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Background: CD4- Vγ2Vδ2 T cells are depleted during human immunodeficiency virus (HIV) infection but can recover to near normal levels in patients who spontaneously control viremia in the absence of therapy. By contrasting Vγ2Vδ2 T-cell numbers, phenotype, and T-cell receptor (TCR) repertoire, we investigate the dynamic tension between active immunity and progressive T-cell destruction during persistent viremia., Methods: Peripheral blood Vγ2Vδ2 T-cell levels and phenotypes were characterized by flow cytometry. Lymphoproliferation assays measured functional responses. Spectratyping characterized damage to the TCR repertoire., Results: Levels, responses to antigen and the proportion of T effector memory Vγ2Vδ2 T cells in patients with persistent viremia, were intermediate between patients with natural virus suppression (NVS) and patients receiving antiretroviral therapy. Damage to the TCR γ-2 chain repertoire and depletion of CD56+ Vγ2Vδ2 T cells were more pronounced in viremic patients, compared with antiretroviral therapy recipients and patients with natural virus suppression., Conclusions: Characteristics of Vγ2Vδ2 T cells in viremic patients reflect both active responses (increasing cell numbers, better antigen responses, and higher proportion of effector memory cells) and ongoing damage (repertoire changes and loss of CD56+ cells). Unlike patients who control viremia to undetectable levels, Vγ2Vδ2 T cells are diminished during persistent viremia and may eventually be lost because of progressive destruction of the TCR repertoire.

T-cell-derived soluble factors that inhibit both X4 and R5 HIV are recognized as important in controlling HIV. Whereas three β chemokines, regulated-on-activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1α, and MIP-1β, account for the suppression of R5 HIV by blockade of HIV entry, the major components responsible for the inhibition of X4 HIV strains have not been identified previously. We identify these factors primarily as a mixture of three β chemokines [macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC), and I-309] and two RNases (angiogenin and RNase 4) of lesser potency and show that in a clade B population, some correlate with clinical status and are produced by both CD4(+) and CD8(+) T cells (chemokines, angiogenin) or only by CD8(+) T cells (RNase 4). The antiviral mechanisms of these HIV X4-suppressive factors differ from those of the previously described HIV R5-suppressive β chemokines.

China has recognized the threat of HIV to its population and responded with a national antiretroviral treatment (ART) program. However, high ART failure rates and the spread of resistance within populations are important realities to consider when developing and managing ART programs in China and worldwide. Concepts which will define treatment success and local and national programmatic goals are 1) access to ART, 2) durability of ART at the patient level, 3) scalability of treatment modalities, and the 4) sustainability of the program at the community or national level. In the face of limited resources, China must also consider when to start ARV therapy, which agents to use, when to switch them, and how to treat highly experienced patients with drug resistance. The optimal ARV regimen to start with is changing frequently with the introduction of new agents and the presentation of new data. Currently, a regimen including tenofovir, emtricitabine or lamivudine and a nonnucleoside reverse transcriptase inhibitor appears to have optimal characteristics to treat HIV/AIDS in China. However, critical to all of these choices is the evaluation of programs implemented to insure wide scale success. China has wisely begun this process of evaluating the performance of local programs through systematic monitoring and evaluation of treatment outcomes. This will allow regimens and programs that work to be expanded, and programs with high failure rates to be eliminated. In the end, evidence based data supporting treatment strategies will allow China to successfully confront its AIDS epidemic early and prevent its tragic consequences.

Human immunodeficiency virus (HIV) infection alters the function and repertoire of peripheral blood gamma delta T cells expressing the V gamma 2/V delta 2 T cell receptor (TCR). A cross-sectional comparison of the V gamma 2 TCR repertoire was performed for 56 HIV-infected subjects, 51 of whom were receiving highly active antiretroviral therapy (HAART), to measure changes in the V gamma 2 TCR repertoire. Longer durations of HAART were associated with partial recovery of the normal TCR repertoire, and recovery was greatest in subjects with complete virus suppression. Changes in the V gamma 2 TCR repertoire are sensitive measures for the effects of HAART and of residual HIV replication.

