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TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection

Nature Immunology volume 13, pages 691–700 (2012)Cite this article

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Abstract

The human leukocyte antigens HLA-B*27 and HLA-B*57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B*27 and HLA-B*57 are unable to control HIV-1. Here we found that HLA-B*27-restricted CD8+ T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B*57-restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.

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Figure 1: Quantification of KK10-specific CD8+ T cell responses.
Figure 2: Functional characteristics of KK10-specific CD8+ T cells.
Figure 3: Neutralization of virus ex vivo by KK10-specific CD8+ T cells.
Figure 4: Recognition of viral variants by KK10-specific CD8+ T cells.
Figure 5: Differences in the antiviral efficacy of clonotypes specific for HLA-B*27–KK10.
Figure 6: Differences in the antiviral efficacy of clonotypes specific for HLA-B*57–TW10.
Figure 7: Differences in the loading and delivery of perforin by clonotypes.

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References

  1. Migueles, S.A. & Connors, M. Long-term nonprogressive disease among untreated HIV-infected individuals. J. Am. Med. Assoc. 304, 194–201 (2010).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  3. Kaslow, R.A. et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2, 405–411 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Carrington, M. & O'Brien, S.J. The influence of HLA genotype on AIDS. Annu. Rev. Med. 54, 535–551 (2003).

    Article  CAS  Google Scholar 

  6. Pereyra, F. et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010).

    Article  PubMed  Google Scholar 

  7. Betts, M.R. et al. Analysis of total human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell responses: relationship to viral load in untreated HIV infection. J. Virol. 75, 11983–11991 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Addo, M.M. et al. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J. Virol. 77, 2081–2092 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Almeida, J.R. et al. Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity. Blood 113, 6351–6360 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Bennett, M.S., Ng, H.L., Dagarag, M., Ali, A. & Yang, O.O. Epitope-dependent avidity thresholds for cytotoxic T-lymphocyte clearance of virus-infected cells. J. Virol. 81, 4973–4980 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Migueles, S.A. et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat. Immunol. 3, 1061–1068 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Migueles, S.A. et al. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 29, 1009–1021 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Hersperger, A.R. et al. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog. 6, e1000917 (2010).

    Article  PubMed  Google Scholar 

  15. Dahirel, V. et al. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. Proc. Natl. Acad. Sci. USA 108, 11530–11535 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Kiepiela, P. et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat. Med. 13, 46–53 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Elahi, S. et al. Protective HIV-specific CD8+ T cells evade Treg cell suppression. Nat. Med. 17, 989–995 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Kaufmann, D.E. et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat. Immunol. 8, 1246–1254 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    Article  CAS  Google Scholar 

  20. Pérez, C.L. et al. Broadly immunogenic HLA class I supertype-restricted elite CTL epitopes recognized in a diverse population infected with different HIV-1 subtypes. J. Immunol. 180, 5092–5100 (2008).

    Article  PubMed  Google Scholar 

  21. Miura, T. et al. HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare Gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphotye recognition. J. Virol. 83, 2743–2755 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Lassen, K.G. et al. Elite suppressor derived HIV-1 envelope glycoproteins exhibit reduced entry efficiency and kinetics. PLoS Pathog. 5, e1000377 (2009).

    Article  PubMed  Google Scholar 

  23. Goulder, P.J. et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3, 212–217 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Lee, K.-H. et al. The immunological synapse balances T cell receptor signaling and degradation. Science 302, 1218–1222 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Kosmrlj, A. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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  PubMed  Google Scholar 

  27. Goulder, P.J. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412, 334–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Almeida, J.R. et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J. Exp. Med. 204, 2473–2485 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Mendoza, D. et al. HLA B*5701+ long-term nonprogressors/elite controllers are not distinguished from progressors by the clonal composition of HIV-specific CD8+ T-cells. J. Virol. 86, 4014–4018 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. van Bockel, D.J. et al. Persistent survival of prevalent clonotypes within an immunodominant HIV Gag-specific CD8+ T cell response. J. Immunol. 186, 359–371 (2011).

    Article  CAS  Google Scholar 

  31. Iglesias, M.C. et al. Escape from highly effective public CD8+ T-cell clonotypes by HIV. Blood 118, 2138–2149 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Day, C.L. et al. Proliferative capacity of epitope-specific CD8 T-cell responses is inversely related to viral load in chronic human immunodeficiency virus type 1 infection. J. Virol. 81, 434–438 (2007).

    Article  CAS  Google Scholar 

  33. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

    Article  CAS  Google Scholar 

  34. Hamann, D.r. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Brockman, M.A., Tanzi, G.O., Walker, B.D. & Allen, T.M. Use of a novel GFP reporter cell line to examine replication capacity of CXCR4- and CCR5-tropic HIV-1 by flow cytometry. J. Virol. Methods 131, 134–142 (2006).

