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In the absence of antiviral therapy, HIV-1 infection progresses to a wide spectrum of clinical manifestations that are the result of an entangled contribution of host, immune and viral factors. The contribution of these factors is not completely established. Several investigations have described the involvement of the immune system in the viral control. In addition, distinct HLA-B alleles, HLA-B27, -B57-58, were associated with infection control. The combination of these elements and antiviral host restriction factors results in different clinical outcomes. The role of the viral proteins in HIV-1 infection has been, however, less investigated. We will review contributions dedicated to the pathogenesis of HIV-1 infection focusing on studies identifying the function of the viral envelope glycoprotein (Env) in the clinical progression because of its essential role in the initial events of the virus life-cycle. Some analysis showed that inefficient viral Envs were dominant in non-progressor individuals. These poorly-functional viral proteins resulted in lower cellular activation, viral replication and minor viral loads. This limited viral antigenic production allows a better immune response and a lower immune exhaustion. Thus, the properties of HIV-1 Env are significant in the clinical outcome of the HIV-1 infection and AIDS pathogenesis.

Background: Less than 1% of Human Immunodeficiency Virus (HIV)-infected individuals are able to achieve spontaneous viral control without requiring antiretroviral therapy (ART). Whether these HIV controllers (HIC) are at risk of HIV-associated comorbidities and could benefit from ART is debated, but recent studies reported decreased T-cell activation upon ART initiation. We report the frequency of ART initiation, reasons to treat, treatment outcome on immunovirological parameters, and rate of side-effects and treatment discontinuation in the French cohort of HIC. Methods: Participants included in the French multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites (ANRS) Cohorte des extremes (CODEX) cohort of HIC between July 6, 2007 and January 3, 2018 were prospectively followed. ART initiation, indication, discontinuation, non-Acquired ImmunoDeficiency Syndrome (AIDS)-defining events, side-effects, and immunovirological parameters were recorded. Undetectable HIC (u-HIC) were defined as participants with strictly undetectable viral loads based on routinely used assays throughout the follow-up and blipper HIC (b-HIC) as participants with possible detectable viral loads above the detection threshold during follow-up. Findings: Among 302 HIC followed for a median of 14.8 years [10.3–20.2], 90 (30%) received ART (7 u-HIC and 83 b-HIC). The main reasons for ART initiation were decreased CD4 T-cell counts (n = 36, 40%), loss of virological control (n = 13, 14%), and non-AIDS-defining events (n = 12, 13%). Sixteen (18%) participants experienced 17 grade 1–2 adverse events. In b-HIC, ART slightly increased the CD4/CD8 ratio (median +0.19, p

HIV-specific CD8 T cells and broadly neutralizing antibodies (bNAbs) both contribute to the control of viremia, but in most cases, neither can completely suppress viral replication. To date, therapeutic vaccines have not been successful in eliciting HIV-specific CD8 T cell or bNAb responses that are capable of preventing long-term viral rebound upon ART cessation. These challenges suggest that a combinatorial approach that harnesses both bNAbs and CD8 T cell responses may be necessary for long term control of viral replication. In this study we demonstrate a synergistic interaction between CD8 T cells and bNAbs using an in vitro model. Our data suggest that this combinatorial approach is very effective at suppressing viral replication in vitro and should be considered in future therapeutic studies.

HIV-specific CD8 T cells and broadly neutralizing antibodies (bNAbs) both contribute to the control of viremia, but in most cases, neither can completely suppress viral replication. To date, therapeutic vaccines have not been successful in eliciting HIV-specific CD8 T cell or bNAb responses that are capable of preventing long-term viral rebound upon ART cessation. These challenges suggest that a combinatorial approach that harnesses both bNAbs and CD8 T cell responses may be necessary for long term control of viral replication. In this study we demonstrate a synergistic interaction between CD8 T cells and bNAbs using an in vitro model. Our data suggest that this combinatorial approach is very effective at suppressing viral replication in vitro and should be considered in future therapeutic studies. [ABSTRACT FROM AUTHOR]

Elite controllers (ECs) are people living with human immunodeficiency virus (HIV) who spontaneously control viral replication without antiretroviral therapy. We observed that elevated anti-cytomegalovirus (CMV) immunoglobulin G (IgG) levels correlated with annual CD4 T-cell count decay in ECs independently of age, sex, and human leukocyte antigen (HLA) type. Elevated anti-CMV titers may favor disease progression in ECs. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus-1 (HIV-1) exploits human host factors to complete its life cycle. Hence, discovery of HIV-regulated host proteins markers would better our understanding of the virus life-cycle and its contribution to pathogenesis and discovery of objective diagnostic and prognostic molecules. We conducted holistic total proteomics analysis of three closely related study populations including patients with HIV type-1 (HIV-1) and HIV type-2 (HIV-2) as well as HIV-1 elite controllers (HIV-1-EC). Peripheral blood plasma (PBP) samples were subjected to label-free quantitative liquid-chromatography tandem mass-spectrometry (LC–MS/MS). Over 314 unique PBP protein species were identified of which 100 (approx. 32%) were significantly differentially expressed (≥2 to ∞ - fold-change; p < 0.05) between the three sample cohorts. Of the 100 proteins, 91 were significantly changed between pairs of HIV-1 versus HIV-1-EC, while 83 of the 100 proteins differed significantly between HIV-2 and HIV-1-EC. Interestingly, 76 proteins (87.5%) overlap between the two data sets indicating that majority of these proteins share similar expression changes between HIV-1 and HIV-2 sample groups. Two of the identified proteins, XRCC5 and PSME1, were implicated in the early phase of the pathway network for HIV life cycle, while others were involved in infectious disease and disease of signal transduction. Among them were MAP2K1, RPL23A, RPS3, CALR, PRDX1, SOD2, LMNB1, PHB, and FGB. Despite the high degree of similarity in protein profiles of HIV-1 and HIV-2, six proteins differed significantly including ETFB, PHB2, S100A9, LMO2, PPP3R1 and Vif, a fragment of virion infectivity factor of HIV-1. Additionally, 15 proteins were uniquely expressed, and one of them (LSP1) is present only in HIV-1-EC but absent in HIV1 and HIV-2 and vice versa for the rest 14 proteins. Altogether, we have identified HIV-specific/related protein expression changes that might potentially be capable of early diagnosis and prognosis of HIV diseases and other related infectious diseases. [ABSTRACT FROM AUTHOR]

Individuals infected with HIV display varying rates of viral control and disease progression, with a small percentage of individuals being able to spontaneously control infection in the absence of treatment. In attempting to define the correlates associated with natural protection against HIV, extreme heterogeneity in the datasets generated from systems methodologies can be further complicated by the inherent variability encountered at the population, individual, cellular and molecular levels. Furthermore, such studies have been limited by the paucity of well-characterised samples and linked epidemiological data, including duration of infection and clinical outcomes. To address this, we selected 10 volunteers who rapidly and persistently controlled HIV, and 10 volunteers each, from two control groups who failed to control (based on set point viral loads) from an acute and early HIV prospective cohort from East and Southern Africa. A propensity score matching approach was applied to control for the influence of five factors (age, risk group, virus subtype, gender, and country) known to influence disease progression on causal observations. Fifty-two plasma proteins were assessed at two timepoints in the 1st year of infection. We independently confirmed factors known to influence disease progression such as the B*57 HLA Class I allele, and infecting virus Subtype. We demonstrated associations between circulating levels of MIP-1α and IL-17C, and the ability to control infection. IL-17C has not been described previously within the context of HIV control, making it an interesting target for future studies to understand HIV infection and transmission. An in-depth systems analysis is now underway to fully characterise host, viral and immunological factors contributing to control.

