Genomic studies involving well-defined multicenter cohorts of HIV-1/AIDS covering multiple populations have led to a greater understanding of the role of host determinants in viral acquisition, disease progression, transmission, and response to anti-retroviral therapy. Similarly, recent knowledge on the virus genetic diversity has helped in elucidating mechanisms leading to the evolution of viral escape mutants and the role played by host immune determinants, in particular the major histocompatibility complex (MHC) associated genes. At least two alleles, HLA-B*27 and B*57, have been identified as ‘protective’ against HIV-1 while B*35 and B*53 act as susceptibility favoring factors. How human leukocyte antigen (HLA)-mediated selection drives the evolution of HIV-1 and which circulating variants are more likely to evade immune surveillance of the population are now beginning to become clear. Importantly, the rare HLA alleles in a population bear a selective advantage to the host because these can induce immune responses against pre-adapted viruses. It is conceivable that previously established protective HLA associations are shifting with the evolving cytotoxic T lymphocyte (CTL) epitopes and may not remain protective in future. At the same time, this process is unraveling novel sub-dominant epitopes of the virus which could now be incorporated as the dominant target CTL epitopes. An insight into the population-specific correlates of protection is hence necessary for designing future anti-HIV therapeutic and/or prophylactic vaccine formulation(s).