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

• Published in: Cell reports (Cambridge) Vol. 38; no. 9; p. 110449
• Main Authors: Pymm, Phillip, Tenzer, Stefan, Wee, Edmund, Weimershaus, Mirjana, Burgevin, Anne, Kollnberger, Simon, Gerstoft, Jan, Josephs, Tracy M., Ladell, Kristin, McLaren, James E., Appay, Victor, Price, David A., Fugger, Lars, Bell, John I., Schild, Hansjörg, van Endert, Peter, Harkiolaki, Maria, Iversen, Astrid K.N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2022; Cell Press
• Subjects: Amino Acid Sequence; Amino Acids; Antigen Presentation; crystal structures; cytotoxic T lymphocytes; differential antigen processing; Epitopes, T-Lymphocyte; HIV Infections; HIV-1; HLA-B Antigens - genetics; HLA-B∗27:05; Humans; immune-response inhibition; KIR3DL1; Life Sciences; natural killer cells; peptide competition; Peptides; viral escape; HIV-1; natural killer cells; viral escape; HLA-B∗27:05; KIR3DL1; cytotoxic T lymphocytes; crystal structures; differential antigen processing; immune-response inhibition; peptide competition; HLA-B(∗)27:05
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110449

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. [Display omitted] •Proteasomal activity creates many length variants of the protective KK10 HIV-epitope•All KK10 length variants bind HLA-B∗27:05 through a conserved N-terminal motif•Short KK10 length variants outcompete immunogenic, longer variants for HLA binding•Epitope variant competition balances protective immune responses and viral escape Pymm et al. investigate how HIV-1 adapts to intracellular epitope processing preferences to escape cellular immune responses. Using the processing of the HLA-B∗27:05-restricted epitope KK10 as a model, they find that processing generates several epitope length variants and demonstrate that peptide competition can dampen cellular immune responses in the context of HLA-B∗27:05.