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 - Buus, Anette Stryhn

AU - Akahoshi, Tomohiro

AU - Gatanaga, Hiroyuki

AU - Oka, Shinichi

AU - Juarez Molina, Claudia

AU - Valenzuela Ponce, Humberto

AU - Avila Rios, Santiago

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 - Reyes Teran, Gustavo

AU - Heckerman, David

AU - Hunter, Eric

AU - Buus, Søren

AU - Takiguchi, Masafumi

AU - Goulder, Philip J R

PY - 2012/12

Y1 - 2012/12

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.

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.

KW - Africa, Southern

KW - CD8-Positive T-Lymphocytes

KW - Disease Progression

KW - Enzyme-Linked Immunospot Assay

KW - Epitopes, T-Lymphocyte

KW - Flow Cytometry

KW - Gene Products, gag

KW - Great Britain

KW - HIV Infections

KW - HIV-1

KW - HLA-B35 Antigen

KW - Humans

KW - Japan

KW - Mexico

KW - Phylogeny

KW - Viral Load

U2 - 10.1128/JVI.01381-12

DO - 10.1128/JVI.01381-12

M3 - Journal article

C2 - 22973023

VL - 86

SP - 12643

EP - 12654

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 23

ER -