Differential Clade-Specific HLA-B*3501 Association with HIV-1 Disease Outcome Is Linked to Immunogenicity of a Single Gag Epitope
- Philippa C. Matthews ,
- Madoka Koyanagi ,
- Henrik N. Kloverpris ,
- Mikkel Harndahl ,
- Anette Stryhn ,
- Tomohiro Akahoshi ,
- Hiroyuki Gatanaga ,
- Shinichi Oka ,
- Claudia Juarez Molina ,
- Humberto Valenzuela Ponce ,
- Santiago Avila Rios ,
- David Cole ,
- Jonathan M. Carlson ,
- Rebecca P. Payne ,
- Anthony Ogwu ,
- Alfred Bere ,
- Thumbi Ndung'u ,
- Kamini Gounder ,
- Fabian Chen ,
- Lynn Riddell ,
- Graz Luzzi ,
- Roger Shaprio ,
- Christian Brander ,
- Bruce Walker ,
- Andrew K. sewell ,
- Gustavo Reyes Teran ,
- David Heckerman ,
- Eric Hunter ,
- Soren Buus ,
- Masafumi Takiguchi ,
- Philip J.R. Goulder
Journal of Virololgy | , Vol 86(23): pp. 12643-12654
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.