The Rwanda national HIV program has been successful at scaling up antiretroviral therapy (ART) to achieve universal access. The AIDSRelief Model of Care focuses on four key principles: (1) earlier initiation of ART; (2) use of durable, highly-potent, and sequence-friendly first-line ART regimens; (3) early detection of treatment failure; and (4) provision of community-based care and support to ensure optimal adherence and follow up/engagement in care. We conducted a retrospective cohort study of randomly-selected HIV-infected patients at AIDSRelief-supported sites using a stratified, random sample of 583 adults (>15 years) who initiated ART from 30 June 2008 to 1 February 2010. At ART initiation, the median patient age was 38 years, and 67% were female. The baseline median CD4+ cell count was 309 cells/mm3. Overall virologic suppression was 91%. Married/ever married status (adjusted prevalence odds ratio [aPOR] 3.75, 95% confidence interval [CI] 1.30-10.78) and self-reported adherence ≥95% in the past month (aPOR 2.76, 95% CI 1.00-7.62) were significantly associated with viral suppression in the multivariable model. Excellent virologic outcomes were achieved in Rwandan AIDSRelief sites utilizing the AIDSRelief Model of Care during the scale-up of ART in the country. [ABSTRACT FROM AUTHOR]

Objectives: To compare the effectiveness of HIV integrase inhibitor monotherapy between raltegravir and dolutegravir as an approach to simplify therapy.Methods: We evaluated and compared the efficacy of 20 week monotherapy with dolutegravir or raltegravir in humanized mice (HSC-NSG) infected with HIVBaL. Plasma HIV RNA was measured by quantitative RT-PCR (limit of detection of 150 copies/45 μL of plasma) and drug levels by LC-MS/MS. Escape viruses were genotyped and analysed for replication capacity and drug susceptibility in tissue culture.Results: Drug-untreated control mice maintained constant viraemia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC50 of <8 nM) and dolutegravir (EC50 of <1 nM). Mice treated with raltegravir or dolutegravir had plasma drug levels comparable to those in humans. Monotherapy with raltegravir initially suppressed HIV viraemia, but failed to maintain suppression in 4/4 mice. Viruses from raltegravir failing mice developed mutations G140G/S and Q148H/K, and were resistant to both raltegravir (EC50 values of >100 nM) and dolutegravir (EC50 values ranging from 8.8 to 13.3 nM). Monotherapy with dolutegravir suppressed viraemia in 5/5 of mice, but viraemia rebounded in one animal. The virus from this mouse had mutations E138K, G140S, Q148H, N155H and S230R, was highly resistant to both raltegravir (EC50 of >1000 nM) and dolutegravir (EC50 of 550 nM), and replicated to levels similar to those of control viruses in PBMCs.Conclusions: Monotherapy with either raltegravir or dolutegravir does not consistently maintain HIV suppression, suggesting that dual therapy may be required in simplification strategies. [ABSTRACT FROM AUTHOR]

Successful propagation of HIV in the human host requires entry into a permissive cell, reverse transcription of viral RNA, integration into the human genome, transcription of the integrated provirus, and assembly/release of new virus particles. Currently, there are antiretrovirals against each of these viral steps, except for provirus transcription. An inhibitor of HIV transcription could both increase potency of treatment and suppress drug-resistant strains. Cellular cyclin-dependent kinase 9 (CDK9) serves as a cofactor for the HIV Tat protein and is required for effective transcription of the provirus. Previous studies have shown that the CDK9 inhibitor Indirubin 3’-monoxime (IM) inhibits HIV transcription in vitro and in short-term in vivo studies of HIV acute infection in humanized mice (PBMC-NSG model), suggesting a therapeutic potential. The objective of this study is to evaluate the toxicity, pharmacokinetics and long-term antiviral activity of IM during chronic HIV infection in humanized mice (HSC-NSG model). We show that IM concentrations above EC50 values are rapidly achieved and sustained for > 3 h in plasma, and that non-toxic concentrations durably reduce HIV RNA levels. In addition, IM enhanced the antiviral activity of antiretrovirals from the reverse transcriptase, protease and integrase inhibitor classes in in vitro infectivity assays. In summary, IM may enhance current antiretroviral treatments and could help achieve a “functional cure” in HIV patients by preventing expression of proviruses. [ABSTRACT FROM AUTHOR]

