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Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection

Abstract

Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (‘elite controllers’) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.

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Figure 1: Thymic selection against fewer self peptides leads to a more cross-reactive T-cell repertoire.
Figure 2: Model of host–pathogen interactions shows superior viral control by cross-reactive CD8 + T-cell repertoires.
Figure 3: HLA-B alleles associated with greater ability to control HIV correlate with smaller self-peptide binding propensities.

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Acknowledgements

Financial support was provided by the Mark and Lisa Schwartz Foundation, the National Institutes of Health (NIH) Director’s Pioneer award (A.K.C.), Philip T and Susan M Ragon Foundation, Jane Coffin Childs Foundation (E.L.R.), the Bill and Melinda Gates Foundation, and the NIAID (B.D.W., T.M.A. and M.A.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors

Contributions

A.K. and E.L.R. contributed equally to this work. A.K.C. and B.D.W. initiated the project. A.K., E.L.R. and A.K.C. developed the computational models. A.K., E.L.R., A.K.C. and B.D.W. analysed computational results. Y.Q., F.P., M.C., S.G.D. and B.D.W. collected and analysed the data from cohorts of HIV-infected people. A.K., E.L.R., T.M.A., M.A., M.C., B.D.W. and A.K.C. contributed to the writing of the manuscript.

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Correspondence to Bruce D. Walker or Arup K. Chakraborty.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Note 1, Supplementary Tables S1-S4, Supplementary Figures S1-S17 with legends, Supplementary Methods, Supplementary Discussions 1-2 and References. (PDF 2809 kb)

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Košmrlj, A., Read, E., Qi, Y. et al. Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature 465, 350–354 (2010). https://doi.org/10.1038/nature08997

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