Antiretroviral therapy (ART) is not curative as HIV-1 persists in long-lived viral reservoirs. Consequently, patients are dependent on life-long drug adherence with possible side effects. To overcome these limitations strategies of a functional cure aim at ART free viral remission. In this study, we sought to identify detailed subsets of anti-viral CD8+ T cell immunity linked to natural long-term control of HIV-1 infection. Here, we analyzed HIV controllers and ART suppressed progressors for in vitro viral suppressive capacity (VSC) at baseline and after peptide stimulation. Functional properties and phenotypes of CD8+ T cells were assessed by IFN-γ ELISPOT and 18 color flow cytometry. HIV controllers showed significantly increased suppression at baseline as well as after peptide stimulation. IFN-γ secretion and the proliferation marker Ki67 positively correlated with VSC. Moreover, the detailed phenotype of three distinct multifunctional memory CD8+ T cell subsets were specific traits of HIV controllers of which two correlated convincingly with VSC. Our results underline the importance of multifunctional CD8+ T cell responses during natural control. Especially the role of CXCR5 expressing cytotoxic subsets emphasizes potential surveillance in sites of reservoir persistence and demand further study.

ObjectiveElite controllers are a rare subset of HIV-1-infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (

Individuals infected with HIV display varying rates of viral control and disease progression, with a small percentage of individuals being able to spontaneously control infection in the absence of treatment. In attempting to define the correlates associated with natural protection against HIV, extreme heterogeneity in the datasets generated from systems methodologies can be further complicated by the inherent variability encountered at the population, individual, cellular and molecular levels. Furthermore, such studies have been limited by the paucity of well-characterised samples and linked epidemiological data, including duration of infection and clinical outcomes. To address this, we selected 10 volunteers who rapidly and persistently controlled HIV, and 10 volunteers each, from two control groups who failed to control (based on set point viral loads) from an acute and early HIV prospective cohort from East and Southern Africa. A propensity score matching approach was applied to control for the influence of five factors (age, risk group, virus subtype, gender, and country) known to influence disease progression on causal observations. Fifty-two plasma proteins were assessed at two timepoints in the 1st year of infection. We independently confirmed factors known to influence disease progression such as the B*57 HLA Class I allele, and infecting virus Subtype. We demonstrated associations between circulating levels of MIP-1α and IL-17C, and the ability to control infection. IL-17C has not been described previously within the context of HIV control, making it an interesting target for future studies to understand HIV infection and transmission. An in-depth systems analysis is now underway to fully characterise host, viral and immunological factors contributing to control. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) is not curative as HIV-1 persists in long-lived viral reservoirs. Consequently, patients are dependent on life-long drug adherence with possible side effects. To overcome these limitations strategies of a functional cure aim at ART free viral remission. In this study, we sought to identify detailed subsets of anti-viral CD8+ T cell immunity linked to natural long-term control of HIV-1 infection. Here, we analyzed HIV controllers and ART suppressed progressors for in vitro viral suppressive capacity (VSC) at baseline and after peptide stimulation. Functional properties and phenotypes of CD8+ T cells were assessed by IFN-γ ELISPOT and 18 color flow cytometry. HIV controllers showed significantly increased suppression at baseline as well as after peptide stimulation. IFN-γ secretion and the proliferation marker Ki67 positively correlated with VSC. Moreover, the detailed phenotype of three distinct multifunctional memory CD8+ T cell subsets were specific traits of HIV controllers of which two correlated convincingly with VSC. Our results underline the importance of multifunctional CD8+ T cell responses during natural control. Especially the role of CXCR5 expressing cytotoxic subsets emphasizes potential surveillance in sites of reservoir persistence and demand further study. [ABSTRACT FROM AUTHOR]

Introduction: Elite controllers (EC) are a rare group of HIV‐1‐positive individuals who suppress viral loads (VL) to undetectable levels with elevated CD4 T‐cell counts in the absence of ART. While rates of short‐ and mid‐term progression have been described in these patients, few studies have focused on their long‐term outcome This study aims to describe the virological and immunological behaviour in a cohort of elite controllers followed up for a median of 17 years in the University Hospital, and to identify factors that may be related to disease progression. Methods: We conducted a descriptive, prospective and single‐centre study of all HIV‐positive adults recorded in the University Hospital database who met the definition criteria for EC. EC were defined as patients having two consecutive undetectable VL without ART for at least one year. Patients were followed from baseline up to December 2019, to the development of a progression event (loss of VL control, CD4+ T cell decline, AIDS or death) or to the censoring date (lost to follow‐up or initiation of ART). Predictive models of progression were calculated. Results: Fifty‐nine EC were identified with a median follow‐up of 17 years contributing 1033 PYFU. The median (95% CI) time duration from HIV‐1 diagnosis to disease progression was four (1.7 to 6.3) years. Forty‐nine (83%) presented progression to the composite end‐point, 44 (74.6%) lost viral control, 39 (66.1%) lost immunological control, two developed AIDS and two died. Only 10 patients (16.9%) did not show progression of any kind. Independent predictors of virological progression were sexual risk of HIV‐1 acquisition and VL blips during the first year of follow‐up (baseline). The only independent predictor detected for progression to a composite end‐point was VL blips during the first year of follow‐up (baseline). Conclusions: The rate of long‐term progression in EC was very high. Only a minority of patients did not show clinical progression after a median of 17 years of follow‐up. These results should be taken in account when considering EC as a model of HIV‐1 remission. [ABSTRACT FROM AUTHOR]

The natural history of human immunodeficiency virus (HIV) infection is well understood. In most individuals sexually exposed to HIV, the risk of becoming infected depends on the viral load and on sexual practices and gender. However, a low percentage of individuals who practice frequent unprotected sexual intercourse with HIV‐infected partners remain uninfected. Although the systematic study of these individuals has made it possible to identify HIV resistance factors including protective genetic patterns, such epidemiological situations remain paradoxical and not fully understood. In vitro experiments have demonstrated that peripheral blood mononuclear cells (PBMCs) from HIV‐free, unexposed blood donors are not equally susceptible to HIV infection; in addition, PBMCs from highly exposed seronegative individuals are generally resistant to infection by primary HIV clinical isolates. We review the literature on permissiveness of PBMCs from healthy blood donors and uninfected hyperexposed individuals to sustained infection and replication of HIV‐1 in vitro. In addition, we focus on recent evidence indicating that the gut microbiota may either contribute to natural resistance to or delay replication of HIV infected individuals. [ABSTRACT FROM AUTHOR]

