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

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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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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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.

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Correspondence to Hendrik Streeck.

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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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