The cytotoxic T-lymphocytes (CTL) response to three histocompatibility leukocyte antigen (HLA)-A2-restricted CTL epitopes was investigated in a cohort of 51 HLA-A2-positive human immunodeficiency-1 (HIV-1)-infected subjects. CTL activity was evaluated by testing peptide stimulated peripheral blood mononuclear cells (PBMC) in chromium release assays. The most prevalent CTL response was directed to the RT-peptide ILKEPVHGV (IV9) recognized by 37.3%. The p17-peptide SLYNTVATL (SL9), reported to be the immunodominant epitope in chronically infected untreated patients, was recognized only by 13.7%. Only 9.8% recognized both IV9 and SL9, and none recognized the RT-peptide VIYQYMDDL (VL9). CTL activity correlated significantly with absolute CD8 T-cell counts but not with CD4 counts, viral load, or antiviral therapy. Analysis of the recognition patterns of amino acid substitutions in the IV9 epitope revealed the presence of at least four functionally different T-cell receptors (TCR) in this cohort. All analyzed mutations within the TCR recognition site of this epitope could abrogate CTL recognition by individual CTL clones, but all were fully immunogenic for other CTL clones with peptide-sensitizing capacities similar to that of IV9. Further studies should be performed to evaluate whether a convergent epitope vaccination strategy using immunogenic variants of CTL epitopes is a feasible approach to broaden the TCR repertoire and to inhibit CTL escape.