Epitope length variants balance protective immune responses and viral escape in HIV-1 infection

Phillip Pymm; Stefan Tenzer; Edmund Wee; Mirjana Weimershaus; Anne Burgevin; Simon Kollnberger; Jan Gerstoft; Tracy M Josephs; Kristin Ladell; James E McLaren; Victor Appay; David A Price; Lars Fugger; John I Bell; Hansjörg Schild; Peter van Endert; Maria Harkiolaki; Astrid K N Iversen

doi:10.1016/j.celrep.2022.110449

Epitope length variants balance protective immune responses and viral escape in HIV-1 infection

Cell Rep. 2022 Mar 1;38(9):110449. doi: 10.1016/j.celrep.2022.110449.

Authors

Phillip Pymm¹, Stefan Tenzer², Edmund Wee³, Mirjana Weimershaus⁴, Anne Burgevin⁴, Simon Kollnberger⁵, Jan Gerstoft⁶, Tracy M Josephs⁷, Kristin Ladell⁵, James E McLaren⁵, Victor Appay⁸, David A Price⁹, Lars Fugger¹⁰, John I Bell¹¹, Hansjörg Schild², Peter van Endert⁴, Maria Harkiolaki¹², Astrid K N Iversen¹³

Affiliations

¹ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DS, UK; Walter and Eliza Hall Institute of Medical Research, University of Melbourne, 1G Royalparade, Parkville, VIC 3052, Australia.
² Institute of Immunology, University Medical Center of the Johannes-Gutenberg University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
³ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DS, UK.
⁴ Institut National de la Santé et de la Recherche Médicale, Unité 1151, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker, 149 Rue de Severs, 75015 Paris, France; Centre National de la Recherche Scientifique, UMR8253, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker, 149 Rue de Severs, 75015 Paris, France.
⁵ Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Heath Park, CF14 4XN Cardiff, UK.
⁶ Department of Infectious Diseases, Rigshospitalet, The National University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
⁷ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, VIC 3052, Australia.
⁸ Institut National de la Santé et de la Recherche Médicale, Unité 1135, Centre d'Immunologie et des Maladies Infectieuses, Sorbonne Université, Boulevard de l'Hopital, 75013 Paris, France; International Research Center of Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto City 860-0811, Japan.
⁹ Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Heath Park, CF14 4XN Cardiff, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Tenovus Building, CF14 4XN Cardiff, UK.
¹⁰ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DS, UK; Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DS Oxford, UK.
¹¹ Office of the Regius Professor of Medicine, The Richard Doll Building, University of Oxford, Old Road Campus, OX3 7LF Oxford, UK.
¹² Structural Biology Group, Wellcome Trust Centre for Human Genetics, University of Oxford, Old Road Campus, OX3 7LF Oxford, UK; Diamond Light Source, Harwell Science and Innovation Campus, Fermi Avenue, OX11 0DE Didcot, UK.
¹³ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DS, UK. Electronic address: astrid.iversen@ndcn.ox.ac.uk.

Abstract

Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B^∗27:05. We find that proteasomal activity generates multiple length variants of KK10 (4-14 amino acids), which bind TAP and HLA-B^∗27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses. Structural analyses reveal that all epitope forms bind HLA-B^∗27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B^∗27:05. Common viral escape mutations abolish (L136M) or impair (R132K) production of KK10 and longer epitope forms. Peptide length influences how well the inhibitory NK cell receptor KIR3DL1 binds HLA-B^∗27:05 peptide complexes and how intraepitope mutations affect this interaction. These results identify a viral escape mechanism from CTL and NK responses based on differential antigen processing and peptide competition.

Keywords: HIV-1; HLA-B(∗)27:05; KIR3DL1; crystal structures; cytotoxic T lymphocytes; differential antigen processing; immune-response inhibition; natural killer cells; peptide competition; viral escape.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Amino Acids
Antigen Presentation
Epitopes, T-Lymphocyte
HIV Infections*
HIV-1*
HLA-B Antigens / genetics
Humans
Peptides

Substances

Amino Acids
Epitopes, T-Lymphocyte
HLA-B Antigens
Peptides

Grants and funding

WT_/Wellcome Trust/United Kingdom