The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host–pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8+ T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection1. Mutation within these epitopes can allow viral escape from CD8+ T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128–135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8+ T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.

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Data deposits

Accession numbers for newly determined viral sequences are included in Supplementary Information.


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This work is funded by grants from the National Institutes of Health (RO1AI46995 (P.G.), 1 R01 AI067073 (B.D.W.), R01AI64060 (E.H.)), the Wellcome Trust (P.G., P.K.), the UK Medical Research Council (J.F., A.P. and P.M.), and the Mark and Lisa Schwartz Foundation, the Ministry of Health, Labour and Welfare (Health and Labour HIV/AIDS Research Grants 012), the NIHR Biomedical Research Centre Programme and the Ministry of Education, Science, Sports and Culture (number 18390141), Japan (M.T.). P.G. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist; J.G.P. is a Marie Curie Fellow (contract number IEF-041811). The authors are also grateful to A. McLean and H. Fryer for discussions of the manuscript.

Author Contributions Y.K., K.P., J.F. and P. M. undertook much of the experimental work and data analysis, and contributed equally. M.T. and P.G. undertook much of the project conception, planning, supervision, analysis and writing of the manuscript, and contributed equally.

Author information


  1. Divisions of Viral Immunology and,

    • Yuka Kawashima
    • , Mamoru Fujiwara
    • , Atsuko Hachiya
    • , Hirokazu Koizumi
    • , Nozomi Kuse
    •  & Masafumi Takiguchi
  2. Infectious Disease, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan

    • Hiroyuki Gatanaga
    •  & Shinichi Oka
  3. Department of Paediatrics,

    • Katja Pfafferott
    • , Philippa Matthews
    • , Rebecca Payne
    • , Andrew Prendergast
    • , Hayley Crawford
    • , Alasdair Leslie
    • , Julia G. Prado
    •  & Philip Goulder
  4. Nuffield Department of Clinical Medicine and,

    • John Frater
    • , Anna Duda
    • , Paul Klenerman
    •  & Rodney Phillips
  5. The James Martin 21st Century School, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK

    • John Frater
    • , Anna Duda
    • , Paul Klenerman
    •  & Rodney Phillips
  6. Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Western Australia 6000, Australia

    • Katja Pfafferott
    • , Mina John
    • , Simon Mallal
    •  & Philip Goulder
  7. Partners AIDS Research Center, Massachusetts General Hospital, 13th Street, Building 149, Charlestown, Boston, Massachusetts 02129, USA

    • Marylyn Addo
    • , Zabrina Brumme
    • , Chanson Brumme
    • , Todd Allen
    • , Christian Brander
    •  & Bruce D. Walker
  8. AIDS Clinical Center, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan

    • Hiroyuki Gatanaga
    • , Atsuko Hachiya
    •  & Shinichi Oka
  9. Fundació IrsiCaixa-HIVACAT, Hospital Germans Trias i Pujol, Badalona and Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona 08916, Spain

    • Christian Brander
  10. University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

    • Richard Kaslow
    •  & James Tang
  11. Emory University Vaccine Center and Yerkes National Primate Research Center, Atlanta, Georgia 30329, USA

    • Eric Hunter
  12. Zambia Emory HIV Research Project, and the Zambia Blood Transfusion Service, Lusaka, Zambia

    • Susan Allen
    •  & Joseph Mulenga
  13. Ladymeade Reference Unit, University of West Indies, Bridgetown BB11156, Barbados

    • Songee Branch
    •  & Tim Roach
  14. Botswana-Harvard School of Public Health AIDS Initiative Partnership, Gaborone, Botswana

    • Anthony Ogwu
    •  & Roger Shapiro
  15. Division of Medicine, Wright Fleming Institute, Imperial College, St Mary’s Hospital, Norfolk Place, Paddington, London W2 1PG, UK

    • Sarah Fidler
    •  & Jonathan Weber
  16. Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3SY, UK

    • Oliver G. Pybus
  17. HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa

    • Thumbi Ndung’u
    • , Bruce D. Walker
    •  & Philip Goulder
  18. Miscrosoft Research, One Microsoft Way, Redmond, Washington 9805, USA

    • P. Richard Harrigan
  19. BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia V6Z 1Y6, Canada

    • David Heckerman
  20. Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA

    • Bruce D. Walker


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Corresponding author

Correspondence to Philip Goulder.

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    Supplementary Information

    This file contains Supplementary Figures 1-7 with Legends, Supplementary Tables 1-3 and Supplementary Notes

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