HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification
Stefan Tenzer,
Hayley Crawford,
Phillip Pymm,
Robert Gifford,
Vattipally B. Sreenu,
Mirjana Weimershaus,
Tulio de Oliveira,
Anne Burgevin,
Jan Gerstoft,
Nadja Akkad,
Daniel Lunn,
Lars Fugger,
John Bell,
Hansjörg Schild,
Peter van Endert,
Astrid K.N. Iversen
Affiliations
Stefan Tenzer
Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
Hayley Crawford
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
Phillip Pymm
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
Robert Gifford
Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA
Vattipally B. Sreenu
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK
Mirjana Weimershaus
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
Tulio de Oliveira
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
Anne Burgevin
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
Jan Gerstoft
Department of Infectious Diseases, Rigshospitalet, The National University Hospital, Blegdamsvej 9, 2100 Kbh Ø Copenhagen, Denmark
Nadja Akkad
Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
Daniel Lunn
Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK
Lars Fugger
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
John Bell
Office of the Regius Professor of Medicine, The Richard Doll Building, University of Oxford, Old Road Campus, Roosevelt Drive 1, Oxford OX3 7LF, UK
Hansjörg Schild
Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
Peter van Endert
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
Astrid K.N. Iversen
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; Corresponding author
Summary: 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. : CD8+ T cell responses against HIV-1 effectively delay disease progression in a minority of patients with relatively rare HLA variants but are ineffective in most. Here, Tenzer et al. identify fundamental HIV-1 adaptation to the conserved human antigen-processing machinery that feeds epitopes to HLA. This adaptation occurs at subtype-specific motifs, facilitates subtype diversification, is predictable, and results in CD8 epitope abundances that correlate inversely with the HLA allele frequencies in affected populations. Thus, HIV vaccine immunogenicity might be increased by unnatural substitutions at subtype-specific motifs.
