Lars Henrik Fugger

HIV-1 Adaptation to Antigen Processing Results in Population-Level Immune Evasion and Affects Subtype Diversification

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Stefan Tenzer, Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
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  • 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., Denmark
  • 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., Denmark
  • Robert Gifford, Aaron Diamond AIDS Research Center, 455 First Avenue, New York, NY 10016, USA., Denmark
  • 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., Denmark
  • 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., Denmark
  • 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.
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  • Jan Gerstoft, Department of Infectious Diseases, Rigshospitalet, The National University Hospital, Blegdamsvej 9, 2100 Kbh Ø Copenhagen, Denmark.
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  • Nadja Akkad, Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
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  • Daniel Lunn, Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK., Denmark
  • Lars Fugger
  • 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.
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  • 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. Electronic address: astrid.iversen@ndcn.ox.ac.uk.

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.

Original languageEnglish
JournalCell Reports
Volume7
Issue2
Pages (from-to)448-63
Number of pages16
ISSN2211-1247
DOIs
Publication statusPublished - 24 Apr 2014

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