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Targeting of conserved gag-epitopes in early HIV infection is associated with lower plasma viral load and slower CD4(+) T cell depletion.

ABSTRACT: We aimed to investigate whether the character of the immunodominant HIV-Gag peptide (variable or conserved) targeted by CD8(+) T cells in early HIV infection would influence the quality and quantity of T cell responses, and whether this would affect the rate of disease progression. Treatment-naive HIV-infected study subjects within the OPTIONS cohort at the University of California, San Francisco, were monitored from an estimated 44 days postinfection for up to 6 years. CD8(+) T cells responses targeting HLA-matched HIV-Gag-epitopes were identified and characterized by multicolor flow cytometry. The autologous HIV gag sequences were obtained. We demonstrate that patients targeting a conserved HIV-Gag-epitope in early infection maintained their epitope-specific CD8(+) T cell response throughout the study period. Patients targeting a variable epitope showed decreased immune responses over time, although there was no limitation of the functional profile, and they were likely to target additional variable epitopes. Maintained immune responses to conserved epitopes were associated with no or limited sequence evolution within the targeted epitope. Patients with immune responses targeting conserved epitopes had a significantly lower median viral load over time compared to patients with responses targeting a variable epitope (0.63 log(10) difference). Furthermore, the rate of CD4(+) T cell decline was slower for subjects targeting a conserved epitope (0.85% per month) compared to subjects targeting a variable epitope (1.85% per month). Previous studies have shown that targeting of antigens based on specific HLA types is associated with a better disease course. In this study we show that categorizing epitopes based on their variability is associated with clinical outcome.

SUBMITTER: Perez CL

PROVIDER: S-EPMC3581067 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Targeting of conserved gag-epitopes in early HIV infection is associated with lower plasma viral load and slower CD4(+) T cell depletion.

Perez Carina L CL Milush Jeffrey M JM Buggert Marcus M Eriksson Emily M EM Larsen Mette V MV Liegler Teri T Hartogensis Wendy W Bacchetti Peter P Lund Ole O Hecht Frederick M FM Nixon Douglas F DF Karlsson Annika C AC

AIDS research and human retroviruses 20130108 3

We aimed to investigate whether the character of the immunodominant HIV-Gag peptide (variable or conserved) targeted by CD8(+) T cells in early HIV infection would influence the quality and quantity of T cell responses, and whether this would affect the rate of disease progression. Treatment-naive HIV-infected study subjects within the OPTIONS cohort at the University of California, San Francisco, were monitored from an estimated 44 days postinfection for up to 6 years. CD8(+) T cells responses ...[more]

PMID: 23140171

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Project description:Deleterious mutations occur frequently in eukaryotes, resulting in individuals carrying multiple alleles that decrease their fitness. At a population level, if unchecked, accumulation of this mutation load can ultimately lead to extinction. How selection counters the accumulation of mutation load, limiting declines in population fitness, is not well understood. Here, we use manipulative experiments in zebrafish (Danio rerio) to investigate the opportunities for selection on mutation load. Inducing high mutation load through mutagenesis, we applied one generation of within-family selection on locomotor performance and characterized both the direct response to this selection and the indirect response of reproductive success. Offspring of slow swimming parents exhibited age-dependent declines in swimming speed, whereas their cousins, with faster swimming parents, did not. This pattern mimics previously documented differences between high and low mutation load populations of zebrafish, suggesting that slow swimming siblings inherited (and transmitted) more mutations than their faster swimming siblings. Crosses among offspring of slow swimming fish had, on average, <75% of the reproductive success of crosses among offspring of fast swimming parents, or crosses of offspring of slow swimmers with offspring of fast swimmers. This evidence of mutationally correlated swimming speed and reproductive success reveals the potential for concordant selection on mutation load through different fitness components. There was no evidence that crosses within families (where parents potentially shared the same mutations inherited from their common ancestor) had lower reproductive success than crosses among families, suggesting that viability selection was not acting predominantly through lethal recessive homozygotes. Rather, patterns of reproductive success are suggestive of effects of mutation number per se on embryo viability. Overall, our results highlight the potential for early life mortality to remove deleterious mutations, and the need to account for this mortality when investigating the evolutionary dynamics of mutation load.

