Project description:Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57(+)) slow progressors and B57(+) rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57(+) individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57.
Project description:BACKGROUND:Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness consequences of human leukocyte antigen (HLA) class I-associated escape mutations in Gag may contribute to this phenotype. This study examines whether similar functional defects occur in Pol proteins of elite controllers. METHODS:Recombinant NL4-3 viruses encoding plasma RNA-derived reverse transcriptase-integrase sequences from 58 elite controllers and 50 untreated chronic progressors were constructed, and replication capacity measured in vitro using a green fluorescent protein (GFP) reporter T-cell assay. Sequences were analyzed for drug resistance and HLA-associated viral polymorphisms. RESULTS:Controller-derived viruses displayed significantly lower replication capacity compared with those from progressors (P < 0.0001). Among controllers, the most attenuated viruses were generated from individuals expressing HLA-B*57 or B*51. In viruses from B*57+ progressors (n = 8), a significant inverse correlation was observed between B*57-associated reverse transcriptase-integrase escape mutations and replication capacity (R = -0.89; P = 0.003); a similar trend was observed in B*57+ controller-derived viruses (n = 20, R = -0.36; P = 0.08). CONCLUSIONS:HIV-1 Pol function seemed to be compromised in elite controllers. As observed previously for Gag, HLA-associated immune pressure in Pol may contribute to viral attenuation and subsequent control of viremia.
Project description:Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8(+) T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8(+) T-cell specificity and function of B*27/57(neg) LTNP/EC (n = 23), B*27/57(pos) LTNP/EC (n = 23) and B*27/57(neg) progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57(neg) LTNP/EC did not target more highly conserved epitopes, their CD8(+) T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57(pos) LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8(+) T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people.
Project description:During chronic human immunodeficiency virus (HIV) infection, virus-specific CD8(+) T cells become functionally exhausted. Unlike most chronically infected individuals, elite controllers of HIV retain CD8(+) T-cell polyfunctionality and cytolytic capacity. It remains unclear whether elite controllers manifest T-cell exhaustion similar to subjects with chronic progression of HIV infection. Here we assessed coexpression of PD-1, Lag-3, CD160, and 2B4 as a measure of T-cell exhaustion in a cohort of elite controllers and in chronic progressors. We found that elite controllers have a high proportion of potentially exhausted (PD1(+)CD160(+)2B4(+)) HIV-specific CD8(+) T cells that is comparable to the proportion in chronic progressors. However, elite controllers also harbor a population of HIV-specific CD160(+)2B4(+) CD8(+) T cells that correlates with cytolytic capacity, as measured by perforin expression, a population not commonly present in chronic progressors. We therefore propose that coexpression of CD160 and 2B4 delineates a population of cytolytic CD8(+) T cells important for the control of HIV.
Project description:Elite controllers or suppressors have the remarkable capacity to maintain HIV-1 plasma RNA levels below the limit of detection of clinical assays (<50 copies/mL) without therapy and have a lower frequency of latently infected cells compared to chronic progressors. While it is unclear how this reduced seeding of the reservoir is achieved, it is possible that effective CTL responses play an in important role in limiting the size of the latent reservoir.Herein, we demonstrate that primary CD8+ T cells from HLA-B*57/5801 elite suppressors were able to efficiently eliminate resting and activated primary CD4+ T cells shortly after viral entry and prior to productive infection. CD8+ T cells from elite suppressors were significantly more effective at eliminating these cells than CD8+ T cells from chronic progressors.Nonproductively infected CD4+ T cells may represent a subpopulation of cells that are precursors to latently infected cells; therefore, the effective elimination of these cells may partially explain why elite suppressors have a much lower frequency of latently infected cells compared to chronic progressors. Thus, a vaccine strategy that elicits early and potent CD8+ T cell responses may have the capacity to limit the seeding of the latent reservoir in HIV-1 infection.
Project description:Variability to HIV infection, its progression as well as responsiveness to antiretroviral therapy (ART) is observed among individuals including viraemia controllers or exposed uninfected, rapid versus slow progressors and ART responders compared to non responders. This differential responsiveness/vulnerability to HIV-1 is governed by multiple host genetic factors that include HLA, cytokines, chemokines, their receptors and others. This review highlights the influence of these genetic factors on HIV/AIDS outcome; however, in India, the information in this area is very limited and most of these genetic studies have been conducted in Caucasian and South African populations. Considering the population-specific differences in the frequencies of protective or susceptibility favouring alleles and their influence on the disease outcome, it is of utmost importance to strengthen ongoing efforts towards defining largely unknown genetic propensity in Indian population, particularly by recruitment of large cohorts of well categorized exposed uninfected individuals, rapid, long term non progressors and elite viraemic controllers. Multi-parametric analysis of these potentially interactive immunogenetic variables in these cohorts may help to define potential targets for diagnostics and therapy in a population specific manner.
Project description:We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment.Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. ?-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected.Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.
Project description:Studies have investigated CCR5 haplotypes (HHA, HHB, HHC, HHD, HHE, HHF*1, HHF*2, HHG*1, HHG*2), defined by seven 5'UTR single nucleotide polymorphisms (SNPs), CCR2-V64I and CCR5?32, in HIV-1 disease. CCR5 cis-regulatory regions were sequenced, CCR2-V64I and CCR5?32 genotyped, and compared in HIV-1-infected black South Africans: 71 HIV-1 controllers (23 elite controllers, 37 viraemic controllers (VCs), 11 high viral load long-term non-progressors) and 74 progressors. The HHE haplotype and 3'UTR +2919?T?>?G SNP heterozygosity were underrepresented in total controllers and VCs vs. progressors (p?=?.004; p?=?.007 and p?=?.002, pbonferroni?=?0.032; p?=?.004, respectively). Possession of the +2919?T?>?G SNP (dominant mode) was associated with HIV-1 progression (controllers vs. progressors: p?=?.001, pbonferroni?=?0.016). The +2919?T?>?G SNP is in linkage disequilibrium (LD; r2?=?0.73) with two 5'UTR SNPs (-2459G?>?A and -2135?T?>?C; r2?=?1: 5'UTR-2SNP-hap). The 5'UTR-2SNP-hap was lower in total controllers and VCs vs. progressors (p?=?.003, pbonferroni?=?0.048; p?=?.01, respectively). Results suggest -2459G?>?A, -2135?T?>?C, and?+?2919?T?>?G as key CCR5 variants in HIV-1 control.