Achievement and maintenance of virologic suppression after cancer diagnosis have been associated with improved outcomes in HIV-infected patients, but few studies have analyzed the virologic and immunologic outcomes after a cancer diagnosis. All HIV-infected patients with a diagnosis of cancer between 2000 and 2011 in an urban clinic population in Baltimore, MD, were included for review. HIV-related outcomes (HIV-1 RNA viral load and CD4 cell count) were abstracted and compared for patients with non-AIDS-defining cancers (NADCs) and AIDS-defining cancers (ADCs). Four hundred twelve patients with baseline CD4 or HIV-1 RNA viral load data were analyzed. There were 122 (30%) diagnoses of ADCs and 290 (70%) NADCs. Patients with NADCs had a higher median age (54 years vs. 43 years, p < .0001) and a higher frequency of hepatitis C coinfection (52% vs. 36%, p = .002). The median baseline CD4 was lower for patients with ADCs (137 cells/mm3 vs. 314 cells/mm3) and patients with NADCs were more likely to be suppressed at cancer diagnosis (59% vs. 25%) (both p < .0001). The median CD4 for patients with NADCs was significantly higher than patients with ADCs at 6 and 12 months after diagnosis and higher at 18 and 24 months, but not significantly. Patients with an NADC had 2.19 times (95% CI 1.04-4.62) the adjusted odds of being suppressed at 12 months and 2.17 times the odds (95% CI 0.92-5.16) at 24 months compared to patients with an ADC diagnosis. For patients diagnosed with ADCs and NADCs in this urban clinic setting, both virologic suppression and immunologic recovery improved over time. Patients with NADCs had the highest odds of virologic suppression in the 2 years following cancer diagnosis. [ABSTRACT FROM AUTHOR]

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Loss of immune control over opportunistic infections can occur at different stages of HIV-1 (HIV) disease, among which mucosal candidiasis caused by the fungal pathogen Candida albicans (C. albicans) is one of the early and common manifestations in HIV-infected human subjects. The underlying immunological basis is not well defined. We have previously shown that compared to cytomegalovirus (CMV)-specific CD4 cells, C. albicans-specific CD4 T cells are highly permissive to HIV in vitro. Here, based on an antiretroviral treatment (ART) naïve HIV infection cohort (RV21), we investigated longitudinally the impact of HIV on C. albicans- and CMV-specific CD4 T-cell immunity in vivo. We found a sequential dysfunction and preferential depletion for C. albicans-specific CD4 T cell response during progressive HIV infection. Compared to Th1 (IFN-γ, MIP-1β) functional subsets, the Th17 functional subsets (IL-17, IL-22) of C. albicans-specific CD4 T cells were more permissive to HIV in vitro and impaired earlier in HIV-infected subjects. Infection history analysis showed that C. albicans-specific CD4 T cells were more susceptible to HIV in vivo, harboring modestly but significantly higher levels of HIV DNA, than CMV-specific CD4 T cells. Longitudinal analysis of HIV-infected individuals with ongoing CD4 depletion demonstrated that C. albicans-specific CD4 T-cell response was preferentially and progressively depleted. Taken together, these data suggest a potential mechanism for earlier loss of immune control over mucosal candidiasis in HIV-infected patients and provide new insights into pathogen-specific immune failure in AIDS pathogenesis. [ABSTRACT FROM AUTHOR]

