To understand how broad recognition of HIV-1 variants may be achieved we examined T-cell reactivity in newly infected persons as well as vaccine recipients to a broad spectrum of potential T-cell epitope (PTE) variants containing conservative, semi-conservative and non-conservative amino acid substitutions. Among early infected persons T-cells recognized epitope variants with one substitution at a significantly higher frequency versus those with two (P=0.0098) and three (P=0.0125) substitutions. Furthermore T-cells recognized variants containing conservative substitutions at a higher frequency versus those containing semi-conservative (P=0.0029) and non-conservative (P<0.0001) substitutions. Similar effects were observed on recognition of variants by vaccine-induced T-cells. Moreover even when variants were recognized, the IFN-gamma and granzyme B responses as well as T-cell proliferation were of lower magnitude. Finally, we show that epitope distribution is strongly influenced by both processing preferences and amino acid entropy. We conclude that induction of broad immunity is likely to require immunogen sequences that encompass multiple variants. However, cost-effective design of peptide and sequence based vaccine immunogens that provide maximal coverage of circulating sequences may be achieved through emphasis on virus domains likely to be T-cell targets.