The structural basis for the increased immunogenicity of two HIV-reverse transcriptase peptide variant/class I major histocompatibility complexes

Designing altered peptide ligands to generate specific immunological reacti vity when bound to class I major histocompatibility complexes is important for both therapeutic and prophylactic reasons. We have previously shown tha t two altered peptides, derived from human immunodeficiency virus (HIV)-rev erse transcriptase (RT) residues 309-317, are more immunogenic in vitro tha n the wild-type peptide. One peptide variant, I1Y, was able to stimulate RT -specific cytotoxic T cells from the blood of three HIV-infected individual s better than the wild-type BT peptide. Both I1Y and I1F peptide variants i ncrease the cell surface half-life of the peptide-class I complex approxima tely 3-fold over that of the RT peptide but have different immunological ac tivities. These peptides are candidates for the design of vaccines for HN d ue to their increased immunogenicity, To understand the basis for the incre ased cell surface stability compared with wild-type peptide and to understa nd the differences in T cell recognition between I1Y and I1F, we determined the x-ray crystal structures of the two class I MHC-peptide complexes, The se structures indicate that the increased cell surface half-life is due to pi-pi stacking interactions between Trp-167 of HLA-A2.1 and the aromatic P1 residues of I1F and I1Y, Comparison of the structures and modeling potenti al T cell receptor (TCR) interactions suggests that T cell interactions and immunogenicity are different between I1Y and I1F for two reasons. First, s ubtle changes in the steric and polar properties of the I1Y peptide affect TCR engagement. Second, water-mediated hydrogen bond interactions between t he P1-Tyr and the P4-Glu peptide residues increase peptide side chain rigid ity of residues critical for TCR engagement.