THE EFFECT OF A SINGLE AMINO-ACID SUBSTITUTION WITHIN THE V3 LOOP OF HIV-1 GP120 ON HLA-DR1-RESTRICTED CD4 T-CELL RECOGNITION

Viral variation has been proposed to play a role in the pathogenesis o f human immunodeficiency virus type-1 (HIV-1) infection, and is an imp ortant consideration in vaccine design. During the course of an infect ion, isolates with sequence changes in CD8 T-cell and B-cell epitopes arise. To determine whether sequence variation within the V3 loop of H IV-1 gp120 affects HLA-DR beta 10101-restricted CD4 T-cell recognitio n, we have generated CD4 T-cell clones (TLC) specific to gp120 V3 loop peptides. Four HLA-DR beta 10101-restricted groups of TLC were defin ed by distinct patterns of responses to a panel of peptides, consisten t with a highly diverse T-cell repertoire recognizing the 30 amino aci d stretch (296-326) of the gp120 V3 loop. Nevertheless, a single resid ue change at position 311 was found to abolish the recognition of two of the four groups of TLC. This was not due to an effect of the residu e at 311 on binding to major histocompatibility complex (MHC), because : (I) irrespective of the residue at 311, peptides competed well with the influenza haemaglutinin peptide 307-319 for binding to cell-bound DR1: and (2) R311-specific TLC were also HLA DR beta 10101 restricted . Instead, the substitution of arginine for serine at position 311 blo cked the interaction of the peptide with the T-cell receptor. Thus, de spite the diversity of the T-cell response to the V3 loop of HIV-1, a single amino acid change can have a considerable influence on the resp onding T-cell population. As residue 311 is one of the most variable o f the V3 loop residues, these results suggest that CD4 recognition can also exert pressure on viral variation consistent with a role for the se cells in antiviral immunity.