Project description:BACKGROUND: The human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) immune response is one of the major factors determining the genetic diversity of human immunodeficiency virus (HIV). There are few population-based analyses of the amino acid variations associated with the host HLA type and their clinical relevance for the Asian population. Here, we identified HLA-associated polymorphisms in the HIV-1 CRF01_AE Gag protein in infected married couples, and examined the consequences of these HLA-selected mutations after transmission to HLA-unmatched recipients. METHODOLOGY/PRINCIPAL FINDINGS: One hundred sixteen HIV-1-infected couples were recruited at a government hospital in northern Thailand. The 1.7-kb gag gene was amplified and directly sequenced. We identified 56 associations between amino acid variations in Gag and HLA alleles. Of those amino acid variations, 35 (62.5%) were located within or adjacent to regions reported to be HIV-specific CTL epitopes restricted by the relevant HLA. Interestingly, a significant number of HLA-associated amino acid variations appear to be unique to the CRF01_AE-infected Thai population. Variations in the capsid protein (p24) had the strongest associations with the viral load and CD4 cell count. The mutation and reversion rates after transmission to a host with a different HLA environment varied considerably. The p24 T242N variant escape from B57/58 CTL had a significant impact on the HIV-1 viral load of CRF01_AE-infected patients. CONCLUSIONS/SIGNIFICANCE: HLA-associated amino acid mutations and the CTL selection pressures on the p24 antigen appear to have the most significant impact on HIV replication in a CRF01_AE-infected Asian population. HLA-associated mutations with a low reversion rate accumulated as a footprint in this Thai population. The novel HLA-associated mutations identified in this study encourage us to acquire more extensive information about the viral dynamics of HLA-associated amino acid polymorphisms in a given population as effective CTL vaccine targets.

Project description:Dendritic cell (DC) therapy is a promising technology for the treatment of HIV infected individuals. HIV-1 Gag- and Nef RNA-loaded DC have previously been shown to induce immune responses ex vivo following coculture with autologous lymphocytes. However, polyfunctionality and memory responses following coculture have not been evaluated. In addition, little is known regarding whether specific HIV-1 proteome components, such as highly conserved regions of the HIV-1, could enhance clinical responses following DC therapy.To determine the breadth of the immune responses to antigen loaded DC, we analyzed polyfunctional T cell response ex vivo to Gag RNA loaded DC. Blood samples were used to generate monocyte derived DC, which were then matured and cocultured with autologous lymphocytes. We found that cytokine-matured DC loaded with Gag RNA was able to induce Gag-specific IFN-? and IL-2 responses after a 12-day coculture. We characterized these responses by polyfunctional intracellular cytokine staining and evaluation of T cell memory phenotypes. Central memory CD8+ T cells were induced ex vivo after DC coculture from each of 3 patients, and the effector memory pool was increased by DC coculture from 2 patients. We also observed a decrease in the terminal effector and intermediate CD8+ T cell pool and an increase in the naïve/other population. There was a reduction in terminal effector and intermediate CD4+ T cells, and a corresponding increase in naïve/other CD4+ T cells. Finally, we evaluated conserved regions of Gag as a novel DC therapy immunogen and found that a conserved element (CE) p24 Gag antigen elicited IFN-? and IL-2 responses comparable to those induced by a full-length Gag antigen.We showed that RNA-loaded DC therapy induced a polyfunctional T cell response ex vivo, supporting the use of such DC-therapy for HIV infection. However, the central and effector memory phenotypes of T cells did not appear to be enhanced during coculture with Gag RNA-loaded DC. Furthermore, comparable antigen-specific responses were induced in HIV infected individuals using full-length Gag or only conserved elements of the Gag p24 protein. This indicates that immune responses can be focused onto the conserved elements of Gag in the absence of other Gag components.

Dataset Information

Targeting of conserved gag-epitopes in early HIV infection is associated with lower plasma viral load and slower CD4(+) T cell depletion.

Publications

Targeting of conserved gag-epitopes in early HIV infection is associated with lower plasma viral load and slower CD4(+) T cell depletion.

Similar Datasets

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