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.
Highlights
Human leukocyte antigen (HLA)-B*27:05 and human leukocyte antigen (HLA)-B*57:01/03 show robust protective effects in human immunodeficiency virus type-1 (HIV-1) infection (Goulder and Walker, 2012)
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 transporter associated with antigen processing (TAP) and HLA-B*27:05
Summary
Human leukocyte antigen (HLA)-B*27:05 and HLA-B*57:01/03 show robust protective effects in human immunodeficiency virus type-1 (HIV-1) infection (Goulder and Walker, 2012). The positive clinical impact of HLA-B*27:05 is linked to CD8+ cytotoxic T lymphocyte (CTL) responses directed against a single HIV-1 epitope in the viral capsid protein p24 Gag (131KRWIILGLNK140) (Feeney et al, 2004; Goulder et al, 1997; Goulder and Watkins, 2008; Nixon et al, 1988). Weaker clinical benefits have been associated with the activity of inhibitory natural killer (NK) cells in HLA-B*27:05+ patients (Martin and Carrington, 2013; Martin et al, 2007) It remains unclear precisely how cellular immune responses directed against a single HIV-1 epitope can delay the onset of acquired immune deficiency syndrome (AIDS) (Goulder and Walker, 2012; Goulder and Watkins, 2008)
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