ObjectiveBoth protective T-cell genotypes and natural killer (NK) cell genotypes have been associated with delayed progression to AIDS and shown to be co-inherited in HIV-1-infected individuals who limit viral replication in absence of antiretroviral therapy ('controllers'). However, a comparative analysis of the genotype and function of the innate and adaptive immune compartments in HIV-1-infected controller individuals has been understudied to date.DesignHere, we simultaneously tested NK and T-cell function in controllers to investigate the mechanism(s) that might account for host immune control over viral replication.MethodsWe measured CD8 T-cell responses against HIV-1 utilizing overlapping 15-mer peptides spanning the HIV-1 consensus clade B Gag protein and tested NK cell degranulation and cytokine secretion against tumor target cells following interferon-α (IFNα) stimulation.ResultsAmong a cohort of 37 controllers, the presence of protective major histocompatibility complex class I human leukocyte antigen (HLA) alleles (such as HLA-B*57) was not correlated with HIV-specific CD8 responses. In contrast, the inheritance of a protective killer inhibitory receptor KIR3DL1*h/*y receptor genotype along with the corresponding HLA-Bw4*80I ligand was associated with significantly heightened target cell-induced NK degranulation and cytokine secretion following IFNα stimulation (P = 0.0201, n = 13). Interestingly, we observed a significant inverse association between the IFNα stimulated NK response to K562 cells and the HIV-specific CD8 T-cell response to Gag among elite controllers (rho = -0.8321, P = 0.0010, n = 12).ConclusionTogether, these results suggest that heightened NK responses can be evidenced independently of HIV-specific T-cell responses in HIV-1-infected elite controllers.

Elite controllers are HIV-1 positive subjects who control viral replication without antiretroviral therapy. Many of these subjects have replication-competent virus and thus represent a model of a functional cure. Peripheral CD4+ T cells in these subjects have small reservoirs with a low frequency of intact proviruses. Furthermore, recent studies suggest that many of these intact proviruses are disproportionally integrated at sites that have limited transcriptional activity raising the possibility that replication-competent viruses do not replicate because they are in a “blocked and locked” state. However, this feature is probably a consequence rather than a cause of elite control. Additionally, evolution of plasma virus has been detected in many elites suggesting that there continues to be ongoing viral replication in other compartments. While exceptional elite controllers with very limited viral reservoirs have recently been described, more work is needed to determine whether these patients have achieved a sterilizing cure.

Summary: Highly efficient CD8+ T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of efficient CD8+ T cell responses. Our results show that SIV-specific CD8+ T cells emerge during primary infection in all animals. The ability of CD8+ T cells to suppress SIV is suboptimal in the acute phase but increases progressively in controller macaques before the establishment of sustained low-level viremia. Controller macaques develop optimal memory-like SIV-specific CD8+ T cells early after infection. In contrast, a persistently skewed differentiation phenotype characterizes memory SIV-specific CD8+ T cells in non-controller macaques. Accordingly, the phenotype of SIV-specific CD8+ T cells defined early after infection appears to favor the development of protective immunity in controllers, whereas SIV-specific CD8+ T cells in non-controllers fail to gain antiviral potency, feasibly as a consequence of early defects imprinted in the memory pool.

Antibody dependent (AD) functions such as AD cellular cytotoxicity (ADCC) were associated with lower viral load (VL) in untreated HIV progressors and protection from HIV infection in the modestly protective RV144 HIV vaccine trial. Target cells used to measure ADCC, AD complement deposition (ADCD), and AD cellular trogocytosis (ADCT) have been either HIV envelope (Env) gp120-coated CEM.NKr.CCR5 cells or HIV infected cell cultures. In HIV infected cell cultures, uninfected bystander cells take up gp120 shed from infected cells. Both gp120-coated and gp120+ bystander cells expose CD4 induced (CD4i) epitopes, which are normally hidden in native trimeric Env expressed by genuinely HIV infected cells since Nef and Vpu downmodulate cell surface CD4. Antibody dependent assays using either of these target cells probe for CD4i Abs that are abundant in HIV+ plasma but that do not recognize HIV-infected cells. Here, we examined ADCC, ADCD, and ADCT functions using a target cell line, sorted HIV-infected cell line cells, whose HIV infection frequency nears 100% and that expresses HIV Env in a native trimeric closed conformation. Using sorted HIV-infected cells (siCEM) as targets, we probed the binding and AD functions of anti-gp120/Env Abs in plasma from HIV-infected untreated progressor (UTP, n = 18) and treated (TP, n = 24) subjects, compared to that in Elite controllers (EC, n = 37) and Viral Controllers (VC, n = 16), which are rare subsets of HIV-infected individuals who maintain undetectable or low VL, respectively, without treatment. Gp120-coated beads were used to measure AD cellular phagocytosis. Equivalent concentrations of input IgG in plasma from UTPs, ECs, and VCs supported higher levels of all AD functions tested than plasma from TPs. When AD activities were normalized to the concentration of anti-gp120/Env-specific Abs, between-group differences largely disappeared. This finding suggests that the anti-gp120/Env Abs concentrations and not their potency determined AD functional levels in these assays. Elite controllers did differ from the other groups by having AD functions that were highly polyfunctional and highly correlated with each other. PCR measurement of HIV reservoir size showed that ADCC activity was higher in ECs and VCs with a reservoir size below the limit of detection compared to those having a measurable HIV reservoir size.

HIV-1 positive elite controllers or suppressors control viral replication without antiretroviral therapy, likely via CTL-mediated elimination of infected cells, and therefore represent a model of an HIV-1 functional cure. Efforts to cure HIV-1 accordingly rely on the existence or generation of antigen-specific cytotoxic T lymphocytes (CTL) to eradicate infected cells upon reversal of latency. Detecting and quantifying these HIV-1-specific CTL responses will be crucial for developing vaccine and T cell-based immunotherapies. A recently developed assay, called MANAFEST, uses T cell receptor (TCR) Vβ sequencing of peptide-stimulated cultures followed by a bioinformatic pipeline to identify neoantigen-specific T cells in cancer patients. This assay is more sensitive than conventional immune assays and therefore has the possibility to identify HIV-1 antigenic targets that have not been previously explored for vaccine or T cell immunotherapeutic strategies. Here we show that a modified version of the MANAFEST assay, called ViraFEST, can identify memory CD8+ T cell responses against autologous HIV-1 Gag and Nef epitope variants in an elite suppressor. Nine TCR Vβ clonotypes were identified and 6 of these were cross-reactive for autologous variants or known escape variants. Our findings are a proof of principle that the ViraFEST assay can be used to detect and monitor these responses for downstream use in immunotherapeutic treatment approaches.

