The propensity of HIV-1 to undergo sequence variation, particularly in the envelope glycoprotein gp120, complicates vaccine development and may enable the virus to evade ongoing immune responses in infected individuals. We present here a molecular analysis of the effects of this variability on human T cell recognition of HIV-1 gp120. Synthetic peptides representing a defined CD4+ human T cell epitope in gp120 were used to survey gp120 molecules from various HIV-1 strains for the capacity to be recognized in the context of a single human MHC molecule, DR4. Variation affected recognition at two levels. For some strains, variation in this epitope was sufficient to alter the interaction of Ag receptors on gp120-specific human T cell clones with peptide-DR4 complexes on APC. In the case of two strains, the natural variation was sufficient to prevent the critical initial interaction between the relevant gp120 peptides and DR4 on the APC. However, these strains were highly divergent from the reference strain. Thus it is encouraging to note that the range of natural sequence variation in this T cell epitope falls, for the most part, within the range of peptide sequences that can be accommodated by the relevant human MHC molecule.

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