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 Kløverpris; Mikkel Harndahl; Anette Stryhn Buus; Tomohiro Akahoshi; Hiroyuki Gatanaga; Shinichi Oka; Claudia Juarez Molina; Humberto Valenzuela Ponce; Santiago Avila Rios; David Cole; Jonathan Carlson; Rebecca P Payne; Anthony Ogwu; Alfred Bere; Thumbi Ndung'u; Kamini Gounder; Fabian Chen; Lynn Riddell; Graz Luzzi; Roger Shapiro; Christian Brander; Bruce Walker; Andrew K Sewell; Gustavo Reyes Teran; David Heckerman; Eric Hunter; Søren Buus; Masafumi Takiguchi; Philip J R Goulder

doi:10.1128/JVI.01381-12

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 Kløverpris, Mikkel Harndahl, Anette Stryhn Buus, Tomohiro Akahoshi, Hiroyuki Gatanaga, Shinichi Oka, Claudia Juarez Molina, Humberto Valenzuela Ponce, Santiago Avila Rios, David Cole, Jonathan Carlson, Rebecca P Payne, Anthony Ogwu, Alfred Bere, Thumbi Ndung'u, Kamini Gounder, Fabian Chen, Lynn RiddellGraz Luzzi, Roger Shapiro, Christian Brander, Bruce Walker, Andrew K Sewell, Gustavo Reyes Teran, David Heckerman, Eric Hunter, Søren Buus, Masafumi Takiguchi, Philip J R Goulder

Department of Immunology and Microbiology

33 Citations (Scopus)

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.

Original language	English
Journal	Journal of Virology
Volume	86
Issue number	23
Pages (from-to)	12643-12654
Number of pages	12
ISSN	0022-538X
DOIs	https://doi.org/10.1128/JVI.01381-12
Publication status	Published - Dec 2012

Keywords

Africa, Southern
CD8-Positive T-Lymphocytes
Disease Progression
Enzyme-Linked Immunospot Assay
Epitopes, T-Lymphocyte
Flow Cytometry
Gene Products, gag
Great Britain
HIV Infections
HIV-1
HLA-B35 Antigen
Humans
Japan
Mexico
Phylogeny
Viral Load

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1128/JVI.01381-12

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Matthews, P. C., Koyanagi, M., Kløverpris, H. N., Harndahl, M., Buus, A. S., Akahoshi, T., Gatanaga, H., Oka, S., Juarez Molina, C., Valenzuela Ponce, H., Avila Rios, S., Cole, D., Carlson, J., Payne, R. P., Ogwu, A., Bere, A., Ndung'u, T., Gounder, K., Chen, F., ... Goulder, P. J. R. (2012). Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope. Journal of Virology, 86(23), 12643-12654. https://doi.org/10.1128/JVI.01381-12

Matthews, PC, Koyanagi, M, Kløverpris, HN, Harndahl, M, Buus, AS, Akahoshi, T, Gatanaga, H, Oka, S, Juarez Molina, C, Valenzuela Ponce, H, Avila Rios, S, Cole, D, Carlson, J, Payne, RP, Ogwu, A, Bere, A, Ndung'u, T, Gounder, K, Chen, F, Riddell, L, Luzzi, G, Shapiro, R, Brander, C, Walker, B, Sewell, AK, Reyes Teran, G, Heckerman, D, Hunter, E, Buus, S, Takiguchi, M & Goulder, PJR 2012, 'Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope', Journal of Virology, vol. 86, no. 23, pp. 12643-12654. https://doi.org/10.1128/JVI.01381-12

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title = "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.",

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author = "Matthews, {Philippa C} and Madoka Koyanagi and Kl{\o}verpris, {Henrik N} and Mikkel Harndahl and Buus, {Anette Stryhn} and Tomohiro Akahoshi and Hiroyuki Gatanaga and Shinichi Oka and {Juarez Molina}, Claudia and {Valenzuela Ponce}, Humberto and {Avila Rios}, Santiago and David Cole and Jonathan Carlson and Payne, {Rebecca P} and Anthony Ogwu and Alfred Bere and Thumbi Ndung'u and Kamini Gounder and Fabian Chen and Lynn Riddell and Graz Luzzi and Roger Shapiro and Christian Brander and Bruce Walker and Sewell, {Andrew K} and {Reyes Teran}, Gustavo and David Heckerman and Eric Hunter and S{\o}ren Buus and Masafumi Takiguchi and Goulder, {Philip J R}",

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language = "English",

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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

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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

SN - 0022-538X

VL - 86

SP - 12643

EP - 12654

JO - Journal of Virology

JF - Journal of Virology

IS - 23

ER -

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

Abstract

Keywords

UN SDGs

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