HIV elite controllers (ECs) are characterized by the spontaneous control of viral replication, and by metabolic and autophagic profiles which favor anti-HIV CD4 and CD8 T-cell responses. Extracellular acyl coenzyme A binding protein (ACBP) acts as a feedback inhibitor of autophagy. Herein, we assessed the circulating ACBP levels in ECs, compared to people living with HIV (PLWH) receiving antiretroviral therapy (ART) or not. We found lower ACBP levels in ECs compared to ART-naïve or ART-treated PLWH (p < 0.01 for both comparisons), independently of age and sex. ACBP levels were similar in ECs and HIV-uninfected controls. The expression of the protective HLA alleles HLA-B*27, *57, or *58 did not influence ACBP levels in ECs. ACBP levels were not associated with CD4 or CD8 T-cell counts, CD4 loss over time, inflammatory cytokines, or anti-CMV IgG titers in ECs. In ART-treated PLWH, ACBP levels were correlated with interleukin (IL)-1β levels, but not with other inflammatory cytokines such as IL-6, IL-8, IL-32, or TNF-α. In conclusion, ECs are characterized by low ACBP plasma levels compared to ART-naïve or ART-treated PLWH. As autophagy is key to anti-HIV CD4 and CD8 T-cell responses, the ACBP pathway constitutes an interesting target in HIV cure strategies.

Abstract Background Despite long-lasting HIV replication control, a significant proportion of elite controller (EC) patients may experience CD4 T-cell loss. Discovering perturbations in immunological parameters could help our understanding of the mechanisms that may be operating in those patients experiencing loss of immunological control. Methods A case–control study was performed to evaluate if alterations in different T-cell homeostatic parameters can predict CD4 T-cell loss in ECs by comparing data from EC patients showing significant CD4 decline (cases) and EC patients showing stable CD4 counts (controls). The partial least-squares–class modeling (PLS-CM) statistical methodology was employed to discriminate between the two groups of patients, and as a predictive model. Results Herein, we show that among T-cell homeostatic alterations, lower levels of naïve and recent thymic emigrant subsets of CD8 cells and higher levels of effector and senescent subsets of CD8 cells as well as higher levels of exhaustion of CD4 cells, measured prior to CD4 T-cell loss, predict the loss of immunological control. Conclusions These data indicate that the parameters of T-cell homeostasis may identify those EC patients with a higher proclivity to CD4 T-cell loss. Our results may open new avenues for understanding the mechanisms underlying immunological progression despite HIV replication control, and eventually, for finding a functional cure through immune-based clinical trials.

AIDS Clinical Trials Group study A5308 found reduced T-cell activation and exhaustion in human immunodeficiency virus (HIV) controllers start antiretroviral therapy (ART). We further assessed HIV-specific T-cell responses and post-ART viral loads. Before ART, the 31% of participants with persistently undetectable viremia had more robust HIV-specific T-cell responses. During ART, significant decreases were observed in a broad range of T-cell responses. Eight controllers in A5308 and the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort showed no viremia above the level of quantification in the first 12 weeks after ART discontinuation. ART significantly reduced HIV-specific T-cell responses in HIV controllers but did not adversely affect controller status after ART discontinuation. [ABSTRACT FROM AUTHOR]

Antibody dependent (AD) functions such as AD cellular cytotoxicity (ADCC) were associated with lower viral load (VL) in untreated HIV progressors and protection from HIV infection in the modestly protective RV144 HIV vaccine trial. Target cells used to measure ADCC, AD complement deposition (ADCD), and AD cellular trogocytosis (ADCT) have been either HIV envelope (Env) gp120-coated CEM.NKr.CCR5 cells or HIV infected cell cultures. In HIV infected cell cultures, uninfected bystander cells take up gp120 shed from infected cells. Both gp120-coated and gp120+ bystander cells expose CD4 induced (CD4i) epitopes, which are normally hidden in native trimeric Env expressed by genuinely HIV infected cells since Nef and Vpu downmodulate cell surface CD4. Antibody dependent assays using either of these target cells probe for CD4i Abs that are abundant in HIV+ plasma but that do not recognize HIV-infected cells. Here, we examined ADCC, ADCD, and ADCT functions using a target cell line, sorted HIV-infected cell line cells, whose HIV infection frequency nears 100% and that expresses HIV Env in a native trimeric closed conformation. Using sorted HIV-infected cells (siCEM) as targets, we probed the binding and AD functions of anti-gp120/Env Abs in plasma from HIV-infected untreated progressor (UTP, n = 18) and treated (TP, n = 24) subjects, compared to that in Elite controllers (EC, n = 37) and Viral Controllers (VC, n = 16), which are rare subsets of HIV-infected individuals who maintain undetectable or low VL, respectively, without treatment. Gp120-coated beads were used to measure AD cellular phagocytosis. Equivalent concentrations of input IgG in plasma from UTPs, ECs, and VCs supported higher levels of all AD functions tested than plasma from TPs. When AD activities were normalized to the concentration of anti-gp120/Env-specific Abs, between-group differences largely disappeared. This finding suggests that the anti-gp120/Env Abs concentrations and not their potency determined AD functional levels in these assays. Elite controllers did differ from the other groups by having AD functions that were highly polyfunctional and highly correlated with each other. PCR measurement of HIV reservoir size showed that ADCC activity was higher in ECs and VCs with a reservoir size below the limit of detection compared to those having a measurable HIV reservoir size. [ABSTRACT FROM AUTHOR]

Sterile α motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) can inhibit reverse transcription of human immunodeficiency virus-1 (HIV-1) by hydrolyzing intracellular deoxy-ribonucleoside triphosphate. However, its role in HIV-1 disease progression has not been extensively studied. To study the impacts of SAMHD1 on HIV-1 disease progression, especially on DNA levels, we investigated SAMHD1 levels in the peripheral blood of HIV-1 elite controllers (ECs), antiretroviral therapy (ART) naive viremic progressors (VPs) and patients with HIV-1 receiving ART (HIV-ARTs) compared with healthy controls. In addition, the present study analyzed the relationship between SAMHD1 and interferon-α, immune activation and HIV-1 DNA levels. The results of the present study demonstrated elevated SAMHD1 expression in the peripheral blood mononuclear cells of all patients withHIV-1, but higher SAMHD1 expression in the CD4+ T cells of only ECs compared with healthy controls. Immune activation was increased in the VPs and decreased in the ECs compared with healthy controls. Substantially lower HIV-1 DNA levels were identified in ECs compared with those in VPs and HIV-ARTs. SAMHD1 expression was associated with low levels of immune activation. No significant correlation was observed between SAMHD1 and HIV-1 DNA levels. Overall, the findings of the present study indicated that SAMHD1 was highly expressed in ECs, which may be associated with low immune activation levels, but was not directly related to HIV-1 DNA levels. [ABSTRACT FROM AUTHOR]

