >10 compared to ≤ 10 years of detectable HIV RNA. Additionally, we observed higher median gp120 and gp41 antibody titers in patients with HIV RNA 10 years of detectable HIV RNA (8/20 [40.0%] versus 3/31 [9.7%] for ≤ 10 years, p = 0.02 and a trend toward greater neutralization in patients with ≤ 5 years of HIV RNA 5 years, p = 0.08. All patients with neutralizing activity mediated successful phagocytosis of VLPs by THP-1 cells after antibody opsonization. Our findings of highly specific antibodies to several structural epitopes of HIV-1 with antibody effector functions and neutralizing activity after long-term suppressive ART, suggest continuous antigenic stimulation and evolution of HIV-specific antibody response occurs before and after suppression with ART. These patients, particularly those with slower HIV progression and more time with detectable viremia prior to initiation of suppressive ART, are a promising population to identify and further study functional antibodies against HIV-1.

  18. Neutralization resistance of virological synapse-mediated HIV-1 Infection is regulated by the gp41 cytoplasmic tail.

    Durham, Natasha D; Yewdall, Alice W; Chen, Ping; Lee, Rebecca; Zony, Chati; Robinson, James E; Chen, Benjamin K

    2012-07-01

    Human immunodeficiency virus type 1 (HIV-1) infection can spread efficiently from infected to uninfected T cells through adhesive contacts called virological synapses (VSs). In this process, cell-surface envelope glycoprotein (Env) initiates adhesion and viral transfer into an uninfected recipient cell. Previous studies have found some HIV-1-neutralizing patient sera to be less effective at blocking VS-mediated infection than infection with cell-free virus. Here we employ sensitive flow cytometry-based infection assays to measure the inhibitory potency of HIV-1-neutralizing monoclonal antibodies (MAb) and HIV-1-neutralizing patient sera against cell-free and VS-mediated infection. To various degrees, anti-Env MAbs exhibited significantly higher 50% inhibitory concentration (IC(50)s) against VS-mediated infection than cell-free infection. Notably, the MAb 17b, which binds a CD4-induced (CD4i) epitope on gp120, displayed a 72-fold reduced efficacy against VS-mediated inocula compared to cell-free inocula. A mutant with truncation mutation in the gp41 cytoplasmic tail (CT) which is unable to modulate Env fusogenicity in response to virus particle maturation but which can still engage in cell-to-cell infection was tested for the ability to resist neutralizing antibodies. The ΔCT mutation increased cell surface staining by neutralizing antibodies, significantly enhanced neutralization of VS-mediated infection, and had reduced or no effect on cell-free infection, depending upon the antibody. Our results suggest that the gp41 CT regulates the exposure of key neutralizing epitopes during cell-to-cell infection and plays an important role in immune evasion. Vaccine strategies should consider immunogens that reflect Env conformations exposed on the infected cell surface to enhance protection against VS-mediated HIV-1 spread. PMID:22553332

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

    Emily E I M Mouser

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

  20. miRNA在HIV-1感染中的生物学功能%Biological function of microRNA in HIV-1 infection: summary of recent progress

    吴还梅; 孟哲峰; 张晓燕

    2013-01-01

    MicroRNA (miRNA) is one of the multifunctional small RNAs that have been extensively investigated in recent years. MiRNA-mediated RNA interference regulates cell proliferation, differentiation, development and plays a critical role in many infectious diseases such as acquired immunodeficiency syndrome (AIDS). MiRNA inhibits HIV-1 replication by targeting the genome RNA or interacting with protein-coding mRNA but it also facilitates HIV-1 infection and AIDS progress by promoting T cell proliferation that is mediated by activating innate immune system and producing cytokines. Meanwhile, miRNA can also affect HIV-1 replication by interacting with viral accessory proteins and host cellular factors. Some miRNAs are involved in HIV-1 latency. Furthermore, miRNA expression profile could be fluctuated with HIV-1 infection which can be used as a diagnostic indicator in the near future.

  1. Monocyte-derived macrophages exhibit distinct and more restricted HIV-1 integration site repertoire than CD4+ T cells

    Yik Lim Kok; Valentina Vongrad; Mohaned Shilaih; Francesca Di Giallonardo; Herbert Kuster; Roger Kouyos; Günthard, Huldrych F.; Metzner, Karin J.

    2016-01-01

    The host genetic landscape surrounding integrated HIV-1 has an impact on the fate of the provirus. Studies analysing HIV-1 integration sites in macrophages are scarce. We studied HIV-1 integration site patterns in monocyte-derived macrophages (MDMs) and activated CD4+ T cells derived from seven antiretroviral therapy (ART)-treated HIV-1-infected individuals whose cells were infected ex vivo with autologous HIV-1 isolated during the acute phase of infection. A total of 1,484 unique HIV-1 integ...