    Article  CAS  Google Scholar 

  36. Schneidewind, A. et al. Structural and functional constraints limit options for cytotoxic T-lymphocyte escape in the immunodominant HLA-B27-restricted epitope in human immunodeficiency virus type 1 capsid. J. Virol. 82, 5594–5605 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Chen, H. et al. Differential neutralization of human immunodeficiency virus (HIV) replication in autologous CD4 T cells by HIV-specific cytotoxic T lymphocytes. J. Virol. 83, 3138–3149 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Julg, B. et al. Infrequent recovery of HIV from but robust exogenous infection of activated CD4+ T cells in HIV elite controllers. Clin. Infect. Dis. 51, 233–238 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Miles, J.J., Douek, D.C. & Price, D.A. Bias in the αβ T-cell repertoire: implications for disease pathogenesis and vaccination. Immunol. Cell Biol. 89, 375–387 (2011).

    Article  CAS  Google Scholar 

  40. Liu, D. et al. Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity 31, 99–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Stewart-Jones, G.B.E. et al. Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA-B*2705. Eur. J. Immunol. 35, 341–351 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. Dong, T. et al. HIV-specific cytotoxic T cells from long-term survivors select a unique T cell receptor. J. Exp. Med. 200, 1547–1557 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Venturi, V. et al. A mechanism for TCR sharing between T cell subsets and individuals revealed by pyrosequencing. J. Immunol. 186, 4285–4294 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Miura, T. et al. Genetic characterization of human immunodeficiency virus type 1 in elite controllers: lack of gross genetic defects or common amino acid changes. J. Virol. 82, 8422–8430 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Allen, T.M. et al. Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection. J. Virol. 78, 7069–7078 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Walker, B.D. et al. Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA 86, 9514–9518 (1989).

    Article  CAS  PubMed  Google Scholar 

  48. Varadarajan, N. et al. A high-throughput single-cell analysis of human CD8+ T cell functions reveals discordance for cytokine secretion and cytolysis. J. Clin. Invest. 121, 4322–4331 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Yang, O.O. et al. Impacts of avidity and specificity on the antiviral efficiency of HIV-1-specific CTL. J. Immunol. 171, 3718–3724 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Wilson, C.C. et al. Ex vivo expansion of CD4 lymphocytes from human immunodeficiency virus type 1-infected persons in the presence of combination antiretroviral agents. J. Infect. Dis. 172, 88–96 (1995).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank J. Wong (Massachusetts General Hospital) for monoclonal antibody 12F6 to CD3 and monoclonal antibody CD3:8 bispecific for CD3 and CD8; and all study participants for their contributions. Supported by the Harvard University Center for AIDS Research (5 P30 AI060354-04), the Bill and Melinda Gates Foundation (B.D.W. and D.C.D.), the Doris Duke Charitable Foundation (B.D.W.), the US National Institutes of Health (AI030914 to B.D.W. and AI074415 to T.M.A.), the Howard Hughes Medical Institute (B.D.W.), the Mark and Lisa Schwartz Foundation (B.D.W.), the Intramural Research Program and the Office of AIDS Research of the US National Institutes of Health (D.C.D. and S.D.), the Canadian Institutes for Health Research (New Investigator Award to Z.L.B.) and the Canada Research Chair in Viral Pathogenesis and Immunity (M.A.B.).

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  1. Huabiao Chen and Zaza M Ndhlovu: These authors contributed equally to this work.

Authors and Affiliations

  1. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts, USA

    Huabiao Chen, Zaza M Ndhlovu, Dongfang Liu, Lindsay C Porter, Justin W Fang, Mark A Brockman, Toshiyuki Miura, Zabrina L Brumme, Arne Schneidewind, Alicja Piechocka-Trocha, Kevin T Cesa, Jennifer Sela, Thai D Cung, Ildiko Toth, Florencia Pereyra, Xu G Yu, Daniel E Kaufmann, Todd M Allen & Bruce D Walker

  2. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Huabiao Chen, Zaza M Ndhlovu, Alicja Piechocka-Trocha & Bruce D Walker

  3. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, Maryland, USA

    Sam Darko & Daniel C Douek

  4. Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada

    Mark A Brockman & Zabrina L Brumme

  5. Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Toshiyuki Miura

  6. Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany

    Arne Schneidewind

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Contributions

H.C. was responsible for the overall conduct of the study, under the supervision of B.D.W.; H.C., Z.M.N. and B.D.W. contributed to the experimental design; H.C., Z.M.N., L.C.P. and J.W.F. did the experiments and analyzed the data; S.D. and D.C.D. did germline analyses; T.M., Z.L.B., K.T.C. and J.S. did virus sequencing; M.A.B., A.S. and T.M.A. constructed HIV-1 variants and GXR cell lines; D.L. and D.E.K. did the imaging experiments; T.D.C. and X.G.Y. helped with TCR sequencing; F.P., A.P.-T. and I.T. provided clinical samples; and H.C., Z.M.N. and B.D.W. wrote the paper and all authors contributed to revisions.

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Correspondence to Bruce D Walker.

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Chen, H., Ndhlovu, Z., Liu, D. et al. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. Nat Immunol 13, 691–700 (2012). https://doi.org/10.1038/ni.2342

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