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Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope.

ABSTRACT: The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8(+) T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P = 2 × 10(-5)). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ?90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8(+) T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8(+) T-cell response in all individuals, irrespective of HLA type.

SUBMITTER: Matthews PC

PROVIDER: S-EPMC3497693 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope.

Matthews Philippa C PC Koyanagi Madoka M Kløverpris Henrik N HN Harndahl Mikkel M Stryhn Anette A Akahoshi Tomohiro T Gatanaga Hiroyuki H Oka Shinichi S Juarez Molina Claudia C Valenzuela Ponce Humberto H Avila Rios Santiago S Cole David D Carlson Jonathan J Payne Rebecca P RP Ogwu Anthony A Bere Alfred A Ndung'u Thumbi T Gounder Kamini K Chen Fabian F Riddell Lynn L Luzzi Graz G Shapiro Roger R Brander Christian C Walker Bruce B Sewell Andrew K AK Reyes Teran Gustavo G Heckerman David D Hunter Eric E Buus Søren S Takiguchi Masafumi M Goulder Philip J R PJ

Journal of virology 20120912 23

The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not ho ...[more]

PMID: 22973023

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Dataset Information

Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope.

Publications

Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope.

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