The HIV reservoir is the main barrier to eradicating HIV infection, and resting memory CD4 T (Trm) cells are one of the most relevant cellular component harboring latent proviruses. This is the first study analyzing the transcriptional profile of Trm cells, in two well-characterized groups of HIV patients with distinct mechanisms of viral replication control (spontaneous versus treatment-induced). We use a systems biology approach to unravel subtle but important differences in the molecular mechanisms operating at the cellular level that could be associated with the host's ability to control virus replication and persistence. Despite the absence of significant differences in the transcriptome of Trm cells between Elite Controllers (ECs) and cART-treated (TX) patients at the single gene level, we found 353 gene ontology (GO) categories upregulated in EC compared with TX. Our results suggest the existence of mechanisms at two different levels: first boosting both adaptive and innate immune responses, and second promoting active viral replication and halting HIV latency in the Trm cell compartment of ECs as compared with TX patients. These differences in the transcriptional profile of Trm cells could be involved in the lower HIV reservoir observed in ECs compared with TX individuals, although mechanistic studies are needed to confirm this hypothesis. Combining transcriptome analysis and systems biology methods is likely to provide important findings to help us in the design of therapeutic strategies aimed at purging the HIV reservoir. Key messages: HIV-elite controllers have the lowest HIV-DNA content in resting memory CD4 T cells. HIV-ECs show a particular transcriptional profile in resting memory CD4 T cells. Molecular mechanisms of enhanced adaptative and innate immune response in HIV-ECs. High viral replication and low viral latency establishment associate to the EC status. [ABSTRACT FROM AUTHOR]

HIV-1 positive elite controllers or suppressors control viral replication without antiretroviral therapy, likely via CTL-mediated elimination of infected cells, and therefore represent a model of an HIV-1 functional cure. Efforts to cure HIV-1 accordingly rely on the existence or generation of antigen-specific cytotoxic T lymphocytes (CTL) to eradicate infected cells upon reversal of latency. Detecting and quantifying these HIV-1-specific CTL responses will be crucial for developing vaccine and T cell-based immunotherapies. A recently developed assay, called MANAFEST, uses T cell receptor (TCR) Vβ sequencing of peptide-stimulated cultures followed by a bioinformatic pipeline to identify neoantigen-specific T cells in cancer patients. This assay is more sensitive than conventional immune assays and therefore has the possibility to identify HIV-1 antigenic targets that have not been previously explored for vaccine or T cell immunotherapeutic strategies. Here we show that a modified version of the MANAFEST assay, called ViraFEST, can identify memory CD8+ T cell responses against autologous HIV-1 Gag and Nef epitope variants in an elite suppressor. Nine TCR Vβ clonotypes were identified and 6 of these were cross-reactive for autologous variants or known escape variants. Our findings are a proof of principle that the ViraFEST assay can be used to detect and monitor these responses for downstream use in immunotherapeutic treatment approaches. [ABSTRACT FROM AUTHOR]

Abstract Background The majority of people living with HIV require antiretroviral therapy (ART) for controlling viral replication, however there are rare HIV controllers who spontaneously and durably control HIV in the absence of treatment. Understanding what mediates viral control in these individuals has provided us with insights into the immune mechanisms that may be important to induce for a vaccine or functional cure for HIV. To date, few African elite controllers from high incidence settings have been described. We identified virological controllers from the CAPRISA 002 cohort of HIV-1 subtype C infected women in KwaZulu Natal, South Africa, two (1%) of whom were elite controllers. We examined the genetic, clinical, immunological and virological characteristics of these two elite HIV controllers in detail, to determine whether they exhibit features of putative viral control similar to those described for elite controllers reported in the literature. Case presentation In this case report, we present clinical features, CD4+ T cell and viral load trajectories for two African women over 7 years of HIV infection. Viral load became undetectable 10 months after HIV infection in Elite Controller 1 (EC1), and after 6 weeks in Elite Controller 2 (EC2), and remained undetectable for the duration of follow-up, in the absence of ART. Both elite controllers expressed multiple HLA Class I and II haplotypes previously associated with slower disease progression (HLA-A*74:01, HLA-B*44:03, HLA-B*81:01, HLA-B*57:03, HLA-DRB1*13). Fitness assays revealed that both women were infected with replication competent viruses, and both expressed higher mRNA levels of p21, a host restriction factor associated with viral control. HIV-specific T cell responses were examined using flow cytometry. EC1 mounted high frequency HIV-specific CD8+ T cell responses, including a B*81:01-restricted Gag TL9 response. Unusually, EC2 had evidence of pre-infection HIV-specific CD4+ T cell responses. Conclusion We identified some features typical of elite controllers, including high magnitude HIV-specific responses and beneficial HLA. In addition, we made the atypical finding of pre-infection HIV-specific immunity in one elite controller, that may have contributed to very early viral control. This report highlights the importance of studying HIV controllers in high incidence settings.

HIV-specific broadly neutralizing antibodies (bnAbs) have been isolated from patients with high viremia but also from HIV controllers that repress HIV-1 replication. In these elite controllers (ECs), multiple parameters contribute to viral suppression, including genetic factors and immune responses. Defining the immune correlates associated with the generation of bnAbs may help in designing efficient immunotherapies. In this study, in ECs either positive or negative for the HLA-B*57 protective allele, in treated HIV-infected and HIV-negative individuals, we characterized memory B cell compartments and HIV-specific memory B cells responses using flow cytometry and ELISPOT. ECs preserved their memory B cell compartments and in contrast to treated patients, maintained detectable HIV-specific memory B cell responses. All ECs presented IgG1+ HIV-specific memory B cells but some individuals also preserved IgG2+ or IgG3+ responses. Importantly, we also analyzed the capacity of sera from ECs to neutralize a panel of HIV strains including transmitted/founder virus. 29% and 21% of HLA-B*57+ and HLA-B*57− ECs, respectively, neutralized at least 40% of the viral strains tested. Remarkably, in HLA-B*57+ ECs the frequency of HIV-Env-specific memory B cells correlated positively with the neutralization breadth suggesting that preservation of HIV-specific memory B cells might contribute to the neutralizing responses in these patients.

Abstract Background A rare phenotype of clinical non-progressors to AIDS is not well understood and the new protocol for universal treatment, may block the understanding of viral control thus it is crucial to define this controversial group. Methods A cohort of 30 persons followed a criteria for viremia control groups 1 (VC1; n = 2) and 2 (VC2; n = 7) and non-viral controllers (NC; n = 21) including number of years of diagnosis, LTCD4+, LTCD8+ counts, plasma viral load and the absence of ART; 241 uninfected control persons were matched to age and sex. Infected persons were regularly examined and submitted to two or three annual laboratory measurements. Polymorphisms and allele frequencies of CCR5Δ32 and SDF1–3’A were detected in the genomic DNA. Plasma levels of cytokines (IL-2, IL-4, IL-5, IL-9, IL-10, IL-13, IL-17 and IFN-y) were measured. Results The group investigated is originated from a miscigenetic population and demographic and social characteristics were not significantly relevant. LTCD4+ median values were higher among VC than NC, but significantly lower than uninfected controls. Evolution of LTCD4+ and LTCD8+ counts, showed a slight increase of LTCD4+ among VC, but a significant decrease in the NC. The percentage of annual change in LTCD4+ was also significantly different between the groups. LTCD4+/LTCD8+ ratio was inverted but not significant among the VC, thus the ratio may be a useful biomarker for the VC. A clear signature indicated a change from Th1 to Th2 cytokine profiles from VC to NC, respectively. Conclusions The knowledge of viral controllers characteristics in different population groups is important to define a strict universal definition for the sake of learning about the pathogenesis of HIV-1. Data on LTCD4+ seems to be stable and repetitive from published data, but the LTCD8+ response and the significance of LTCD4+/LTCD8+ ratio values are in need to further exploration as biomarkers. The change from Th1 to Th2 cytokine profile may help to design and adjust specific treatment protocols for the group.

