title: Antagonism of cytotoxic T lymphocyte-mediated lysis by natural HIV-1 altered peptide ligands requires simultaneous presentation of agonist and antagonist peptides.
abstract: 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 restricted epitope SLYNTVATL on recognition by anti-HIV CTL. Most of these naturally occurring mutants escaped killing by one CTL line and the majority acted as CTL antagonists. We also investigated whether CTL exposed to a strict antagonist peptide restricted by HLA A2 were unresponsive when exposed to targets presenting the wild-type sequence. The results show that antagonism of anti-HIV CTL killing requires the simultaneous presence of agonist and antagonist peptide. We found no evidence that CTL exposed to an antagonist received a functionally negative signal since these CTL retained an unimpaired capacity to lyse targets bearing wild-type peptide.
authors.affiliation: Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, GB. asewell@worf.molbiol.ox.ac.uk
authors.forename: A K
authors.initials: AK
authors.lastname: Sewell
authors.forename: G C
authors.initials: GC
authors.lastname: Harcourt
authors.forename: P J
authors.initials: PJ
authors.lastname: Goulder
authors.forename: D A
authors.initials: DA
authors.lastname: Price
authors.forename: R E
authors.initials: RE
authors.lastname: Phillips
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D017635:Clonal Anergy; D003602:Cytotoxicity, Immunologic; D015683:Gene Products, gag / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D008024:Ligands; D010455:Peptides / Q000276:immunology*; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D015683:Gene Products, gag; D015488:HIV Antigens; D015789:HLA-A2 Antigen; D008024:Ligands; D010455:Peptides; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1