Determinants of natural HIV-1 control

HIV-1 infection usually progresses to AIDS within 10 years in antiretroviral therapy untreated individuals, but there is a group of infected individuals, known as controllers, who maintain low plasma HIV-1 RNA levels and normal CD4+ T-cell counts for many years. Evidence suggests that the mechanisms of viral control in these individuals are heterogeneous. In this review, we highlight the viral and host factors, particularly host immunological and immunogenetic factors that are associated with controller status. Despite the broad heterogeneity within controllers, there is compelling evidence that cytotoxic CD8+ T lymphocyte responses act as the main driver of control in the majority of these individuals, especially in those with protective HLA-I alleles. Further investigation of controllers without protective HLA-I alleles is required as it seems that this subset exhibits more durable control of HIV-1 disease progression. Understanding the immune defense mechanisms in controllers provides hope for harnessing these responses in the general population, either for protective or therapeutic vaccines or to achieve a functional cure in infected individuals.