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.


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)-B27:05. We find that proteasomal activity generates multiple length variants of KK10 (4-14 amino acids), which bind TAP and HLA-B27:05. 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-B27:05 via a conserved N-terminal motif, and competition experiments show that the truncated epitope forms outcompete immunogenic epitope forms for binding to HLA-B27:05. 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-B27:05 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


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