HIV-infected patients have an increased risk for both Hodgkin and non-Hodgkin lymphomas. A retrospective cohort of all HIV-infected patients diagnosed with lymphoma in urban clinics from 2000–2013 was evaluated to characterize the distribution and determine effects of sub-type and immunophenotype on survival. Of 160 cases identified, 131 (82%) had complete information and were analyzed. The most common sub-types were diffuse large B cell (41%), Burkitt (21%) and Hodgkin lymphoma (18%). Advanced (78% stage III/IV) and extranodal disease (82%) at presentation were common. CD20 was the most commonly expressed immunophenotypic marker (89%). Overall mortality rate was high (26.1 per 100 person-years). Lower mortality was noted in CD10 + and CD20 + lymphomas, but differences were not statistically significant. After adjustment, low CD4 count (≤ 200) at diagnosis was associated with higher mortality (adjusted hazard ration (AHR) = 1.75; 95% CI = 1.00–3.61). Mortality in this cohort of patients with HIV-associated lymphomas was high and exceeds that from published data from the general population. [ABSTRACT FROM PUBLISHER]

The humoral response to human immunodeficiency virus (HIV) remains incompletely understood. In this report, we describe biased λ light chain use during the HIV Env glycoprotein (Env) response in HIV infection and vaccination. We examined HIV Env binding (and neutralization) in the context of light chain use in subjects with acute HIV infection, chronic HIV infection, and among HIV vaccinees. In all populations tested, there was a λ chain bias for HIV Env binding antibodies, compared with other HIV antigens (such as p24) or tetanus toxoid. In subjects with chronic HIV infection, a λ bias was noted for neutralization, with λ antibodies accounting for up to 90% of all neutralization activity observed. This is the first report of antibody function in a human infection being tied to light chain use. In HIV infection, antibodies expressing λ light chains tended to have longer CDRL3s, increased light chain contact with HIV Env, and less hypermutation in the heavy chain, compared with antibodies using the κ light chain. These data also support an evolutionary model for the understanding the various κ to λ light chain ratios observed across species and suggest that the λ light chain bias against HIV provides the host an advantage in developing a more efficient humoral response. [ABSTRACT FROM AUTHOR]

Background: The association between HIV viremia and non-AIDS-defining cancers (NADCs) is not well characterized. Viremia may contribute directly or indirectly to cancer development and may have a differential impact on various cancer types. Our objective was to characterize patterns of HIV viremia in a retrospective, urban, clinical cohort (N = 320) of patients diagnosed with NADCs. Findings: The most common NADC's were lung (n = 60), prostate (n = 47), oropharyngeal (n = 32), liver (n = 29), and anal cancer (n = 20) and Hodgkin lymphoma (n = 18). In the year before cancer diagnosis, 66 % of all patients were virally suppressed. Patients with oropharyngeal (70 %) and prostate cancer (78 %) had a higher proportion of visits with suppressed viral loads. Patients diagnosed with anal cancer and Hodgkin lymphoma were infrequently virally suppressed and more frequently had viral loads ≥5 log10 copies/ml in the ten years prior to cancer diagnosis. Conclusions: In this cohort of HIV-infected patients diagnosed with NADCs, there were important differences in the patterns and levels of viremia between the different NADCs in the ten years prior to cancer diagnosis. Patients with anal cancer and Hodgkin lymphoma had the highest proportion of high level viremia in the ten years before cancer and the lowest frequency of viral load suppression at cancer diagnosis. [ABSTRACT FROM AUTHOR]

HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains. [ABSTRACT FROM AUTHOR]

Background. Targeting host-cell pathways to increase the potency of nucleoside/nucleotide analog reverse transcriptase inhibitors (NRTIs) is an important strategy for clinical investigation. Resveratrol is a natural product that inhibits cellular ribonucleotide reductase, prolonging the S phase of the cell cycle and preferentially lowering dATP levels.Methods. We performed in vitro evaluation of resveratrol on the antiviral activity of adenosine analog tenofovir (TFV) against sensitive and drug-resistant human immunodeficiency virus type 1 (HIV-1), from subtypes B and C, in primary cells.Results. Resveratrol enhanced the antiviral activity of TFV by up to 10-fold and restored susceptibility of TFV-resistant viruses. Resveratrol prevented wild-type HIV-1 from developing phenotypic resistance to TFV. Notably, resveratrol enhanced TFV activity against sensitive and resistant HIV-1 from both subtypes B and C.Conclusions. Prolonged wide-scale use of thymidine analogs in the setting of viral failure has limited the efficacy of second-line NRTI-based regimens in Africa. Moreover, the extensive use of ddI and d4T has led to high frequencies of the K65R mutation, further compromising TFV efficacy. In light of increasing resistance to commonly used NRTIs in global HIV treatment programs, targeting nucleoside biosynthesis with resveratrol, or derivatives with improved bioavailabilities, is a potential strategy to maintain, enhance, and restore susceptibility of commonly used NRTIs. [ABSTRACT FROM PUBLISHER]

