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Association of HLA-DRB1–restricted CD4+ T cell responses with HIV immune control

Nature Medicine volume 19, pages 930–933 (2013)Cite this article

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Abstract

The contribution of HLA class II–restricted CD4+ T cell responses to HIV immune control is poorly defined. Here, we delineated previously uncharacterized peptide-DRB1 restrictions in functional assays and analyzed the host genetic effects of HLA-DRB1 alleles on HIV viremia in a large cohort of HIV controllers and progressors. We found distinct stratifications in the effect of HLA-DRB1 alleles on HIV viremia, with HLA-DRB1*15:02 significantly associated with low viremia and HLA-DRB1*03:01 significantly associated with high viremia. Notably, a subgroup of HLA-DRB1 variants linked with low viremia showed the ability to promiscuously present a larger breadth of peptides with lower functional avidity when compared to HLA-DRB1 variants linked with high viremia. Our data provide systematic evidence that HLA-DRB1 variant expression has a considerable impact on the control of HIV replication, an effect that seems to be mediated primarily by the protein specificity of CD4+ T cell responses to HIV Gag and Nef.

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Figure 1: HLA-DR variants show promiscuity and specificity in the number of HIV-specific CD4+ T cell peptides presented.
Figure 2: Association of HLA-DRB1 allele expression with HIV viral load at the population level.
Figure 3: HLA-DRB1 variants linked with low viremia present a greater breadth of peptides recognized by HIV-specific CD4+ T cells at low functional avidity.

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References

  1. Aubert, R.D. et al. Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection. Proc. Natl. Acad. Sci. USA 108, 21182–21187 (2011).

    Article  CAS  Google Scholar 

  2. Wilkinson, T.M. et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat. Med. 18, 274–280 (2012).

    Article  CAS  Google Scholar 

  3. Soghoian, D.Z. et al. HIV-specific cytolytic CD4 T cell responses during acute HIV-1 infection predict disease outcome. Sci. Transl. Med. 4, 123ra25 (2012).

    Article  Google Scholar 

  4. Whitmire, J.K. Induction and function of virus-specific CD4+ T cell responses. Virology 411, 216–228 (2011).

    Article  CAS  Google Scholar 

  5. Soghoian, D.Z. & Streeck, H. Cytolytic CD4+ T cells in viral immunity. Expert Rev. Vaccines 9, 1453–1463 (2010).

    Article  CAS  Google Scholar 

  6. Streeck, H., D'Souza, M.P., Littman, D.R. & Crotty, S. Harnessing CD4+ T cell responses in HIV vaccine development. Nat. Med. 19, 143–149 (2013).

    Article  CAS  Google Scholar 

  7. Douek, D.C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002).

    Article  CAS  Google Scholar 

  8. Ranasinghe, S. et al. HIV-specific CD4 T cell responses to different viral proteins have discordant associations with viral load and clinical outcome. J. Virol. 86, 277–283 (2012).

    Article  CAS  Google Scholar 

  9. Carrington, M. & Walker, B.D. Immunogenetics of spontaneous control of HIV. Annu. Rev. Med. 63, 131–145 (2012).

    Article  CAS  Google Scholar 

  10. International HIV Controller Study. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010).

  11. Apps, R. et al. Influence of HLA-C expression level on HIV control. Science 340, 87–91 (2013).

    Article  CAS  Google Scholar 

  12. Malhotra, U. et al. Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment. J. Clin. Invest. 107, 505–517 (2001).

    Article  CAS  Google Scholar 

  13. Julg, B. et al. Possession of HLA class II DRB1*1303 associates with reduced viral loads in chronic HIV-1 clade C and B infection. J. Infect. Dis. 203, 803–809 (2011).

    Article  CAS  Google Scholar 

  14. Southwood, S. et al. Several common HLA-DR types share largely overlapping peptide binding repertoires. J. Immunol. 160, 3363–3373 (1998).

    CAS  PubMed  Google Scholar 

  15. Gerlach, J.T. et al. Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins. J. Virol. 79, 12425–12433 (2005).

    Article  CAS  Google Scholar 

  16. Schulze zur Wiesch, J. et al. Broad repertoire of the CD4+ TH cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes. J. Immunol. 175, 3603–3613 (2005).

