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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Migueles, S. A. et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc. Natl Acad. Sci. USA 97, 2709–2714 (2000)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Deeks, S. G. & Walker, B. D. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27, 406–416 (2007)

    CAS  Article  Google Scholar 

  3. 3

    Jin, X. et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189, 991–998 (1999)

    CAS  Article  Google Scholar 

  4. 4

    Peters, B. et al. The immune epitope database and analysis resource: from vision to blueprint. PLoS Biol. 3, e91 (2005)

    Article  Google Scholar 

  5. 5

    Rao, X., Fontaine Costa, A. I. C. A., van Baarle, D. & Keşmir, C. A comparative study of HLA binding affinity and ligand diversity: implications for generating immunodominant CD8+ T cell responses. J. Immunol. 182, 1526–1532 (2009)

    CAS  Article  Google Scholar 

  6. 6

    Hubbard, T. J. et al. Ensembl 2009. Nucleic Acids Res. 37, D690–D697 (2009)

    CAS  Article  Google Scholar 

  7. 7

    Huseby, E. S., Crawford, F., White, J., Marrack, P. & Kappler, J. W. Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptide. Nature Immunol. 7, 1191–1199 (2006)

    CAS  Article  Google Scholar 

  8. 8

    Huseby, E. S. et al. How the T cell repertoire becomes peptide and MHC specific. Cell 122, 247–260 (2005)

    CAS  Article  Google Scholar 

  9. 9

    Košmrlj, A., Jha, A. K., Huseby, E. S., Kardar, M. & Chakraborty, A. K. How the thymus designs antigen-specific and self-tolerant T cell receptor sequences. Proc. Natl Acad. Sci. USA 105, 16671–16676 (2008)

    ADS  Article  Google Scholar 

  10. 10

    Košmrlj, A., Chakraborty, A. K., Kardar, M. & Shakhnovich, E. I. Thymic selection of T-cell receptors as an extreme value problem. Phys. Rev. Lett. 103, 068103 (2009)

    ADS  Article  Google Scholar 

  11. 11

    Chao, D. L., Davenport, M. P., Forrest, S. & Perelson, A. S. The effects of thymic selection on the range of T cell cross-reactivity. Eur. J. Immunol. 35, 3452–3459 (2005)

    CAS  Article  Google Scholar 

  12. 12

    Naeher, D. et al. A constant affinity threshold for T cell tolerance. J. Exp. Med. 204, 2553–2559 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Turnbull, E. L. et al. HIV-1 epitope-specific CD8+ T cell responses strongly associated with delayed disease progression cross-recognize epitope variants efficiently. J. Immunol. 176, 6130–6146 (2006)

    CAS  Article  Google Scholar 

  14. 14

    Gillespie, G. M. et al. Cross-reactive cytotoxic T lymphocytes against a HIV-1 p24 epitope in slow progressors with B*57. AIDS 16, 961–972 (2002)

    CAS  Article  Google Scholar 

  15. 15

    Yu, X. G. et al. Mutually exclusive T-cell receptor induction and differential susceptibility to human immunodeficiency virus type 1 mutational escape associated with a two-amino-acid difference between HLA class I subtypes. J. Virol. 81, 1619–1631 (2007)

    CAS  Article  Google Scholar 

  16. 16

    Moon, J. J. et al. Naive CD4+ T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27, 203–213 (2007)

    CAS  Article  Google Scholar 

  17. 17

    Altfeld, M. et al. HLA alleles associated with delayed progression to AIDS contribute strongly to the initial CD8+ T cell response against HIV-1. PLoS Med. 3, e403 (2006)

    Article  Google Scholar 

  18. 18

    Althaus, C. L. & De Boer, R. J. Dynamics of immune escape during HIV/SIV infection. PLoS Comput. Biol. 4, e1000103 (2008)

