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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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.
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Kawashima, Y., Pfafferott, K., Frater, J. et al. Adaptation of HIV-1 to human leukocyte antigen class I. Nature 458, 641–645 (2009). https://doi.org/10.1038/nature07746
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