title: HIV-1 adaptation to antigen processing results in population-level immune evasion and affects subtype diversification.
abstract: The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8(+) T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.
authors.affiliation: Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK; Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Crawford
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK; Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK.
authors.forename: Phillip
authors.initials: P
authors.lastname: Pymm
authors.affiliation: Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gifford
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK.
authors.forename: Vattipally B
authors.initials: VB
authors.lastname: Sreenu
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1151, Centre National de la Recherche Scientifique, UMR8253, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Weimershaus
authors.affiliation: Africa Centre for Health and Population Studies, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, KwaZulu-Natal 3935, South Africa; Research Department of Infection, University College London, Cruciform Building, 90 Gower Street, London WC1E 6BT, UK.
authors.forename: Tulio
authors.initials: T
authors.lastname: de Oliveira
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1151, Centre National de la Recherche Scientifique, UMR8253, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Burgevin
authors.affiliation: Department of Infectious Diseases, Rigshospitalet, The National University Hospital, Blegdamsvej 9, 2100 Kbh Ø Copenhagen, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.affiliation: Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Akkad
authors.affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lunn
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK; Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK.
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.affiliation: Office of the Regius Professor of Medicine, The Richard Doll Building, University of Oxford, Old Road Campus, Roosevelt Drive 1, Oxford OX3 7LF, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.affiliation: Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1151, Centre National de la Recherche Scientifique, UMR8253, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK; Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK. Electronic address: astrid.iversen@ndcn.ox.ac.uk.
authors.forename: Astrid K N
authors.initials: AKN
authors.lastname: Iversen
mesh_terms: D000222:Adaptation, Physiological; D000353:Africa, Southern; D000595:Amino Acid Sequence; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005060:Europe; D005787:Gene Frequency; D015658:HIV Infections / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D015788:HLA-A1 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D008969:Molecular Sequence Data; D011153:Population / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000939:Epitopes; D015788:HLA-A1 Antigen
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