    Article  CAS  Google Scholar 

  17. Gao, X. et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N. Engl. J. Med. 344, 1668–1675 (2001).

    Article  CAS  Google Scholar 

  18. Trachtenberg, E. et al. Advantage of rare HLA supertype in HIV disease progression. Nat. Med. 9, 928–935 (2003).

    Article  CAS  Google Scholar 

  19. Mallone, R. et al. Functional avidity directs T-cell fate in autoreactive CD4+ T cells. Blood 106, 2798–2805 (2005).

    Article  CAS  Google Scholar 

  20. Caserta, S. et al. Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens. J. Immunol. 185, 6545–6554 (2010).

    Article  CAS  Google Scholar 

  21. Streeck, H., Frahm, N. & Walker, B.D. The role of IFN-γ Elispot assay in HIV vaccine research. Nat. Protoc. 4, 461–469 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all individuals whose participation enabled this study. This study was funded by the US National Institutes of Health (NIH) (R01 AI091450 and R01 AI094602). H.S. is funded through R01 AI091450 and R01 AI094602 and the Henry M. Jackson Foundation by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of Defense (W81XWH-07-2-0067). S.R. is supported by a Harvard CFAR Scholar Award (NIH/National Institute of Allergy and Infectious Diseases (NIAID) 5P30AI060354-09), Center for HIV/AIDS Immunology and Immunogen Discovery (CHAVI-ID) and MGH Executive Committee on Research Fund for Medical Discovery. This project has also been funded in part with federal funds from the US Intramural Research Program of the US National Institutes of Health, National Cancer Institute (NCI), Center for Cancer Research, under contract HHSN261200800001E. The UCSF SCOPE cohort was supported by the Centers for AIDS Research at UCSF (PO AI27763), CFAR Network of Integrated Systems (R24 AI067039), the UCSF Clinical and Translational Science Institute (UL1 RR024131), and NIAID (RO1 AI087145 and K24 AI069994). The MGH cohort was supported by the Mark and Lisa Schwartz Foundation and the Collaboration of AIDS Vaccine Discovery of the Bill & Melinda Gates Foundation. This research has been supported in part by the International HIV Controllers Study, funded by the Bill & Melinda Gates Foundation, the AIDS Healthcare Foundation and CFAR, an NIH-funded program (P30 AI060354) that is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, National Institute on Aging, Fogarty International Center and Organization for Autism Research. We thank M. Ghebremichael for statistical assistance and Y. Yuki for HLA genotyping. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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Author notes

  1. Richard Lu, Gregory Kranias & Hendrik Streeck

    Present address: Present address: US Military HIV Research Program, Henry M. Jackson Foundation, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.,

Authors and Affiliations

  1. Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA

    Srinika Ranasinghe, Sam Cutler, Isaiah Davis, Richard Lu, Damien Z Soghoian, Gregory Kranias, Michael D Flanders, Madelene Lindqvist, Bjorn Kuhl, Galit Alter, Bruce D Walker, Mary Carrington & Hendrik Streeck

  2. Cancer and Inflammation Program, Laboratory of Experimental Immunology, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, USA

    Ying Qi, Xiaojiang Gao & Mary Carrington

  3. La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    John Sidney & Alessandro Sette

  4. University of California–San Francisco (UCSF) Department of Medicine, San Francisco General Hospital, San Francisco, California, USA

    Steven G Deeks

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

    Bruce D Walker

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  1. Srinika Ranasinghe
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Contributions

S.R. designed the study, performed experiments, analyzed data, and wrote the manuscript; S.C., I.D., R.L., D.Z.S., G.K., M.D.F., M.L., B.K. and G.A. contributed to in vitro studies and experimental design; J.S. and A.S. generated the HLA-DR–transfected L cells and conducted peptide–HLA-DRB1 binding assays; Y.Q., X.G. and M.C. performed high-resolution HLA typing and analyzed HLA-DRB1 associations with viral control; S.G.D. and B.D.W. provided clinical samples from HIV-infected subjects enrolled in the SCOPE and MGH cohorts; M.C. and B.D.W. gave intellectual input; H.S. conceived of and designed the study, analyzed data, wrote the manuscript and was responsible for the overall study.

Corresponding author

Correspondence to Hendrik Streeck.

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The authors declare no competing financial interests.

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Ranasinghe, S., Cutler, S., Davis, I. et al. Association of HLA-DRB1–restricted CD4+ T cell responses with HIV immune control. Nat Med 19, 930–933 (2013). https://doi.org/10.1038/nm.3229

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