Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8+ T cell antiviral responses

Research in Viral Eradication of Reservoirs (RIVER) trial study group

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Persistence of HIV through integration into host DNA in CD4+ T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8+ T cells are triggered to kill infected CD4+ T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with “beneficial” HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8+ T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4+ T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

    Original languageEnglish
    Article number109103
    JournalCell Reports
    Volume35
    Issue number6
    DOIs
    Publication statusPublished - 11 May 2021

    Bibliographical note

    Funding Information:
    The authors would like to thank Emma Gostick, Immunocore Ltd, for reagent preparation. MS data acquisition was performed in the Target Discovery Institute Mass Spectrometry Laboratory run by Benedikt M. Kessler. This work was supported in part by UK National Institute for Health Research (NIHR) infrastructure through the National Institute for Health Research (NIHR) Biomedical Research Centres based at University of Oxford, Imperial College Healthcare NHS Trust and Imperial College London, University of Cambridge, and King’s College London. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. GSK provided the ChAdV63 vector used in the RIVER study. GlaxoSmithKline Biologicals SA provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation. This work was supported by the Australian Research Council ( FT100100297 to J.M.), Australian National Health and Medical Research Council Project Grant ( 1121697 to J.M.), the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement No. 681137 to C.B.), and the UK Medical Research Council ( G0502048 to L.D.).

    Funding Information:
    The authors would like to thank Emma Gostick, Immunocore Ltd, for reagent preparation. MS data acquisition was performed in the Target Discovery Institute Mass Spectrometry Laboratory run by Benedikt M. Kessler. This work was supported in part by UK National Institute for Health Research (NIHR) infrastructure through the National Institute for Health Research (NIHR) Biomedical Research Centres based at University of Oxford, Imperial College Healthcare NHS Trust and Imperial College London, University of Cambridge, and King's College London. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. GSK provided the ChAdV63 vector used in the RIVER study. GlaxoSmithKline Biologicals SA provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation. This work was supported by the Australian Research Council (FT100100297 to J.M.), Australian National Health and Medical Research Council Project Grant (1121697 to J.M.), the European Union's Horizon 2020 Research and Innovation Programme (Grant Agreement No. 681137 to C.B.), and the UK Medical Research Council (G0502048 to L.D.). Study design or conception: H.Y. C.B. N.T. and L.D. Methodology: H.Y. G.M.G. and A.K. Investigation: H.Y. A.L. S.C. A.C. D.B.L. W.S. and N.T. Resources: J.F. S.F. B.M. J.M. C.B. N.T. and L.D. Writing ? Original Draft: H.Y. A.v.D. N.T. and L.D. Writing ? Review & Editing: H.Y. A.L. G.G. A.K. S.F. B.M. J.M. C.B. N.T. and L.D. Visualization: H.Y. A.v.D. D.B.L. N.T. and L.D. Supervision: C.B. N.T. and L.D. Funding acquisition: J.F. S.F. J.M. C.B. N.T. and L.D. L.D. is an employee of Immunocore Ltd. A.K. and D.B.L. were previously employees of Immunocore Ltd.

    Publisher Copyright:
    © 2021 The Author(s)

    Keywords

    • antigen presentation
    • CD8 T cells
    • cytotoxic T lymphocytes
    • Gag
    • HIV
    • HLA
    • immunopeptidome
    • kinetics
    • mass spectrometry
    • peptides

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