PMID- 31748275 OWN - NLM STAT- MEDLINE DCOM- 20200413 LR - 20240422 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 116 IP - 49 DP - 2019 Dec 3 TI - Contribution of proteasome-catalyzed peptide cis-splicing to viral targeting by CD8(+) T cells in HIV-1 infection. PG - 24748-24759 LID - 10.1073/pnas.1911622116 [doi] AB - Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8(+) T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a relatively minor component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8(+) T cell responses relatively infrequently during infection, CD8(+) T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection. CI - Copyright (c) 2019 the Author(s). Published by PNAS. FAU - Paes, Wayne AU - Paes W AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom; wayne.paes@ndm.ox.ac.uk nicola.ternette@ndm.ox.ac.uk persephone.borrow@ndm.ox.ac.uk. FAU - Leonov, German AU - Leonov G AUID- ORCID: 0000-0002-6763-5903 AD - York Cross-Disciplinary Centre for Systems Analysis, University of York, York YO10 5DD, United Kingdom. FAU - Partridge, Thomas AU - Partridge T AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom. FAU - Chikata, Takayuki AU - Chikata T AD - Centre for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan. FAU - Murakoshi, Hayato AU - Murakoshi H AD - Centre for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan. FAU - Frangou, Anna AU - Frangou A AD - Big Data Institute, University of Oxford, Oxford OX3 7LF, United Kingdom. FAU - Brackenridge, Simon AU - Brackenridge S AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom. FAU - Nicastri, Annalisa AU - Nicastri A AD - Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom. FAU - Smith, Andrew G AU - Smith AG AD - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. AD - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. FAU - Learn, Gerald H AU - Learn GH AUID- ORCID: 0000-0003-0434-7733 AD - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. AD - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. FAU - Li, Yingying AU - Li Y AD - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. AD - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. FAU - Parker, Robert AU - Parker R AD - Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom. FAU - Oka, Shinichi AU - Oka S AD - Centre for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan. AD - AIDS Clinical Centre, National Centre for Global Health and Medicine, Tokyo 162-8655, Japan. FAU - Pellegrino, Pierre AU - Pellegrino P AD - Centre for Sexual Health and HIV Research, University College London, London WC1E 6JB, United Kingdom. FAU - Williams, Ian AU - Williams I AD - Centre for Sexual Health and HIV Research, University College London, London WC1E 6JB, United Kingdom. FAU - Haynes, Barton F AU - Haynes BF AD - Department of Medicine, Duke University School of Medicine, Durham, NC 27710. AD - Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710. FAU - McMichael, Andrew J AU - McMichael AJ AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom. FAU - Shaw, George M AU - Shaw GM AD - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. AD - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. FAU - Hahn, Beatrice H AU - Hahn BH AD - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. AD - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. FAU - Takiguchi, Masafumi AU - Takiguchi M AD - Centre for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan. FAU - Ternette, Nicola AU - Ternette N AD - Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom; wayne.paes@ndm.ox.ac.uk nicola.ternette@ndm.ox.ac.uk persephone.borrow@ndm.ox.ac.uk. FAU - Borrow, Persephone AU - Borrow P AUID- ORCID: 0000-0002-3877-9780 AD - Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom; wayne.paes@ndm.ox.ac.uk nicola.ternette@ndm.ox.ac.uk persephone.borrow@ndm.ox.ac.uk. LA - eng GR - MC_UU_12009/MRC_/Medical Research Council/United Kingdom GR - UM1 AI100645/AI/NIAID NIH HHS/United States GR - 097813/Z/11/B#/WT_/Wellcome Trust/United Kingdom GR - MR/M00919X/1/MRC_/Medical Research Council/United Kingdom GR - MR/K012037/MRC_/Medical Research Council/United Kingdom GR - MC_UU_12025/MRC_/Medical Research Council/United Kingdom GR - P01 AI131251/AI/NIAID NIH HHS/United States GR - R01 AI118549/AI/NIAID NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - UM1 AI144371/AI/NIAID NIH HHS/United States GR - G0902418/MRC_/Medical Research Council/United Kingdom GR - MR/K012037/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191120 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (AIDS Vaccines) RN - 0 (Antigens, Viral) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Peptides) RN - 0 (RNA, Viral) RN - 0 (Viral Proteins) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) SB - IM MH - AIDS Vaccines/immunology/therapeutic use MH - Antigens, Viral/genetics/immunology/metabolism MH - CD8-Positive T-Lymphocytes/*immunology/metabolism MH - Cell Line MH - Cohort Studies MH - Cross Reactions/immunology MH - Cross-Priming/*genetics MH - Datasets as Topic MH - Epitopes, T-Lymphocyte/genetics/immunology/metabolism MH - HIV Infections/blood/*immunology/therapy/virology MH - HIV-1/genetics/*immunology MH - Histocompatibility Antigens Class I/immunology/metabolism MH - Humans MH - Immune Evasion MH - Peptides/genetics/immunology/metabolism MH - Proteasome Endopeptidase Complex/immunology/*metabolism MH - RNA Splicing/immunology MH - RNA, Viral/blood/genetics/isolation & purification MH - RNA-Seq MH - Viral Proteins/genetics/immunology/metabolism PMC - PMC6900506 OTO - NOTNLM OT - T cell epitope OT - human immunodeficiency virus OT - immunopeptidome OT - peptide splicing OT - proteasome COIS- The authors declare no competing interest. EDAT- 2019/11/22 06:00 MHDA- 2020/04/14 06:00 PMCR- 2019/11/20 CRDT- 2019/11/22 06:00 PHST- 2019/11/22 06:00 [pubmed] PHST- 2020/04/14 06:00 [medline] PHST- 2019/11/22 06:00 [entrez] PHST- 2019/11/20 00:00 [pmc-release] AID - 1911622116 [pii] AID - 201911622 [pii] AID - 10.1073/pnas.1911622116 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24748-24759. doi: 10.1073/pnas.1911622116. Epub 2019 Nov 20.