  2. Antiviral molecules correlate with vitamin D pathway genes and are associated with natural resistance to HIV-1 infection.

    Aguilar-Jimenez, Wbeimar; Zapata, Wildeman; Rugeles, María T

    2016-01-01

    The relationship between the immunomodulatory effects of Vitamin D (VitD) and the expression of anti-HIV-1 molecules has not been explored in HIV-1-exposed seronegative individuals (HESNs). Higher mRNA levels of cathelicidin and HAD-4 in oral-mucosa and peripheral-blood, along with higher CYP24A1 mRNA in vaginal-mucosa and lower TLR2 mRNA in endocervical-mucosa were found in HESNs compared to non-exposed controls. Furthermore, the mRNA of anti-HIV molecules Elafin, TRIM5, Cathelicidin, HAD-4 and RNase7, previously associated with natural resistance to HIV-1 infection, positively correlated with the mRNA expression of VDR in HESNs, suggesting the potential participation of VitD in natural resistance to HIV-1. PMID:27083474

  3. CTL Responses to Regulatory Proteins Tat and Rev in HIV-1 B'/C Virus-Infected Individuals

    MING-MING JIA; KUN-XUE HONG; JIAN-PING CHEN; HONG-WEI LIU; SHA LIU; XIAO-QING ZHANG; HONG-JING ZHAO; YI-MING SHAO

    2008-01-01

    To characterize HIV-1 specific CTL responses to regulatory proteins Tat and Rev in HIV-B'/C vires-infected ART-naive individuals. Methods HIV-1-specific CTL responses were analyzed by IFN-γ ELISPOT assay using overlapping peptides spanning the consensus sequences of HIV-1 clade C Tat and Rev proteins. Statistical analysis and graphical presentation were performed using SIGMAPLOT 10.0 and SIGMASTAT 3.5. For samples with a positive response, the magnitude of CTL responses was compared between HIV-1 C proteins by Wilcoxon rank sum test, and the significance threshold was P<0.05. Results Tat and Rev were frequently recognized, with 23% and 52% of the tested individuals having detectable responses to these proteins, respectively. Several immunodominant regions were detected in Rev. No significant correlation was observed between the magnitude and breadth of CTL responses to regulatory proteins and the control of virus replication in this study. Conclusion Tat and Rev can serve as targets for HIV-1-specific CTL, and several immunodominant regions are detectable in Rev. Further characterization of epitopes and their role in virus control may shed light on pathogenesis of HIV-1 natural infection and also be useful for the design and testing of candidate vaccines.

  4. Huwe1, a novel cellular interactor of Gag-Pol through integrase binding, negatively influences HIV-1 infectivity.

    Yamamoto, Seiji P; Okawa, Katsuya; Nakano, Takashi; Sano, Kouichi; Ogawa, Kanako; Masuda, Takao; Morikawa, Yuko; Koyanagi, Yoshio; Suzuki, Youichi

    2011-04-01

    Integration, an indispensable step for retrovirus replication, is executed by integrase (IN), which is expressed as a part of a Gag-Pol precursor. Although mechanistic detail of the IN-catalyzed integration reaction is well defined, numerous evidence have demonstrated that IN is involved in multiple steps of retrovirus replication other than integration. In this study, Huwe1, a HECT-type E3 ubiquitin ligase, was identified as a new cellular interactor of human immunodeficiency virus type 1 (HIV-1) IN. The interaction was mediated through the catalytic core domain of IN and a wide-range region of Huwe1. Interestingly, although depletion of Huwe1 in target cells did not affect the early phase of HIV-1 infection in a human T cell line, we found that infectivity of HIV-1 released from the Huwe1 knockdown cells was significantly augmented more than that of virus produced from control cells. The increase in infectivity occurred in proviral DNA synthesis. Further analysis revealed that Huwe1 interacted with HIV-1 Gag-Pol precursor protein through an IN domain. Our results suggest that Huwe1 in HIV-1 producer cells has a negative impact on early post-entry events during the next round of virus infection via association with an IN region of Gag-Pol. PMID:21167302

  5. Similar Neutralizing Activity in the HIV-1 Infected Long Term Non-progressors(LTNPs) and Typical Progressors(TPs)

    Zheng Wang; Si-yang Liu; Lin Li; Tian-yi Li; Jing-yun Li; Li-li Chen; Yong-jian Liu; Han-ping Li; Zuo-yi Bao; Xiao-lin Wang; Dao-min Zhuang

