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Analysis of antibody binding specificities in twin and SNP-genotyped cohorts reveals that antiviral antibody epitope selection is a heritable trait

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Thiagarajan Venkataraman, Cristian Valencia, Massimo Mangino, William Morgenlander, Steven J. Clipman, Thomas Liechti, Ana Valencia, Paraskevi Christofidou, Tim Spector, Mario Roederer, Priya Duggal, H. Benjamin Larman

Original languageEnglish
Pages (from-to)174-184.e5
JournalImmunity
Volume55
Issue number1
DOIs
Published11 Jan 2022

Bibliographical note

Funding Information: We are grateful to Stephen J. Elledge (Harvard Medical School) for generously providing the VirScan library used in this study. We are grateful to the twins who took part in TwinsUK and the whole TwinsUK team, which includes laboratory technicians, administrative staff, and research managers. TwinsUK and M.M. are supported by the National Institute for Health Research (NIHR) -funded BioResource , the Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King’s College London . C.V. was supported by the Burroughs-Wellcome funded, Maryland: Genetics, Epidemiology and Medicine training program at the Johns Hopkins University . Funding Information: Funding: National Institute of General Medical Sciences (NIGMS), grant R01GM136724 (H.B.L.); National Institute of Allergy and Infectious Diseases (NIAID), grant U24AI118633 (H.B.L.); NIH , Intramural Research Program of the Vaccine Research Center , (NIAID) (M.R. and T.L.); Wellcome Trust 212904/Z/18/Z (M.M., T.S., and P.C.), and European Union H2O20 contract # 733100 (M.M., T.S., and P.C.). Funding Information: We are grateful to Stephen J. Elledge (Harvard Medical School) for generously providing the VirScan library used in this study. We are grateful to the twins who took part in TwinsUK and the whole TwinsUK team, which includes laboratory technicians, administrative staff, and research managers. TwinsUK and M.M. are supported by the National Institute for Health Research (NIHR)-funded BioResource, the Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. C.V. was supported by the Burroughs-Wellcome funded, Maryland: Genetics, Epidemiology and Medicine training program at the Johns Hopkins University. Funding: National Institute of General Medical Sciences (NIGMS), grant R01GM136724 (H.B.L.); National Institute of Allergy and Infectious Diseases (NIAID), grant U24AI118633 (H.B.L.); NIH, Intramural Research Program of the Vaccine Research Center, (NIAID) (M.R. and T.L.); Wellcome Trust 212904/Z/18/Z (M.M. T.S. and P.C.), and European Union H2O20 contract #733100 (M.M. T.S. and P.C.). Conceptualization, M.M. P.D. and H.B.L.; formal analysis, T.V. C.V. M.M. W.M. S.J.C. A.V. and P.C.; funding acquisition, T.S. P.D. and H.B.L.; supervision, T.S. M.R. P.D. and H.B.L.; writing ? original draft, T.V. and H.B.L.; writing ? review & editing, T.V. C.V. M.M. T.L. M.R. P.D. and H.B.L. H.B.L. is an inventor on a patent describing the VirScan technology (US patent no. 15/105,722). H.B.L. is a founder of Portal Bioscience, Alchemab and ImmuneID, and is an advisor to TScan Therapeutics. Publisher Copyright: © 2021 Elsevier Inc.

King's Authors

Abstract

Human immune responses to viral infections are highly variable, but the genetic factors that contribute to this variability are not well characterized. We used VirScan, a high-throughput epitope scanning technology, to analyze pan-viral antibody reactivity profiles of twins and SNP-genotyped individuals. Using these data, we determined the heritability and genomic loci associated with antibody epitope selection, response breadth, and control of Epstein-Barr virus (EBV) viral load. 107 EBV peptide reactivities were heritable and at least two Epstein-Barr nuclear antigen 2 (EBNA-2) reactivities were associated with variants in the MHC class II locus. We identified an EBV serosignature that predicted viral load in peripheral blood mononuclear cells and was associated with variants in the MHC class I locus. Our study illustrates the utility of epitope profiling to investigate the genetics of pathogen immunity, reports heritable features of the antibody response to viruses, and identifies specific HLA loci important for EBV epitope selection.

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