MOLECULAR ANALYSIS OF PRESENTATION BY HLA-A2.1 OF A PROMISCUOUSLY BINDING V3 LOOP PEPTIDE FROM THE HIV-1 ENVELOPE PROTEIN TO HUMAN CYTOTOXIC T-LYMPHOCYTES

P18(IIIB) is a highly immunogenic peptide from the V3 loop of the HIV- 1 gp160 envelope protein that is presented promiscuously by multiple c lass I MHC molecules, Understanding the molecular basis for promiscuou s presentation may have many practical applications, As the highly pre valent HLA-A2.1 class I molecule is known to present P18(IIIB) for rec ognition by cytotoxic T lymphocytes (CTL) found in peripheral blood mo nonuclear cells of HIV+ donors, a P18(IIIB)-specific CTL line was gene rated from an HLA-A2(+), HIV- donor in order to define the molecular b asis for, and ultimately improve upon the binding of, this peptide to HLA-A2.1. The minimal epitope recognized by the line was a decamer, I1 0, with the sequence RGPGRAFVTI. Interestingly, this decamer is identi cal to the minimal epitope from P18(IIIB) seen by murine CTL restricte d by H-2D(d), A panel of Ala-substituted peptides was employed in MHC- binding and T cell response studies to identify MHC- and TCR-binding r esidues, Notably, many of the agretopic and epitopic residues identifi ed were identical to those involved in the corresponding interactions of I10 with the H-2D(d) MHC molecule and murine Il0-specific CTL, The I10 peptide does not contain the described HLA-A2.1 binding motif. ins tead a Pro at P3, a Phe at P7 and an Ile at P10 are utilized for MHC b inding, Agretopic residue similarities with the hepatitis a nucleocaps id decamer suggest that these residues may comprise an alternative mot if of anchors utilized by decamers for binding to HLA-A2.1.