The effect of epitope variation on the profile of cytotoxic T lymphocyte responses to the HIV envelope glycoprotein

To address the relationship between viral and host factors during HIV infec tion, we analyzed the effect of viral mutations on T cell responses in sero positive, asymptomatic HLA-A2(+) individuals using four envelope (env)-spec ific peptides with the HLA-A*0201 binding motif. We showed that the natural sequence Variation was frequent within epitopes located in the C-terminal region of the env glycoprotein and was largely responsible for a lower env- specific cytotoxic T lymphocyte (CTL) activity in the peptide-stimulated cu ltures. The highest CTL responses in vitro were induced with conserved epit opes D1 and 4.3 that mapped to the N-terminal region of the env glycoprotei n, These peptides exhibited high binding affinity for HLA-A*0201 molecules and stimulated CD8(+) T cells of relatively limited TCR V beta chain repert oire. Decreased CTL activities to the D1 epitope were observed in the absen ce of any detectable viral mutation, and were associated with lower prolife rative responses and expression of the CD28 antigen. Results of this study demonstrate that the degree of sequence variation within a stimulatory epit ope of the viral quasispecies, as well as proliferative potential of the ef fector cells, are among the factors underlying decreased CTL activity in HI V-infected patients. These experiments also provide evidence that the D1 pe ptide might be useful for the development of vaccines and immune-based ther apy.