Infection with human immunodeficiency virus remains a global concern with a significant number of incident infections still reported worldwide. The use of prophylaxis prior to exposure to the virus to prevent infection has been a growing area of recent research. Results in nonhuman primates and clinical trials in high-risk patient populations using preexposure prophylaxis have shown promising results in terms of efficacy and safety, especially relating to oral preexposure prophylaxis. The potential use of oral antiretroviral agents traditionally used for human immunodeficiency virus treatment as prophylaxis raises interesting considerations, such as the best agents available for such a role, long-term safety in healthy individuals, and the potential development of resistance to these agents should infection occur. From a public health perspective, the cost-effectiveness of implementing this preventive strategy has not been fully defined at this point in time. [ABSTRACT FROM AUTHOR]

Long-lived memory B cells (BMem) provide an archive of historic Ab responses. By contrast, circulating Abs typically decline once the immunogen is cleared. Consequently, circulating Abs can underestimate the nature of cognate humoral immunity. On the other hand, the BMem pool should provide a comprehensive picture of Ab specificities that arise over the entire course of infection. To test this hypothesis, we compared circulating Ab and BMem from natural virus suppressors who control HIV-1 without therapy and maintain a relatively intact immune system. We found high frequencies of BMem specific for the conserved neutralizing CD4 induced or CD4 binding site epitopes of gp120, whereas low Ab titers to these determinants were detected in contemporaneous plasma. These data suggest that plasma Ab repertoires can underestimate the breadth of humoral immunity, and analyses of BMem should be included in studies correlating Ab specificity with protective immunity to HIV-1. [ABSTRACT FROM AUTHOR]

Background. The current goal of human immunodeficiency virus type 1 (HIV-1) therapy is to maximally suppress viral replication. Securing this goal requires new drugs and treatment classes. The chemokine receptor CCR5 provides an entry portal for HIV-1, and PRO 140 is a humanized monoclonal antibody that binds to CCR5 and potently inhibits CCR5-tropic (R5) HIV-1 in vitro. Methods. A randomized, double-blind, placebo-controlled, dose-escalating study was conducted in 39 individuals with HIV-1 RNA levels ⩾5000 copies/mL, CD4+ cell counts ⩾250 cells/μL, no antiretroviral therapy for 3 months, and only R5 HIV-1 detectable. Cohorts were randomized 3:10 to receive placebo or doses of PRO 140 of 0.5, 2, or 5 mg/kg. Subjects were monitored for 58 days for safety, antiviral effects, and serum concentrations of PRO 140. Results. PRO 140 was generally well tolerated and demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. Mean reductions in HIV-1RNAlevel of 0.58 log10, 1.20 log10 (P = .0002) and 1.83 log10 (P < .0001) were observed for the 0.5-, 2-, and 5-mg/kg dose groups, respectively. Reductions in mean viral load of ⩾10-fold were observed within 4 days and persisted for 2-3 weeks after treatment. Conclusions. This trial established clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity after a single dose. Trial registration. ISRCTN Register: ISRCTN45537485. [ABSTRACT FROM AUTHOR]