    2012-01-01

    Neutralizing antibodies are considered to be an important protective parameter used in HIV-l vaccine evaluation.However,the exact role that neutralizing antibodies plays in controlling the disease progression of HIV-1 infected peoples is still undetermined.In this paper,we compared the protective function of the neutralizing antibody response in the plasma from LTNP and TP against clade B and clade C pseudoviruses.No difference in the neutralizing activities between the plasma from LTNP and TP was found,which was consistent with the most recent reports.In addition,no correlations between the titer or breadth and CD4+ or viral load in HIV-1 infected individuals were found.The protective roles played by neutralizing antibodies in controlling disease progression of HIV-1 infected people need to be considered in a new viewpoint.

  6. Regional Differences in Prevalence of HIV-1 Discordance in Africa and Enrollment of HIV-1 Discordant Couples into an HIV-1 Prevention Trial

    Jairam R Lingappa; Lambdin, Barrot; Bukusi, Elizabeth Ann; Ngure, Kenneth; Kavuma, Linda; Inambao, Mubiana; Kanweka, William; Allen, Susan; Kiarie, James N.; Were, Edwin; Manongi, Rachel; Coetzee, David; de Bruyn, Guy; Delany-Moretlwe, Sinead; MAGARET, Amalia

    2008-01-01

    Background: Most HIV-1 transmission in Africa occurs among HIV-1-discordant couples (one partner HIV-1 infected and one uninfected) who are unaware of their discordant HIV-1 serostatus. Given the high HIV-1 incidence among HIV-1 discordant couples and to assess efficacy of interventions for reducing HIV-1 transmission, HIV-1 discordant couples represent a critical target population for HIV-1 prevention interventions and prevention trials. Substantial regional differences exist in HIV-1 preval...

  7. HIV-1 with multiple CCR5/CXCR4 chimeric receptor use is predictive of immunological failure in infected children.

    Mariangela Cavarelli

    Full Text Available BACKGROUND: HIV-1 R5 viruses are characterized by a large phenotypic variation, that is reflected by the mode of coreceptor use. The ability of R5 HIV-1 to infect target cells expressing chimeric receptors between CCR5 and CXCR4 (R5(broad viruses, was shown to correlate with disease stage in HIV-1 infected adults. Here, we ask the question whether phenotypic variation of R5 viruses could play a role also in mother-to-child transmission (MTCT of HIV-1 and pediatric disease progression. METHODOLOGY/PRINCIPAL FINDINGS: Viral isolates obtained from a total of 59 HIV-1 seropositive women (24 transmitting and 35 non transmitting and 28 infected newborn children, were used to infect U87.CD4 cells expressing wild type or six different CCR5/CXCR4 chimeric receptors. HIV-1 isolates obtained from newborn infants had predominantly R5(narrow phenotype (n = 20, but R5(broad and R5X4 viruses were also found in seven and one case, respectively. The presence of R5(broad and R5X4 phenotypes correlated significantly with a severe decline of the CD4+ T cells (CDC stage 3 or death within 2 years of age. Forty-three percent of the maternal R5 isolates displayed an R5(broad phenotype, however, the presence of the R5(broad virus was not predictive for MTCT of HIV-1. Of interest, while only 1 of 5 mothers with an R5X4 virus transmitted the dualtropic virus, 5 of 6 mothers carrying R5(broad viruses transmitted viruses with a similar broad chimeric coreceptor usage. Thus, the maternal R5(broad phenotype was largely preserved during transmission and could be predictive of the phenotype of the newborn's viral variant. CONCLUSIONS/SIGNIFICANCE: Our results show that R5(broad viruses are not hampered in transmission. When transmitted, immunological failure occurs earlier than in children infected with HIV-1 of R5(narrow phenotype. We believe that this finding is of utmost relevance for therapeutic interventions in pediatric HIV-1 infection.