Abstract Background Ongoing intra-host HIV-1 evolution has been shown in individuals that naturally suppress the viremia to low levels (HIV controllers) by the analysis of the RNA in plasma compartment. Detection of evolution at the DNA proviral compartment in HIV controllers, however, has been more challenging and the precise correlation between the systemic viral suppression level and rate of reservoir’s reseeding in those individuals is not fully understood. In this sense, we examined the proviral DNA quasispecies by single genome amplification of the env gene in a cohort of 23 HIV controllers from Brazil, divided in three groups, according to the level of systemic viral suppression: (1) elite controllers with persistent undetectable viral load (PEC, n = 6); (2) elite controllers with occasional episodes of transient (51–400 copies/mL) viremia (EEC, n = 7); and (3) viremic controllers with persistent low-level (80–2000 copies/mL) viremia (VC, n = 10). Results The HIV-1 diversity of the PBMC-associated proviral quasispecies in EC was significantly (P

Among the top priorities of the HIV field is the search for therapeutic interventions that can lead to sustained antiretroviral therapy (ART)-free HIV remission. Although the majority of HIV-infected persons will experience rapid viral rebound after ART interruption, there are rare individuals, termed post-treatment controllers (PTCs), who demonstrate sustained virologic suppression for months or years after treatment cessation. These individuals are considered an ideal example of durable HIV control, with direct implications for HIV cure research. However, understanding of the mechanisms behind the capacity of PTCs to control HIV remains incomplete. This is in part due to the scarcity of PTCs identified through any one research center or clinical trial, and in part because of the limited scope of studies that have been performed in these remarkable individuals. In this review, we summarize the results of both clinical and basic research studies of PTCs to date, explore key differences between PTCs and HIV spontaneous controllers, examine potential mechanisms of post-treatment control, and discuss unanswered questions and future research directions in this field.

Elite controllers (EC) are able to control HIV-1 replication to extremely low levels (

HIV +Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4 +T cells with resistance specific to R5-tropic HIV, reversed after introduction of ccr5. R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4 +T cells of these EC/VCs had lower ccr2 and ccr5 RNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of ccr2 and ccr5, despite having more accessible chromatin by ATAC-seq. Other nearby genes were also down-regulated, over a region of ~500 kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with ccr2/ccr5 down-regulation, suggesting that the phenotype is heritable.

There is a continuous search for an HIV cure as the success of ART in blocking HIV replication and the role of CD4+ T cells in HIV pathogenesis and immunity do not entirely eradicate HIV. The Berlin patient, who is virus-free, serves as the best model for a 'sterilizing cure' and many experts are trying to mimic this approach in other patients. Although failures were reported among Boston and Essen patients, the setbacks have provided valuable lessons to strengthen cure strategies. Following the Berlin patient, two more patients known as London and Düsseldorf patients might be the second and third person to be cured of HIV. In all the cases, the patients underwent chemotherapy regimen due to malignancy and hematopoietic stem cell transplantation (HSCT) which required matching donors for CCR5Δ32 mutation – an approach that may not always be feasible. The emergence of newer technologies, such as long-acting slow-effective release ART (LASER ART) and CRISPR/Cas9 could potentially overcome the barriers due to HIV latency and persistency and eliminate the need for CCR5Δ32 mutation donor. Appreciating the failure and success stories learned from these HIV breakthroughs would provide some insight for future HIV eradication and cure strategies. [ABSTRACT FROM AUTHOR]

Among the top priorities of the HIV field is the search for therapeutic interventions that can lead to sustained antiretroviral therapy (ART)-free HIV remission. Although the majority of HIV-infected persons will experience rapid viral rebound after ART interruption, there are rare individuals, termed post-treatment controllers (PTCs), who demonstrate sustained virologic suppression for months or years after treatment cessation. These individuals are considered an ideal example of durable HIV control, with direct implications for HIV cure research. However, understanding of the mechanisms behind the capacity of PTCs to control HIV remains incomplete. This is in part due to the scarcity of PTCs identified through any one research center or clinical trial, and in part because of the limited scope of studies that have been performed in these remarkable individuals. In this review, we summarize the results of both clinical and basic research studies of PTCs to date, explore key differences between PTCs and HIV spontaneous controllers, examine potential mechanisms of post-treatment control, and discuss unanswered questions and future research directions in this field. [ABSTRACT FROM AUTHOR]

Background: Elite controllers (ECs) spontaneously control plasma human immunodeficiency virus type 1 (HIV-1) RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers.Methods: Plasma samples from ECs who spontaneously lost virological control (transient controllers [TCs]), at 2 years and 1 year before the loss of control, were compared with a control group of ECs who persistently maintained virological control during the same follow-up period (persistent controllers [PCs]). Comparative plasma shotgun proteomics was performed with tandem mass tag (TMT) isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry.Results: Eighteen proteins exhibited differences comparing PC and preloss TC timepoints. These proteins were involved in proinflammatory mechanisms, and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. Coagulation factor XI, α-1-antichymotrypsin, ficolin-2, 14-3-3 protein, and galectin-3-binding protein were considered potential biomarkers.Conclusions: The proteomic signature associated with the spontaneous loss of virological control was characterized by higher levels of inflammation, transendothelial migration, and coagulation. Galectin-3 binding protein could be considered as potential biomarker for the prediction of virological progression and as therapeutic target in ECs. [ABSTRACT FROM AUTHOR]

As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these innate immune cell populations results in improved IL-15-dependent cNK cell survival and cytotoxicity, paired with a metabolic profile biased toward IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display a programmed IL-15 response signature and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1. [Display omitted] • Enhanced activating histone marks on IL2R β and BCL2 genes in cNK cells from ECs • Elevated levels of IL-15 transcription in myeloid DCs from ECs • Improved survival and increased cytotoxicity in cNK cells after IL-15 stimulation • Increased glycolytic activities in cNK cells from ECs after IL-15 stimulation Hartana et al. observed elevated IL-15 responsiveness of cNK cells from HIV-1 elite controllers, paired with increased levels of IL-15 transcription in mDCs. These results suggest that immune crosstalk between mDCs and cNK cells results in distinct IL-15 response signatures and may contribute to drug-free control of HIV-1 replication. [ABSTRACT FROM AUTHOR]

Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4+ T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4+ T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8+ T cells were not able to eliminate autologous resting CD4+ T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8+ T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8+ T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8+ T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies.

