TY - JOUR
T1 - Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single gag epitope
AU - Matthews, Philippa C.
AU - Koyanagi, Madoka
AU - Kløverpris, Henrik N.
AU - Harndahl, Mikkel
AU - Stryhn, Anette
AU - Akahoshi, Tomohiro
AU - Gatanaga, Hiroyuki
AU - Oka, Shinichi
AU - Molina, Claudia J.
AU - Ponce, Humberto Valenzuela
AU - Rios, Santiago Avila
AU - Cole, David
AU - Carlson, Jonathan
AU - Payne, Rebecca P.
AU - Ogwu, Anthony
AU - Bere, Alfred
AU - Ndung'u, Thumbi
AU - Gounder, Kamini
AU - Chen, Fabian
AU - Riddell, Lynn
AU - Luzzi, Graz
AU - Shapiro, Roger
AU - Brander, Christian
AU - Walker, Bruce
AU - Sewell, Andrew K.
AU - Teran, Gustavo R.
AU - Heckerman, David
AU - Hunter, Eric
AU - Buus, Søren
AU - Takiguchi, Masafumi
AU - Goulder, Philip J.R.
PY - 2012/12/1
Y1 - 2012/12/1
N2 - 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. © 2012, American Society for Microbiology.
AB - 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. © 2012, American Society for Microbiology.
U2 - 10.1128/JVI.01381-12
DO - 10.1128/JVI.01381-12
M3 - Article
SN - 0022-538X
VL - 86
SP - 12643
EP - 12654
JO - Journal of Virology
JF - Journal of Virology
IS - 23
ER -