    ADS  MathSciNet  Article  Google Scholar 

  19. 19

    Nowak, M. A. et al. Antigenic oscillations and shifting immunodominance in HIV-1 infections. Nature 375, 606–611 (1995)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Wodarz, D. & Thomsen, A. R. Effect of the CTL proliferation program on virus dynamics. Int. Immunol. 17, 1269–1276 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Cao, J. H., McNevin, J., Malhotra, U. & McElrath, M. J. Evolution of CD8+ T cell immunity and viral escape following acute HIV-1 infection. J. Immunol. 171, 3837–3846 (2003)

    CAS  Article  Google Scholar 

  22. 22

    Price, D. A. et al. Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection. J. Exp. Med. 206, 923–936 (2009)

    CAS  Article  Google Scholar 

  23. 23

    Kiepiela, P. et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432, 769–775 (2004)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Thio, C. L. et al. HLA-Cw*04 and hepatitis C virus persistence. J. Virol. 76, 4792–4797 (2002)

    CAS  Article  Google Scholar 

  25. 25

    McKiernan, S. M. et al. Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology 40, 108–114 (2004)

    CAS  Article  Google Scholar 

  26. 26

    Bhalerao, J. & Bowcock, A. M. The genetics of psoriasis: a complex disorder of the skin and immune system. Hum. Mol. Genet. 7, 1537–1545 (1998)

    CAS  Article  Google Scholar 

  27. 27

    Chessman, D. et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28, 822–832 (2008)

    CAS  Article  Google Scholar 

  28. 28

    López de Castro, J. A. HLA-B27 and the pathogenesis of spondyloarthropathies. Immunol. Lett. 108, 27–33 (2007)

    Article  Google Scholar 

  29. 29

    Bowness, P. HLA B27 in health and disease: a double-edged sword? Rheumatology 41, 857–868 (2002)

    CAS  Article  Google Scholar 

  30. 30

    Streeck, H. et al. Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells. J. Virol. 83, 7641–7648 (2009)

    CAS  Article  Google Scholar 

  31. 31

    Peters, B. et al. A community resource benchmarking predictions of peptide binding to MHC-I molecules. PLoS Comput. Biol. 2, e65 (2006)

    ADS  Article  Google Scholar 

  32. 32

    Gulukota, K., Sidney, J., Sette, A. & DeLisi, C. Two complementary methods for predicting peptides binding major histocompatibility complex molecules. J. Mol. Biol. 267, 1258–1267 (1997)

    CAS  Article  Google Scholar 

  33. 33

    Peters, B., Tong, W., Sidney, J., Sette, A. & Weng, Z. Examining the independent binding assumption for binding of peptide epitopes to MHC-I molecules. Bioinformatics 19, 1765–1772 (2003)

    CAS  Article  Google Scholar 

  34. 34

    Miyazawa, S. & Jernigan, R. L. Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. J. Mol. Biol. 256, 623–644 (1996)

    CAS  Article  Google Scholar 

  35. 35

    Sachsenberg, N. et al. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J. Exp. Med. 187, 1295–1303 (1998)

    CAS  Article  Google Scholar 

  36. 36

    Stafford, M. A. et al. Modeling plasma virus concentration during primary HIV infection. J. Theor. Biol. 203, 285–301 (2000)

    CAS  Article  Google Scholar 

  37. 37

    Parera, M., Fernandez, G., Clotet, B. & Martinez, M. A. HIV-1 protease catalytic efficiency effects caused by random single amino acid substitutions. Mol. Biol. Evol. 24, 382–387 (2007)

    CAS  Article  Google Scholar 

  38. 38

    Pereyra, F. et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J. Infect. Dis. 197, 563–571 (2008)

    Article  Google Scholar 

  39. 39

    Hosmer, D. W., Jovanovic, B. & Lemeshow, S. Best subsets logistic-regression. Biometrics 45, 1265–1270 (1989)

    Article  Google Scholar 

  40. 40

    Cheverud, J. M. A simple correction for multiple comparisons in interval mapping genome scans. Heredity 87, 52–58 (2001)

    CAS  Article  Google Scholar 

Download references


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.

Author information




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.

Corresponding authors

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

Ethics declarations

Competing interests

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)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.