PMID- 35486690 OWN - NLM STAT- MEDLINE DCOM- 20220503 LR - 20240214 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 119 IP - 18 DP - 2022 May 3 TI - Human herpesvirus diversity is altered in HLA class I binding peptides. PG - e2123248119 LID - 10.1073/pnas.2123248119 [doi] LID - e2123248119 AB - Herpesviruses are ubiquitous, genetically diverse DNA viruses, with long-term presence in humans associated with infrequent but significant pathology. Human leukocyte antigen (HLA) class I presents intracellularly derived peptide fragments from infected tissue cells to CD8+ T and natural killer cells, thereby directing antiviral immunity. Allotypes of highly polymorphic HLA class I are distinguished by their peptide binding repertoires. Because this HLA class I variation is a major determinant of herpesvirus disease, we examined if sequence diversity of virus proteins reflects evasion of HLA presentation. Using population genomic data from Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and Varicella-Zoster virus, we tested whether diversity differed between the regions of herpesvirus proteins that can be recognized, or not, by HLA class I. Herpesviruses exhibit lytic and latent infection stages, with the latter better enabling immune evasion. Whereas HLA binding peptides of lytic proteins are conserved, we found that EBV and HCMV proteins expressed during latency have increased peptide sequence diversity. Similarly, latent, but not lytic, herpesvirus proteins have greater population structure in HLA binding than nonbinding peptides. Finally, we found patterns consistent with EBV adaption to the local HLA environment, with less efficient recognition of EBV isolates by high-frequency HLA class I allotypes. Here, the frequency of CD8+ T cell epitopes inversely correlated with the frequency of HLA class I recognition. Previous analyses have shown that pathogen-mediated natural selection maintains exceptional polymorphism in HLA residues that determine peptide recognition. Here, we show that HLA class I peptide recognition impacts diversity of globally widespread pathogens. FAU - Palmer, William H AU - Palmer WH AUID- ORCID: 0000-0002-0348-6339 AD - Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO 80045. AD - Department of Immunology and Microbiology, University of Colorado, Aurora, CO 80045. FAU - Telford, Marco AU - Telford M AD - Neurogenomics Group, Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain. AD - Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510. FAU - Navarro, Arcadi AU - Navarro A AD - Institut de Biologia Evolutiva (Universitat Pompeu Fabra - Consejo Superior de Investigaciones Cientificas), Department of Medicine and Life Sciences (MELIS), Barcelona Biomedical Research Park, Universitat Pompeu Fabra, 08003 Barcelona, Spain. AD - Institucio Catalana de Recerca i Estudis Avancats and Universitat Pompeu Fabra, 08010 Barcelona, Spain. AD - Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain. AD - Barcelona Beta Brain Research Center, Pasqual Maragall Foundation, 08005 Barcelona, Spain. FAU - Santpere, Gabriel AU - Santpere G AD - Neurogenomics Group, Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM), Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain. AD - Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510. FAU - Norman, Paul J AU - Norman PJ AUID- ORCID: 0000-0001-8370-7703 AD - Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, CO 80045. AD - Department of Immunology and Microbiology, University of Colorado, Aurora, CO 80045. LA - eng GR - R01 AI158410/AI/NIAID NIH HHS/United States GR - R01 HG010898/HG/NHGRI NIH HHS/United States GR - R01 AI151549/AI/NIAID NIH HHS/United States GR - F32 AI161790/AI/NIAID NIH HHS/United States GR - R56 AI151549/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20220429 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 (Histocompatibility Antigens Class I) RN - 0 (Peptides) SB - IM MH - Genetic Variation MH - *Herpesviridae/genetics/immunology MH - *Histocompatibility Antigens Class I/genetics MH - Humans MH - *Peptides/genetics PMC - PMC9170163 OTO - NOTNLM OT - EBV OT - HCMV OT - HLA OT - herpesvirus OT - population genetics COIS- The authors declare no competing interest. EDAT- 2022/04/30 06:00 MHDA- 2022/05/04 06:00 PMCR- 2022/10/29 CRDT- 2022/04/29 14:23 PHST- 2022/04/29 14:23 [entrez] PHST- 2022/04/30 06:00 [pubmed] PHST- 2022/05/04 06:00 [medline] PHST- 2022/10/29 00:00 [pmc-release] AID - 202123248 [pii] AID - 10.1073/pnas.2123248119 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2123248119. doi: 10.1073/pnas.2123248119. Epub 2022 Apr 29.