Our aim was to analyze the relationship between plasma inflammatory biomarkers and CD4+ T-cells evolution in human immunodeficiency virus (HIV) elite controllers (HIV-ECs) with a suppressed viremia. We carried out a retrospective study in 30 HIV-ECs classified into two groups: those showing no significant loss of CD4+ T-cells during the observation period (stable CD4+, n = 19) and those showing a significant decrease of CD4+ T-cells (decline CD4+, n = 11). Baseline plasma biomarkers were measured using a multiplex immunoassay: sTNF-R1, TRAIL, sFas (APO), sFasL, TNF-α, TNF-β, IL-8, IL-18, IL-6, IL-10, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, SDF1α, GRO-α, and CCL11. Baseline levels of sTNF-R1 and CCL11 and sTNF-R1/TNF-α ratio correlated with the slope of CD4+ T-cells (cells/μl/year) during follow-up [r = −0.370 (p = 0.043), r = −0.314 (p = 0.091), and r = −0.381 (p = 0.038); respectively]. HIV-ECs with declining CD4+ T-cells had higher baseline plasma levels of sTNF-R1 [1,500.7 (555.7; 2,060.7) pg/ml vs. 450.8 (227.9; 1,263.9) pg/ml; p = 0.018] and CCL11 [29.8 (23.5; 54.9) vs. 19.2 (17.8; 29.9) pg/ml; p = 0.041], and sTNF-R1/TNF-α ratio [84.7 (33.2; 124.2) vs. 25.9 (16.3; 75.1); p = 0.012] than HIV-1 ECs with stable CD4+ T-cells. The area under the receiver operating characteristic (ROC) curve [area under ROC curve (AUROC)] were 0.758 ± 0.093 (sTNF-R1), 0.727 ± 0.096 (CCL11), and 0.777 ± 0.087 (sTNF-R1/TNF-α). The cut-off of 75th percentile (high values) for these biomarkers had 71.4% positive predictive value and 73.9% negative predictive value for anticipating the evolution of CD4+ T-cells. In conclusion, the loss of CD4+ T-cells in HIV-ECs was associated with higher levels of two plasma inflammatory biomarkers (sTNF-R1 and CCL11), which were also reasonably accurate for the prediction of the CD4+ T-cells loss.

The inaugural FASEB HIV Reservoirs and Immune Control Conference brought researchers together from across the globe to discuss reservoir dynamics in clinical cohorts. It extended over 4 days in the seaside town of Malahide, Ireland. The scientific sessions covered a broad range of topics, including: 1) HIV pathogenesis and control, 2) reservoirs and viral expression, 3) pediatric reservoirs, 4) innate immunity and B cell responses, 5) environmental factors affecting pathogenesis, 6) loss of virologic control, and 7) HIV-2. The following article provides a brief summary of the meeting proceedings and includes a supplementary document with the meeting abstracts., Competing Interests: The authors report no competing financial interests., (Copyright © 2023 Pathogens and Immunity.)

Objectives: HIV elite controllers (ECs) are a unique subgroup of HIV‐positive patients who are long‐term virologically suppressed in the absence of antiretroviral treatment (ART). The prevalence of this subgroup is estimated to be < 1%. Various cohorts of ECs have been described in developed countries, most of which have been demographically heterogeneous. The aim of this study was to identify ECs in two large African cohorts and to estimate their prevalence in a relatively genetically homogenous population. Methods: We screened two cohorts of HIV‐positive Ethiopian patients. The first cohort resided in Mekelle, Ethiopia. The second was comprised of HIV‐positive Ethiopian immigrants in Israel. In the Mekelle cohort, ART‐naïve subjects with stable CD4 counts were prospectively screened using two measurements of viral load 6 months apart. Subjects were defined as ECs when both measurements were undetectable. In the Israeli cohort, subjects with consistently undetectable viral loads (mean of 17 viral load measurements/patient) and stable CD4 count > 500 cells/μL were defined as ECs. Results: In the Mekelle cohort, 16 of 9515 patients (0.16%) fitted the definition of EC, whereas seven of 1160 (0.6%) in the Israeli cohort were identified as ECs (P = 0.011). Conclusions: This is the first large‐scale screening for HIV‐positive ECs to be performed in entirely African cohorts. The overall prevalence of ECs is within the range of that previously described in developing countries. The significant difference in prevalence between the two cohorts of similar genetic background is probably a consequence of selection bias but warrants further investigation into possible environmental factors which may underlie the EC state. [ABSTRACT FROM AUTHOR]

HIV-1 mucosal transmission in genital epithelia occurs through infection of Langerhans cells and subsequent transinfection of CD4+ T cells. We previously reported that the vasodilator neuropeptide calcitonin gene-related peptide (CGRP), secreted upon activation of sensory peripheral neurons that innervate all mucosal epithelia, significantly inhibits transinfection. To investigate the association between CGRP and HIV-1 during infection, we evaluated circulating CGRP levels in HIV-1-infected patients. Plasma was obtained from combination antiretroviral therapy (cART)-naive or cART-treated patients with primary/acute (PHI) or chronic (CHI) HIV-1 infection, as well as from individuals who naturally control HIV-1 infection, namely exposed seronegatives (ESNs), elite controllers (ECs), and long-term nonprogressors (LTNPs). CGRP plasma levels were measured using an enzyme immunoassay. Compared with healthy HIV-1-negative controls, CGRP plasma levels significantly decreased in PHI patients and even further in CHI patients, but remained unchanged in ESNs, ECs, and LTNPs. Moreover, CGRP plasma levels were restored to baseline upon cART in both PHI and CHI. Finally, CGRP plasma levels directly correlated with CD4+ T cell counts and inversely with viral loads. Altogether, CGRP could serve as a novel diagnostic plasma biomarker for progression of HIV-1 infection. Moreover, administration of CGRP to cART-naive HIV-1-infected patients, to compensate for CGRP decline, could help controlling on-going HIV-1 infection. [ABSTRACT FROM AUTHOR]

Background: Throughout the world, there are antiretroviral therapy–naive HIV+ individuals who maintain elevated peripheral CD4+ T-cell counts, historically referred to as long-term nonprogressors (LTNPs). With recent improvements in viral load (VL) detection methods to levels as low as 20 copies per milliliter, 2 subsets of LTNPs have been defined: elite controllers (ECs), with undetectable VLs for at least 6–12 months, and viremic controllers (VCs), with VLs between 200 and 2000 copies per milliliter. ECs and VCs have been extensively studied in the developed world to determine underlying mechanisms responsible for virologic control. In sub-Saharan Africa, most studies have characterized LTNPs based on immunologic criteria making it difficult to compare findings with the Western cohorts, which use virologic criteria. Here, we describe a cohort of Uganda ECs and VCs attending a large HIV ambulatory center in Kampala, Uganda, based initially on CD4 counts and confirmed by repeated VL measurements. Methods: A cross-sectional study was conducted among 14,492 HIV-infected, antiretroviral therapy–naive individuals aged 18 years and older under care for at least 5 years with serial peripheral CD4 counts ≥500 cells/μL. Among those, we determined the frequency of individuals with VLs <2000 copies per milliliter for at least 6 months. Results: We report a prevalence of 0.26% (38/14,492) of HIV controllers in the clinic. We identified 36 ECs and 2 VCs. These individuals were middle-aged with an average CD4 count of 858 ± 172 (mean ± SD, 95% confidence interval: 795 to 921). Their average duration in HIV care was 7.4 ± 2.1 years (mean ± SD, 95% confidence interval: 6.6 to 8.1). The majority of EC/VCs were women (87%, 33/38), reflecting the demographics of the urban clinic. Conclusions: For the first time, this study demonstrates the frequency of EC/VCs in a large urban clinic in Uganda. Further study of these East African subjects may provide insights into how some individuals are able to control HIV in the absence of medications. [ABSTRACT FROM AUTHOR]

