ANTAGONISM OF CYTOTOXIC T-LYMPHOCYTE-MEDIATED LYSIS BY NATURAL HIV-1 ALTERED PEPTIDE LIGANDS REQUIRES SIMULTANEOUS PRESENTATION OF AGONIST AND ANTAGONIST PEPTIDES

Mutations in human immunodeficiency virus (HIV) cluster in cytotoxic T lymphocyte (CTL) epitopes (Phillips, R. E. et al., Nature 1991. 354: 453) and are subject to immune-mediated positive selection (Price, D. A. et al., Proc. Natl. Acad. Sci. USA 1997. 94: 1890). We studied the effects of naturally occurring mutations in the HIV-1 p17 Gag HLA A2 r estricted epitope SLYNTVATL on recognition by anti-HIV CTL. Most of th ese naturally occurring mutants escaped killing by one CTL line and th e majority acted as CTL antagonists. We also investigated whether CTL exposed to a strict antagonist peptide restricted by HLA A2 were unres ponsive when exposed to targets presenting the wild-type sequence. The results show that antagonism of anti-HIV CTL killing requires the sim ultaneous presence of agonist and antagonist peptide. We found no evid ence that CTL exposed to an antagonist received a functionally negativ e signal since these CTL retained an unimpaired capacity to lyse targe ts bearing wild-type peptide.