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

Pymm, Phillip, Tenzer, Stefan, Wee, Edmund, Weimershaus, Mirjana, Burgevin, Anne, Kollnberger, Simon, Gerstoft, Jan, Josephs, Tracy M., Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, McLaren, James E. ORCID: https://orcid.org/0000-0002-7021-5934, Appay, Victor, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Fugger, Lars, Bell, John I., Schild, Hansjörg, van Endert, Peter, Harkiolaki, Maria and Iversen, Astrid K.N. 2022. Epitope length variants balance protective immune responses and viral escape in HIV-1 infection. Cell Reports 38 (9) , 110449. 10.1016/j.celrep.2022.110449

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Publisher:	Cell Press
ISSN:	2211-1247
Date of First Compliant Deposit:	25 March 2022
Date of Acceptance:	7 February 2022
Last Modified:	03 May 2023 17:16
URI:	https://orca.cardiff.ac.uk/id/eprint/148900

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