In cross-sectional studies of chronically infected individuals, lymphoproliferative responses to human immunodeficiency virus (HIV) type 1 p24 Gag antigen have previously been associated with lower virus load. It was not known whether this association would be predictive of better clinical outcome in longitudinal studies. Although response to recall antigens did not correlate with clinical indices of disease progression, positive baseline lymphoproliferative responses to p24 and TT were associated with lower plasma levels of HIV- 1 RNA. Persistently positive lymphoproliferative responses to the antigens also inversely correlated with repeated measurements of virus load, although the significance was lost once the measurements were adjusted for virus load and CD4+ cell count at baseline, by use of generalized estimating equation analysis. These observations suggest that the effect of the association between lymphoproliferative response and virus load is established early during HIV-1 infection and does not increase over time and suggest that antigen- specific lymphoproliferative responses reflect the dynamic state of HIV-1 infection and are inversely associated with virus load. [ABSTRACT FROM AUTHOR]

To detect human immunodeficiency virus (HIV) antibodies in a simple enzyme-linked immunoassay (CBre3-EIA), we used an Escherichia coli-expressed polypeptide antigen, representing the carboxy-terminal third of the external membrane glycoprotein gene fused with the amino-terminal half of the transmembrane glycoprotein gene. Over a 3-month period, 2707 consecutive serum samples referred for confirmatory testing for human T-lymphotrophic virus type III (HTLV-III) antibodies were evaluated by both Western blot and CBre3-EIA. On a single determination for each sample, the CBre3-EIA was found to have an estimated sensitivity (99.9%) and specificity (99.1%) similar or superior to the more cumbersome Western blot method. This study shows that all HIV-seropositive subjects have antibodies to the virus envelope protein; no other virus antigens are required for construction of highly sensitive immunoassays. [ABSTRACT FROM AUTHOR]

Background: HIV-1 natural viral suppressors (NVS) are individuals that control HIV replication without antiretrovirals (also know as HIV elite controllers). We have recently shown that these individuals have an elevated rate of hepatitis C virus (HCV) clearance. Given the association of IL28B genotype, specifically the rs12979860 single nucleotide polymorphism (SNP) based CC genotype, with HCV clearance, we studied its association with HIV control in 172 African American HIV subjects and 173 race-matched controls. Findings: The frequency of the CC genotype was 12.5% in the NVS, 14.7% in the LVL ('low viral load' cohort with 400-20,000 HIV-1 RNA copies/mL), 17.8% in the MHVL ('medium/high viral load' cohort with >20,000 HIV-1 RNA copies/mL), and 11.6% in an HIV-negative cohort. There was no statistical significance in the CC genotype distribution between these cohorts ( p= 0.48 between the NVS and non-NVS HIV positive controls, p= 0.85 between NVS and HIV-negatives). We also did not observe any association between CC genotype distribution and HIV RNA viral load, as a continuous measure. Conclusions: The IL28B CC genotype does not account for the noted HIV control in our specific NVS cohort. Further studies will be needed to determine if a common genetic factor can primarily account for any joint clearance of HCV and control of HIV. Clin Trans Sci 2011; Volume 4: 282-284 [ABSTRACT FROM AUTHOR]

Abstract: Mutations in the HIV-1 proviral genomes delay the progression of the disease. We compared the mutation status in full-length proviral genomes of 23 HIV-infected patients with undetectable viral loads in the absence of therapy named natural viral suppressors (NVS) or Elite Controllers with 23 HIV-infected controls (10 patients on HAART treatment and 13 untreated patients). Provirus DNA was extracted from PBMC for amplification and sequencing to determine the mutation status. Nine (39 %) of the 23 NVS patients had defective proviral genomes, compared to 4 of the treated controls (40%, p=0.96) and only one of the untreated controls (8%, p=0.059). Most of the defective genomes resulted from Gto-A hypermutation. Among patients with hypermutation, the rate ratio for mutation was significantly higher for the NVS compared to treated controls (p=0.043). Our data suggests that inactivation of the virus through the APOBEC3G system may contribute to the NVS phenotype. [Copyright &y& Elsevier]

