HIV-1-specific CTLs, which can kill HIV-1-infected cells, play an important role in control HIV-1 replication. There are growing evidences that they select HIV-1 escape mutations so that escape HIV-1 mutants become dominant in the donors. A recent study analyzing approximately 2800 HIV-1 infected individuals in 9 different cohorts demonstrated that HIV escape mutants accumulated in the cohorts, demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.