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Pathogenesis and Immunity

HLA-B*57 Micropolymorphism Shapes HLA Allele-Specific Epitope Immunogenicity, Selection Pressure, and HIV Immune Control

Henrik N. Kloverpris, Anette Stryhn, Mikkel Harndahl, Mary van der Stok, Rebecca P. Payne, Philippa C. Matthews, Fabian Chen, Lynn Riddell, Bruce D. Walker, Thumbi Ndung'u, Søren Buus, Philip Goulder
Henrik N. Kloverpris
aDepartment of Paediatrics, University of Oxford, Peter Medawar Building, Oxford, United Kingdom
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Anette Stryhn
bDepartment of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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Mikkel Harndahl
bDepartment of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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Mary van der Stok
cHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
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Rebecca P. Payne
aDepartment of Paediatrics, University of Oxford, Peter Medawar Building, Oxford, United Kingdom
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Philippa C. Matthews
aDepartment of Paediatrics, University of Oxford, Peter Medawar Building, Oxford, United Kingdom
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Fabian Chen
eDepartment of Sexual Health, Royal Berkshire Hospital, Reading, United Kingdom
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Lynn Riddell
fDepartment of Genitourinary Medicine, Northhamptonshire Healthcare National Health Service Trust, Northhampton General Hospital, Cliftonville, Northhampton, United Kingdom
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Bruce D. Walker
cHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
dRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, Massachusetts, USA
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Thumbi Ndung'u
cHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
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Søren Buus
bDepartment of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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Philip Goulder
aDepartment of Paediatrics, University of Oxford, Peter Medawar Building, Oxford, United Kingdom
cHIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
dRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, Massachusetts, USA
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DOI: 10.1128/JVI.06150-11
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ABSTRACT

The genetic polymorphism that has the greatest impact on immune control of human immunodeficiency virus (HIV) infection is expression of HLA-B*57. Understanding of the mechanism for this strong effect remains incomplete. HLA-B*57 alleles and the closely related HLA-B*5801 are often grouped together because of their similar peptide-binding motifs and HIV disease outcome associations. However, we show here that the apparently small differences between HLA-B*57 alleles, termed HLA-B*57 micropolymorphisms, have a significant impact on immune control of HIV. In a study cohort of >2,000 HIV C-clade-infected subjects from southern Africa, HLA-B*5703 is associated with a lower viral-load set point than HLA-B*5702 and HLA-B*5801 (medians, 5,980, 15,190, and 19,000 HIV copies/ml plasma; P = 0.24 and P = 0.0005). In order to better understand these observed differences in HLA-B*57/5801-mediated immune control of HIV, we undertook, in a study of >1,000 C-clade-infected subjects, a comprehensive analysis of the epitopes presented by these 3 alleles and of the selection pressure imposed on HIV by each response. In contrast to previous studies, we show that each of these three HLA alleles is characterized both by unique CD8+ T-cell specificities and by clear-cut differences in selection pressure imposed on the virus by those responses. These studies comprehensively define for the first time the CD8+ T-cell responses and immune selection pressures for which these protective alleles are responsible. These findings are consistent with HLA class I alleles mediating effective immune control of HIV through the number of p24 Gag-specific CD8+ T-cell responses generated that can drive significant selection pressure on the virus.

FOOTNOTES

    • Received 6 September 2011.
    • Accepted 27 October 2011.
    • Accepted manuscript posted online 16 November 2011.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/JVI.06150-11.

  • Copyright © 2012, American Society for Microbiology. All Rights Reserved.
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HLA-B*57 Micropolymorphism Shapes HLA Allele-Specific Epitope Immunogenicity, Selection Pressure, and HIV Immune Control
Henrik N. Kloverpris, Anette Stryhn, Mikkel Harndahl, Mary van der Stok, Rebecca P. Payne, Philippa C. Matthews, Fabian Chen, Lynn Riddell, Bruce D. Walker, Thumbi Ndung'u, Søren Buus, Philip Goulder
Journal of Virology Dec 2011, 86 (2) 919-929; DOI: 10.1128/JVI.06150-11

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HLA-B*57 Micropolymorphism Shapes HLA Allele-Specific Epitope Immunogenicity, Selection Pressure, and HIV Immune Control
Henrik N. Kloverpris, Anette Stryhn, Mikkel Harndahl, Mary van der Stok, Rebecca P. Payne, Philippa C. Matthews, Fabian Chen, Lynn Riddell, Bruce D. Walker, Thumbi Ndung'u, Søren Buus, Philip Goulder
Journal of Virology Dec 2011, 86 (2) 919-929; DOI: 10.1128/JVI.06150-11
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