Abstract
The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells1,2,3. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity4,5. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles6,7,8. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.
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Acknowledgements
We thank those who made possible the collection of blood samples for the study, in particular the patients and staff at Cato Manor Clinic and Sinikithemba Clinic, Durban, South Africa. We also thank S. McAdam, J. Webster and R. Phillips for comments and suggestions. This work was supported by a contract from the National Institutes of Health (B.D.W.), with additional support from the Wellcome Trust (P.J.R.G., A.J.L., P.Z., P.K.), the Elizabeth Glaser Pediatric AIDS Foundation (P.J.R.G., B.T.K.), the National Institutes of Health and the Doris Duke Charitable Foundation. P.J.R.G. and B.T.K. are Elizabeth Glaser Pediatric AIDS Foundation Scientists, B.D.W. is a Doris Duke Distinguished Science Professor.
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Supplementary information
Supplementary Information Table 1
Peptides recognized in association with individual HLA class I allele expression. (PDF 68 kb)
Supplementary Information Table 2
List of the 69 associations identified between HLA class I expression and overlapping peptide targeted, for which 0.05<p<0.001. (PDF 62 kb)
Supplementary Information Table 3
Linkage disequilibrium involving the alleles that were identified in association with high or low viral loads. (PDF 41 kb)
Supplementary Information Figure 1
HLA restriction and epitope optimisation for 10 additional epitopes where the HLA-peptide association was identified by the statistical approach described in the text. (PDF 75 kb)
Supplementary Information Figure 2
HLA class I molecule expression and absolute CD4 count in chronically infected Zulu/Xhosa (n=706). (PDF 50 kb)
Supplementary Information Methods
Detailed description of the statistical methods used in this study. (DOC 25 kb)
Supplementary Data
GenBank accession number information. (DOC 19 kb)
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Kiepiela, P., Leslie, A., Honeyborne, I. et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432, 769–775 (2004). https://doi.org/10.1038/nature03113
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DOI: https://doi.org/10.1038/nature03113
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