With improved access to antiretroviral therapy in resource-constrained settings, long-term retention in HIV clinics has become an important means of reducing costs and improving outcomes. Published data on retention in HIV clinics beyond 24 months are, however, limited. In our clinic in rural Haiti, we hypothesized that individuals residing in locations with higher transportation costs to clinic would have poorer retention than those who had lower costs.We used a retrospective cohort design to evaluate potential predictors of HIV clinic retention. Patient information was abstracted from the electronic medical records. Cox proportional hazards regression was used to identify independent predictors of 4-year clinic retention.There were 410 patients in our cohort, 266 (64.9%) females and 144 (35.1%) males. Forty-five (11%) patients lived in locations with transportation costs >$2. Males were 1.5 times more likely to live in municipalities with transportation costs to clinic of >$2. Multivariate analysis suggested that age <30 years, male gender, and transportation cost were independent predictors of loss to follow-up (LTFU): risk ratio of 2.98, 95% confidence interval (CI): 1.73 to 4.96, P < 0.001; 1.71, CI: 1.08 to 2.70, P = 0.02; and 1.91, CI: 1.08 to 3.36, P = 0.02, respectively.Patients with transportation costs greater than $2 were 1.9 times more likely to be lost to care compared with those who paid less for transportation. HIV treatment programs in resource-constrained settings may need to pay closer attention to issues related to transportation cost to improve patient retention. [ABSTRACT FROM AUTHOR]

To examine the relationship between HIV-1 antigenic load (plasma RNA copies/mL) and broad HIV-1 neutralizing antibody activity.Plasma from 120 HIV-1-infected patients, including HIV-1 natural viral suppressors (similar to elite controllers), was tested for neutralization against 15 Tier 1/Tier 2 HIV-1 pseudoviruses. Broad HIV-1 neutralizing antibody activity was confirmed with immunoglobulin G and heterlogous clade testing (18 pseudoviruses from Clades A, C, and CRF02_AG). Statistical analysis was performed to determine factors associated with broad HIV-1 neutralizing antibody activity.Ten individuals with broad HIV-1 neutralizing antibody activity were identified. These individuals had a median CD4 count of 589 cells per microliter (range 202-927), 1611 HIV-1 RNA copies per milliliter (range 110-8964), and 13 years since HIV diagnosis (range 1-22). There was a significant correlation between the presence of broadly neutralizing antibodies in those with HIV-1 RNA between 100 and 10,000 copies per milliliter compared with those <100 or >10,000 copies per milliliter (P = 0.0003 and 0.0245, respectively). Individuals with HIV-1 RNA 100-10,000 copies per milliliter had a higher number of Tier 2 viruses neutralized compared with the <100 or >10,000 copies per milliliter groups (P ≤ 0.0001 and P = 0.076, respectively). Male sex was associated with broad HIV-1 neutralizing antibody activity (P = 0.016).These results indicate that low but persistent HIV antigen expression correlates with broad HIV-1 neutralizing antibody activity. At higher levels of plasma viremia, neutralization titers were diminished. Conversely, at lower levels, there seems to be insufficient antigen stimulation to maintain high neutralization titers. These findings may have important implications in furthering the understanding of the humoral response to HIV infection. [ABSTRACT FROM AUTHOR]

Abstract: Maraviroc, the only CCR5 antagonist HIV inhibitor currently approved, has potent antiviral activity in treatment-experienced individuals infected with CCR5-using HIV-1 (R5 HIV-1). However, recent data from the MOTIVATE trials indicate that R5 HIV-1 can develop resistance to Maraviroc, underscoring the need for additional CCR5 antagonists. The CCR5 antagonist aplaviroc (APL) is active against Maraviroc-resistant viral strains but its clinical development has ended because of dose-related toxicity. Here we demonstrate that reduction of CCR5 density (receptors/cell) with the immunomodulatory drug rapamycin (RAPA) enhances the antiviral activity of APL, allowing lower, non-toxic effective doses. In the presence of RAPA, the concentration of APL required for 90% inhibition of R5 HIV-1 in primary CD4 lymphocytes was reduced by as much as 25-fold. We conclude that low doses of RAPA may reduce the anti-HIV effective dose of APL-derivatives currently in development and thus minimize their potential toxicity. Combinations of RAPA and CCR5 antagonists could provide an effective means to control drug-resistant R5 HIV in patients, most notably those infected with Maraviroc-resistant viruses. [Copyright &y& Elsevier]

The article presents a study which investigates the epidemiologic characteristics and natural history of HIV-1 natural viral suppressors (NVSs). Result shows that NVS cohort has demonstrated noteworthy quality and a low rate of progression over many years. It notes that detailed evaluation of viral-host immune regulatory factors associated with persistent HIV-1 natural viral suppression has the potential to provide important new perception in HIV pathogenesis.

