The ability of HIV-1 to mutate represents a major challenge to current vaccine approaches. However, some individuals achieving control of HIV during natural infection seem unique in their dominant targeting by cellular immune responses of conserved regions of HIV that, if mutated, exact a substantial impact on viral replicative capacity, or fitness. Notably, the partial suppression of HIV in treated individuals harboring viruses with drug-resistant mutations has also been linked to impaired viral fitness. The convergence of these observations suggests that vaccines designed to focus immune responses narrowly against regions of HIV susceptible to highly deleterious mutations might prove effective in controlling viral replication to levels that slow disease progression and reduce transmission. Therefore, it will be crucial to identify these "Achilles heels" of HIV that might represent uniquely susceptible targets, and test whether vaccine constructs enabling specific targeting of CD8(+) T-cell responses against such regions would enable the control of HIV and SIV.