Human herpesvirus diversity is altered in HLA class I binding peptides

Palmer, William H.; Telford, Marco, 1984-; Navarro i Cuartiellas, Arcadi, 1969-; Santpere Baró, Gabriel, 1981-; Norman, Paul J.

Human herpesvirus diversity is altered in HLA class I binding peptides

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dc.contributor.author Palmer, William H.
dc.contributor.author Telford, Marco, 1984-
dc.contributor.author Navarro i Cuartiellas, Arcadi, 1969-
dc.contributor.author Santpere Baró, Gabriel, 1981-
dc.contributor.author Norman, Paul J.
dc.date.accessioned 2022-11-08T07:12:44Z
dc.date.available 2022-11-08T07:12:44Z
dc.date.issued 2022
dc.description.abstract 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.
dc.description.sponsorship This work was supported AQ15 by NIH Grants R56 AI151549 (to P.J.N) and R01 AI158410 (to P.J.N). W.H.P is supported by NIH Grant F32 AI161790. A.N. is supported by Ministerio de Ciencia e Innovación, Spain Grant PGC2018-101927-B-I00, Ministerio de Economía y Competitividad/Fondo Europeo de Desarrollo Regional, Union Europea and by “Unidad de Excelencia María de Maeztu” funded by MINECO Grant MDM-2014-0370. G.S. is supported by Instituto de Salud Carlos III (Spain) Grant MS20/00064 and cofunded by European Social Fund Grant PID2019-104700GA-I00 funded by Agencia Estatal de Investigación, Spain and NIH Grant R01HG010898-01. We thank Oscar MacLean for helpful comments and suggestions.
dc.format.mimetype application/pdf
dc.identifier.citation Palmer WH, Telford M, Navarro A, Santpere G, Norman PJ. Human herpesvirus diversity is altered in HLA class I binding peptides. Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2123248119. DOI: 10.1073/pnas.2123248119
dc.identifier.doi http://dx.doi.org/10.1073/pnas.2123248119
dc.identifier.issn 0027-8424
dc.identifier.uri http://hdl.handle.net/10230/54741
dc.language.iso eng
dc.publisher National Academy of Sciences
dc.relation.ispartof Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2123248119
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-101927-B-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104700GA-I00
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword EBV
dc.subject.keyword HCMV
dc.subject.keyword HLA
dc.subject.keyword Herpesvirus
dc.subject.keyword Population genetics
dc.title Human herpesvirus diversity is altered in HLA class I binding peptides
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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