HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703

Philippa C Matthews; Emily Adland; Jennifer Listgarten; Alasdair Leslie; Nompumelelo Mkhwanazi; Jonathan M Carlson; Mikkel Harndahl; Anette Stryhn Buus; Rebecca P Payne; Anthony Ogwu; Kuan-Hsiang Gary Huang; John Frater; Paolo Paioni; Henrik Kloverpris; Pieter Jooste; Dominique Goedhals; Cloete van Vuuren; Dewald Steyn; Lynn Riddell; Fabian Chen; Graz Luzzi; Thambiah Balachandran; Thumbi Ndung'u; Søren Buus; Mary Carrington; Roger Shapiro; David Heckerman; Philip J R Goulder

doi:10.4049/jimmunol.1003711

HLA-A7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B5703

Philippa C Matthews, Emily Adland, Jennifer Listgarten, Alasdair Leslie, Nompumelelo Mkhwanazi, Jonathan M Carlson, Mikkel Harndahl, Anette Stryhn Buus, Rebecca P Payne, Anthony Ogwu, Kuan-Hsiang Gary Huang, John Frater, Paolo Paioni, Henrik Kloverpris, Pieter Jooste, Dominique Goedhals, Cloete van Vuuren, Dewald Steyn, Lynn Riddell, Fabian ChenGraz Luzzi, Thambiah Balachandran, Thumbi Ndung'u, Søren Buus, Mary Carrington, Roger Shapiro, David Heckerman, Philip J R Goulder

Department of Immunology and Microbiology

41 Citations (Scopus)

Abstract

The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.

Original language	English
Journal	Journal of Immunology
Volume	186
Issue number	10
Pages (from-to)	5675-86
Number of pages	12
ISSN	1550-6606
DOIs	https://doi.org/10.4049/jimmunol.1003711
Publication status	Published - 15 May 2011

Keywords

Africa
Alleles
CD4 Lymphocyte Count
CD8-Positive T-Lymphocytes
Epitopes, T-Lymphocyte
Female
Flow Cytometry
HIV Infections
HIV-1
HLA-A Antigens
HLA-B Antigens
Humans
Linkage Disequilibrium
Molecular Sequence Data
Sequence Analysis, Protein
Viral Load
Viremia
gag Gene Products, Human Immunodeficiency Virus
nef Gene Products, Human Immunodeficiency Virus
pol Gene Products, Human Immunodeficiency Virus
rev Gene Products, Human Immunodeficiency Virus

UN SDGs

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

Access to Document

10.4049/jimmunol.1003711

Cite this

Matthews, P. C., Adland, E., Listgarten, J., Leslie, A., Mkhwanazi, N., Carlson, J. M., Harndahl, M., Buus, A. S., Payne, R. P., Ogwu, A., Huang, K.-H. G., Frater, J., Paioni, P., Kloverpris, H., Jooste, P., Goedhals, D., van Vuuren, C., Steyn, D., Riddell, L., ... Goulder, P. J. R. (2011). HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703. Journal of Immunology, 186(10), 5675-86. https://doi.org/10.4049/jimmunol.1003711

Matthews, PC, Adland, E, Listgarten, J, Leslie, A, Mkhwanazi, N, Carlson, JM, Harndahl, M, Buus, AS, Payne, RP, Ogwu, A, Huang, K-HG, Frater, J, Paioni, P, Kloverpris, H, Jooste, P, Goedhals, D, van Vuuren, C, Steyn, D, Riddell, L, Chen, F, Luzzi, G, Balachandran, T, Ndung'u, T, Buus, S, Carrington, M, Shapiro, R, Heckerman, D & Goulder, PJR 2011, 'HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703', Journal of Immunology, vol. 186, no. 10, pp. 5675-86. https://doi.org/10.4049/jimmunol.1003711

@article{92e4256a17294a1f9e4c7a3668c12384,

title = "HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703",

abstract = "The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.",

keywords = "Africa, Alleles, CD4 Lymphocyte Count, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Female, Flow Cytometry, HIV Infections, HIV-1, HLA-A Antigens, HLA-B Antigens, Humans, Linkage Disequilibrium, Molecular Sequence Data, Sequence Analysis, Protein, Viral Load, Viremia, gag Gene Products, Human Immunodeficiency Virus, nef Gene Products, Human Immunodeficiency Virus, pol Gene Products, Human Immunodeficiency Virus, rev Gene Products, Human Immunodeficiency Virus",

author = "Matthews, {Philippa C} and Emily Adland and Jennifer Listgarten and Alasdair Leslie and Nompumelelo Mkhwanazi and Carlson, {Jonathan M} and Mikkel Harndahl and Buus, {Anette Stryhn} and Payne, {Rebecca P} and Anthony Ogwu and Huang, {Kuan-Hsiang Gary} and John Frater and Paolo Paioni and Henrik Kloverpris and Pieter Jooste and Dominique Goedhals and {van Vuuren}, Cloete and Dewald Steyn and Lynn Riddell and Fabian Chen and Graz Luzzi and Thambiah Balachandran and Thumbi Ndung'u and S{\o}ren Buus and Mary Carrington and Roger Shapiro and David Heckerman and Goulder, {Philip J R}",

year = "2011",

month = may,

day = "15",

doi = "10.4049/jimmunol.1003711",

language = "English",

volume = "186",

pages = "5675--86",

journal = "Journal of Immunology",

issn = "1550-6606",

publisher = "American Association of Immunologists",

number = "10",

}

TY - JOUR

T1 - HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703

AU - Matthews, Philippa C

AU - Adland, Emily

AU - Listgarten, Jennifer

AU - Leslie, Alasdair

AU - Mkhwanazi, Nompumelelo

AU - Carlson, Jonathan M

AU - Harndahl, Mikkel

AU - Buus, Anette Stryhn

AU - Payne, Rebecca P

AU - Ogwu, Anthony

AU - Huang, Kuan-Hsiang Gary

AU - Frater, John

AU - Paioni, Paolo

AU - Kloverpris, Henrik

AU - Jooste, Pieter

AU - Goedhals, Dominique

AU - van Vuuren, Cloete

AU - Steyn, Dewald

AU - Riddell, Lynn

AU - Chen, Fabian

AU - Luzzi, Graz

AU - Balachandran, Thambiah

AU - Ndung'u, Thumbi

AU - Buus, Søren

AU - Carrington, Mary

AU - Shapiro, Roger

AU - Heckerman, David

AU - Goulder, Philip J R

PY - 2011/5/15

Y1 - 2011/5/15

N2 - The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.

AB - The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.

KW - Africa

KW - Alleles

KW - CD4 Lymphocyte Count

KW - CD8-Positive T-Lymphocytes

KW - Epitopes, T-Lymphocyte

KW - Female

KW - Flow Cytometry

KW - HIV Infections

KW - HIV-1

KW - HLA-A Antigens

KW - HLA-B Antigens

KW - Humans

KW - Linkage Disequilibrium

KW - Molecular Sequence Data

KW - Sequence Analysis, Protein

KW - Viral Load

KW - Viremia

KW - gag Gene Products, Human Immunodeficiency Virus

KW - nef Gene Products, Human Immunodeficiency Virus

KW - pol Gene Products, Human Immunodeficiency Virus

KW - rev Gene Products, Human Immunodeficiency Virus

U2 - 10.4049/jimmunol.1003711

DO - 10.4049/jimmunol.1003711

M3 - Journal article

C2 - 21498667

SN - 1550-6606

VL - 186

SP - 5675

EP - 5686

JO - Journal of Immunology

JF - Journal of Immunology

IS - 10

ER -