Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children

Goulder, Philip; Berthou, Christian; Annamalai, Ken; Mngqundaniso, Nolwandle; Govender, Ugene; Tang, Yanhua; He, Suqin; Hartman, Kelly E.; O’Callaghan, Chris; Ogg, Graham S.; Altfeld, Marcus; Rosenberg, Eric S.; Cao, Huyen; Kalams, Spyros A.; Hammond, M. G.; Bunce, Mike; Pelton, Stephen I.; Burchett, Sandra; McIntosh, Kenneth; Coovadia, Hoosen M.; Walker, Bruce D.

doi:10.1128/jvi.74.12.5679-5690.2000

Cited by 109 publications

(106 citation statements)

References 65 publications

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“…Two separate studies have shown that while p17 is highly targeted in subtype B HIV-1-infected individuals, p24 was mostly targeted by subtype C-infected individuals in Africa (39,40). In contrast, we identified epitope-rich regions in both p17 and p24 that are targeted by CD8 ϩ T cells, and the peptide stretch, TGTEELRSLYNTVATLYCVHAGIEV, in p17 was recognized at the highest frequency (35%) and contained multiple epitopes.…”

Section: Discussionmentioning

confidence: 77%

Novel and Promiscuous CTL Epitopes in Conserved Regions of Gag Targeted by Individuals with Early Subtype C HIV Type 1 Infection from Southern Africa

Masemola

Mashishi

Khoury

et al. 2004

The Journal of Immunology

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Characterization of optimal CTL epitopes in Gag can provide crucial information for evaluation of candidate vaccines in populations at the epicenter of the HIV-1 epidemic. We screened 38 individuals with recent subtype C HIV-1 infection using overlapping consensus C Gag peptides and hypothesized that unique HLA-restricting alleles in the southern African population would determine novel epitope identity. Seventy-four percent of individuals recognized at least one Gag peptide pool. Ten epitopic regions were identified across p17, p24, and p2p7p1p6, and greater than two-thirds of targeted regions were directed at: TGTEELRSLYNTVATLY (p17, 35%); GPKEPFRDYVDRFFKTLRAEQATQDV (p24, 19%); and RGGKLDKWEKIRLRPGGKKHYMLKHL (p17, 15%). After alignment of these epitopic regions with consensus M and a consensus subtype C sequence from the cohort, it was evident that the regions targeted were highly conserved. Fine epitope mapping revealed that five of nine identified optimal Gag epitopes were novel: HLVWASREL, LVWASRELERF, LYNTVATLY, PFRDYVDRFF, and TLRAEQATQD, and were restricted by unique HLA-Cw*08, HLA-A*30/B*57, HLA-A*29/B*44, and HLA-Cw*03 alleles, respectively. Notably, three of the mapped epitopes were restricted by more than one HLA allele. Although these epitopes were novel and restricted by unique HLA, they overlapped or were embedded within previously described CTL epitopes from subtype B HIV-1 infection. These data emphasize the promiscuous nature of epitope binding and support our hypothesis that HLA diversity between populations can shape fine epitope identity, but may not represent a constraint for universal recognition of Gag in highly conserved domains.

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Section: Discussionmentioning

confidence: 77%

Novel and Promiscuous CTL Epitopes in Conserved Regions of Gag Targeted by Individuals with Early Subtype C HIV Type 1 Infection from Southern Africa

Masemola

Mashishi

Khoury

et al. 2004

The Journal of Immunology

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“…Increasing evidence suggests that a comprehensive assessment of CD8 ϩ T cell responses against HIV-1 is necessary to interpret the entire magnitude and breadth of these responses (8,16). We have recently demonstrated that the use of overlapping peptide spanning the HIV-1 structural as well as regulatory proteins allows for a detailed characterization of HIV-1-specific CTL responses and the identification of novel CTL epitopes within these proteins (9,16,23,24,27,36). However, the relative contribution of CTL responses directed against the accessory HIV-1 proteins Vpr, Vpu, and Vif have not been studied to date.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were added to the wells at 50,000 -100,000 cells/well. The plates were incubated at 37°C, 5% CO 2 overnight (14 -16 h) and then processed as described (23,24). IFN-␥-producing cells were counted by direct visualization and are expressed as spot-forming cells (SFCs) per 10 6 cells.…”

Section: Elispot Assaymentioning

confidence: 99%

Vpr Is Preferentially Targeted by CTL During HIV-1 Infection

Altfeld

Addo

Eldridge

et al. 2001

The Journal of Immunology

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101

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The HIV-1 accessory proteins Vpr, Vpu, and Vif are essential for viral replication, and their cytoplasmic production suggests that they should be processed for recognition by CTLs. However, the extent to which these proteins are targeted in natural infection, as well as precise CTL epitopes within them, remains to be defined. In this study, CTL responses against HIV-1 Vpr, Vpu, and Vif were analyzed in 60 HIV-1-infected individuals and 10 HIV-1-negative controls using overlapping peptides spanning the entire proteins. Peptide-specific IFN-γ production was measured by ELISPOT assay and flow-based intracellular cytokine quantification. HLA class I restriction and cytotoxic activity were confirmed after isolation of peptide-specific CD8+ T cell lines. CD8+ T cell responses against Vpr, Vpu, and Vif were found in 45%, 2%, and 33% of HIV-1-infected individuals, respectively. Multiple CTL epitopes were identified in functionally important regions of HIV-1 Vpr and Vif. Moreover, in infected individuals in whom the breadth of HIV-1-specific responses was assessed comprehensively, Vpr and p17 were the most preferentially targeted proteins per unit length by CD8+ T cells. These data indicate that despite the small size of these proteins Vif and Vpr are frequently targeted by CTL in natural HIV-1 infection and contribute importantly to the total HIV-1-specific CD8+ T cell responses. These findings will be important in evaluating the specificity and breadth of immune responses during acute and chronic infection, and in the design and testing of candidate HIV vaccines.

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“…The region of HIV-1 Gag corresponding to peptide 46 contributes to the total immune response in HIV-1 infection in terms of frequency of recognition (35), immunodominance (18,36), and avidity (22). This frequently targeted and highly immunogenic region of Gag can be restricted by both CD4 (21, 37) and CD8 (35) T cells as well as by a variety of HLA haplotypes (38).…”

Section: Figurementioning

confidence: 99%

Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection

Leligdowicz

Yindom²,

Onyango³

et al. 2007

J. Clin. Invest.

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Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children

Cited by 109 publications

References 65 publications

Novel and Promiscuous CTL Epitopes in Conserved Regions of Gag Targeted by Individuals with Early Subtype C HIV Type 1 Infection from Southern Africa

Novel and Promiscuous CTL Epitopes in Conserved Regions of Gag Targeted by Individuals with Early Subtype C HIV Type 1 Infection from Southern Africa

Vpr Is Preferentially Targeted by CTL During HIV-1 Infection

Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection

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