Tat is among the required regulatory genes of human immunodeficiency virus type 1 (HIV-1). Tat functions both within infected cells as a transcription factor and as an extracellular factor that binds and alters bystander cells. Some functions of extracellular Tat can be neutralized by immune serum or monoclonal antibodies. In order to understand the antibody response to Tat, we are defining antibody epitopes and the effects of natural Tat sequence variation on antibody recognition. The dominant Tat epitope in macaque sera is within the first 15 amino acids of the protein amino terminus. Together with a subdominant response to amino acids 57 to 60, these two regions account for most of the macaque response to linear Tat epitopes and both regions are also sites for the binding of neutralizing antibodies. However, the dominant and subdominant epitope sequences differ among virus strains, and this natural variation can preclude antibody binding and Tat neutralization. We also examined serum samples from 31 HIV-positive individuals that contained Tat binding antibodies; 23 of the 31 sera recognized the amino terminus peptide. Similar to binding in macaques, human antibody binding to the amino terminus was affected by variations at positions 7 and 12, sequences that are distinct for clade B compared to other viral clades. Tat-neutralizing antibodies to the dominant amino terminus epitope are affected by HIV clade variation. [ABSTRACT FROM AUTHOR]

Summary Anti-HIV-1 envelope broadly neutralizing monoclonal antibodies (bNAbs) isolated from memory B cells may not fully represent HIV-1-neutralizing profiles measured in plasma. Accordingly, we characterized near-pan-neutralizing antibodies extracted directly from the plasma of two “elite neutralizers.” Circulating anti-gp120 polyclonal antibodies were deconvoluted using proteomics to guide lineage analysis of bone marrow plasma cells. In both subjects, a single lineage of anti-CD4-binding site (CD4bs) antibodies explained the plasma-neutralizing activity. Importantly, members of these lineages potently neutralized 89%–100% of a multi-tier 117 pseudovirus panel, closely matching the specificity and breadth of the circulating antibodies. X-ray crystallographic analysis of one monoclonal, N49P7, suggested a unique ability to bypass the CD4bs Phe43 cavity, while reaching deep into highly conserved residues of Layer 3 of the gp120 inner domain, likely explaining its extreme potency and breadth. Further direct analyses of plasma anti-HIV-1 bNAbs should provide new insights for developing antibody-based antiviral agents and vaccines. [ABSTRACT FROM AUTHOR]

The common properties of broadly cross-reactive HIV-1 neutralization antibodies found in certain HIV-1-infected individuals holds significant value for understanding natural and vaccine-mediated anti-HIV immunity. Recent efforts have addressed this question by deriving neutralizing monoclonal anti-envelope antibodies from memory B cell pools of selected subjects. However, it has been more difficult to identify whether broadly neutralizing antibodies circulating in plasma possess shared characteristics among individuals. To address this question, we used affinity chromatography and isoelectric focusing to fractionate plasma immunoglobulin from 10 HIV-1-infected subjects (5 subjects with broad HIV-1 neutralizing activity and 5 controls). We find that plasma neutralizing activity typically partitions into at least two subsets of antibodies. Antibodies with restricted neutralization breadth have relatively neutral isoelectric points and preferentially bind to envelope monomers and trimers versus core antigens from which variable loops and other domains have been deleted. In comparison, broadly neutralizing antibodies account for a minor fraction of the total anti-envelope response. They are consistently distinguished by more basic isoelectric points and specificity for epitopes shared by monomeric gp120, gp120 core, or CD4-induced structures. Such biochemical properties might be exploited to reliably predict or produce broad anti-HIV immunity. [ABSTRACT FROM AUTHOR]