  8. Etravirine (TMC-125: The evidence for its place in the treatment of HIV-1 infection

    Hans-Jürgen Stellbrink

    2009-07-01

    Full Text Available Hans-Jürgen StellbrinkInfektionsmedizinisches Centrum Hamburg (iCH, Hamburg, GermanyIntroduction: Etravirine is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI specifically designed to suppress the replication of viruses resistant to the three currently approved NNRTIs efavirenz, nevirapine, and delavirdine.Aims: To assess the evidence for the place of etravirine in the treatment of HIV-1 infection.Evidence review: In combination with a ritonavir-boosted protease inhibitor etravirine has demonstrated high antiviral activity against strains exhibiting up to three NNRTI resistance mutations. The drug appears to be well tolerated, with only nausea and rash occuring significantly more frequently with etravirine compared with placebo. Of note, neuropsychologic side effects that frequently limit the use of efavirenz were not reported more frequently with etravirine.Place in therapy: Given its high activity against most NNRTI-resistant strains and its very good tolerability, etravirine is of high value for pretreated patients with NNRTI resistance and protease inhibitor exposure. Efforts should be made to demonstrate activity in switching strategies (due to toxicity and earlier lines of failure or in the setting of primary NNRTI resistance in order to explore the potential of the drug beyond salvage therapy.Keywords: etravirine, HIV-1, evidence

  9. Endotoxemia is associated with altered innate and adaptive immune responses in untreated HIV-1 infected individuals.

    Anne Roslev Bukh

    Full Text Available BACKGROUND: Microbial translocation may contribute to the immunopathogenesis in HIV infection. We investigated if microbial translocation and inflammation were associated with innate and adaptive immune responses in adults with HIV. METHODOLOGY/PRINCIPAL FINDINGS: This was an observational cohort study. Sera from HIV-infected and HIV-uninfected individuals were analyzed for microbial translocation (soluble CD14, lipopolysaccharides [LPS], endotoxin core antibody, and anti-α-galactosyl antibodies and inflammatory markers (high sensitivity C-reactive protein, IL-6, IL-1 receptor antagonist, soluble tumor necrosis factor receptor II, and IL-10 with enzyme-linked immunosorbent assays. Peripheral blood mononuclear cells (PBMC from HIV-infected persons and healthy controls (primed with single-stranded HIV-1-derived RNA were stimulated with LPS, and cytokine production was measured. Finally, HIV-infected patients were immunized with Prevnar 7vPnC±CpG 7909 followed by Pneumo Novum PPV-23. Effects of microbial translocation and inflammation on immunization were analyzed in a predictive regression model. We included 96 HIV-infected individuals, 76 on highly active antiretroviral therapy (HAART, 20 HAART-naive, and 50 healthy controls. Microbial translocation and inflammatory markers were higher among HIV-infected persons than controls. Cytokine levels following LPS stimulation were increased in PBMCs from HAART-naive compared to HAART-treated HIV-infected persons. Further, RNA-priming of PBMCs from controls acted synergistically with LPS to augment cytokine responses. Finally, high serum LPS levels predicted poor vaccine responses among HAART-naive, but not among HAART-treated HIV-infected individuals. CONCLUSIONS/SIGNIFICANCE: LPS acts synergistically with HIV RNA to stimulate innate immune responses in vitro and increasing serum LPS levels seem to predict poor antibody responses after vaccination among HAART-naive HIV-infected persons. Thus, our

  10. HIV-1 subtype D infections among Caucasians from Northwestern Poland--phylogenetic and clinical analysis.

    Miłosz Parczewski

    Full Text Available BACKGROUND: HIV-1 subtype D infections, which are associated with a faster rate of progression and lymphocyte CD4 decline, cognitive deficit and higher mortality, have rarely been found in native Europeans. In Northwestern Poland, however, infections with this subtype had been identified. This study aimed to analyze the sequence and clinical data for patients with subtype D using molecular phylogeography and identify transmission clusters and ancestry, as well as drug resistance, baseline HIV tropism and antiretroviral treatment efficacy. METHODS: Phylogenetic analyses of local HIV-1 subtype D sequences were performed, with time to the most recent common ancestor inferred using bayesian modeling. Sequence and drug resistance data were linked with the clinical and epidemiological information. RESULTS: Subtype D was found in 24 non-immigrant Caucasian, heterosexually infected patients (75% of females, median age at diagnosis of 49.5 years; IQR: 29-56 years. Partial pol sequences clustered monophyletically with the clades of Ugandan origin and no evidence of transmission from other European countries was found. Time to the most common recent ancestor was 1989.24 (95% HPD: 1968.83-1994.46. Baseline drug resistance to nucleoside reverse transcriptase inhibitors was observed in 54.5% of cases (mutations: M41L, K103N, T215S/D with evidence of clustering, no baseline integrase or protease resistance and infrequent non-R5 tropism (13.6%. Virologic failure was observed in 60% of cases and was associated with poor adherence (p<0.001 and subsequent development of drug resistance (p = 0.008, OR: 20 (95%CI: 1.7-290. CONCLUSIONS: Local subtype D represented an independently transmitted network with probably single index case, high frequency of primary drug resistance and evidence of transmission clusters.