Our aim was to analyze the relationship between plasma inflammatory biomarkers and CD4+ T-cells evolution in human immunodeficiency virus (HIV) elite controllers (HIV-ECs) with a suppressed viremia. We carried out a retrospective study in 30 HIV-ECs classified into two groups: those showing no significant loss of CD4+ T-cells during the observation period (stable CD4+, n = 19) and those showing a significant decrease of CD4+ T-cells (decline CD4+, n = 11). Baseline plasma biomarkers were measured using a multiplex immunoassay: sTNF-R1, TRAIL, sFas (APO), sFasL, TNF-α, TNF-β, IL-8, IL-18, IL-6, IL-10, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, SDF1α, GRO-α, and CCL11. Baseline levels of sTNF-R1 and CCL11 and sTNF-R1/TNF-α ratio correlated with the slope of CD4+ T-cells (cells/μl/year) during follow-up [r = −0.370 (p = 0.043), r = −0.314 (p = 0.091), and r = −0.381 (p = 0.038); respectively]. HIV-ECs with declining CD4+ T-cells had higher baseline plasma levels of sTNF-R1 [1,500.7 (555.7; 2,060.7) pg/ml vs. 450.8 (227.9; 1,263.9) pg/ml; p = 0.018] and CCL11 [29.8 (23.5; 54.9) vs. 19.2 (17.8; 29.9) pg/ml; p = 0.041], and sTNF-R1/TNF-α ratio [84.7 (33.2; 124.2) vs. 25.9 (16.3; 75.1); p = 0.012] than HIV-1 ECs with stable CD4+ T-cells. The area under the receiver operating characteristic (ROC) curve [area under ROC curve (AUROC)] were 0.758 ± 0.093 (sTNF-R1), 0.727 ± 0.096 (CCL11), and 0.777 ± 0.087 (sTNF-R1/TNF-α). The cut-off of 75th percentile (high values) for these biomarkers had 71.4% positive predictive value and 73.9% negative predictive value for anticipating the evolution of CD4+ T-cells. In conclusion, the loss of CD4+ T-cells in HIV-ECs was associated with higher levels of two plasma inflammatory biomarkers (sTNF-R1 and CCL11), which were also reasonably accurate for the prediction of the CD4+ T-cells loss. [ABSTRACT FROM AUTHOR]

CD8 T lymphocytes can reduce the production of human immunodeficiency virus 1 (HIV-1) by CD4 T cells by cytotoxic and non-cytotoxic mechanisms. To investigate the involvement of human leukocyte antigen (HLA) class I compatibility in anti-HIV responses, we co-cultured primary CD8 T cells, isolated from the peripheral blood of HIV-1-infected individuals, with panels of autologous and heterologous acutely HIV-1-infected primary CD4 T cells. Altogether, CD8 T cell anti-HIV activity was evaluated in more than 200 co-cultures. Marked heterogeneity in HIV-1 replication levels was observed among the co-cultures sharing a common CD8 T cell source. The co-cultures that exhibited greater than 50% reduction in HIV production were found to have significantly increased numbers of matching HLA class I alleles (Yates chi-square = 54.21; p < 0.001). With CD8 T cells from HIV controllers and asymptomatic viremic individuals, matching HLA-B and/or HLA-C alleles were more predictive of strong anti-HIV activity than matching HLA-A alleles. Overall, HLA class I genotype matches were more closely associated with CD8 T cell anti-HIV activity than supertype pairings. Antibodies against HLA class I and CD3 reduced the CD8 T cell anti-HIV activity. Stimulated CD8 T cells exhibited increased anti-HIV activity and reduced dependency on HLA compatibility. These findings provide evidence that the maximal suppression of HIV replication by CD8 T cells requires the recognition of multiple epitopes. These studies provide insight for HIV vaccine development, and the analytic approach can be useful for the functional characterization of HLA class I alleles and tentative HLA class I supertypes. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type-1 (HIV-1) elite controllers (ELCs) represent a unique population that control viral replication in the absence of antiretroviral therapy (cART). It is well established that expression of multiple inhibitory receptors on CD8+ T cells is associated with HIV-1 disease progression. However, whether reduced co-expression of inhibitory receptors on CD4+ T cells is linked to natural viral control and slow HIV-1 disease progression remains undefined. Here, we report on the expression pattern of numerous measurable inhibitory receptors, associated with T cell exhaustion (programmed cell death-1, CTLA-4, and TIGIT), on different CD4+ T cell memory populations in ELCs and HIV-infected subjects with or without long-term cART. We found that the co-expression pattern of inhibitory receptors was significantly reduced in ELCs compared with HIV-1 cART-treated and viremic subjects, and similar to healthy controls. Markers associated with T cell exhaustion varied among different memory CD4+ T cell subsets and highest levels were found mainly on transitional memory T cells. CD4+ T cells co-expressing all inhibitory markers were positively correlated to T cell activation (CD38+ HLA-DR+) as well as the transcription factors Helios and FoxP3. Finally, clinical parameters such as CD4 count, HIV-1 viral load, and the CD4/CD8 ratio all showed significant associations with CD4+ T cell exhaustion. We demonstrate that ELCs are able to maintain lower levels of CD4+ T cell exhaustion despite years of ongoing viral replication compared with successfully cART-treated subjects. Our findings suggest that ELCs harbor a “healthy” state of inhibitory receptor expression on CD4+ T cells that might play part in maintenance of their control status.

HIV-1 controllers (HIC) are extremely rare patients with the ability to control viral replication, maintain unchanging CD4 T-cell count, and evade disease progression for extensive periods of time, in the absence of antiretroviral therapy. In order to establish the representation of key genetic correlates of atypical disease progression within a cohort of HIV-1+ individuals who control viral replication, we examine four-digit resolution HLA type and single-nucleotide polymorphisms (SNP) previously identified to be correlated to non-progressive infection, in strictly defined HIC. Clinical histories were examined to identify patients exhibiting HIC status. Genomic DNA was extracted, and high definition HLA typing and genome-wide SNP analysis was performed. Data were compared with frequencies of SNP in European long-term non-progressors (LTNP) and primary infection cohorts. HLA-B alleles associated with atypical disease progression were at very high frequencies in the group of five HIC studied. All four HIC of European ancestry were HLA-B*57+ and half were also HLA-B*27+. All HIC, including one of self-reported African ethnicity, had the HLA-Cw*0602 allele, and the HLA-DQ9 allele was present only in HIC of European ancestry. A median 95% of the top 19 SNP known to be associated with LTNP status was observed in European HIC (range 78–100%); 17/19 of the SNP considered mapped to chromosome 6 in the HLA region, whereas 2/19 mapped to chromosome 8. The HIC investigated here demonstrated high enrichment of HLA types and SNP previously associated with long-term non-progression. These findings suggest that the extreme non-progressive phenotype considered here is associated with a genetic signature characterized by a single-genetic unit centered around the HLA-B*57 haplotype and the possible additive effect of HLA-B*27.