Unravelling the mechanisms of durable control of HIV-1

Untreated HIV-1 infection typically progresses to AIDS within 10 years, but less than 1% of infected individuals remain healthy and have normal CD4(+) T cell counts and undetectable viral loads; some individuals have remained this way for 35 years and counting. Through a combination of large population studies of cohorts of these 'HIV-1 controllers' and detailed studies of individual patients, a heterogeneous picture has emerged regarding the basis for this remarkable resistance to AIDS progression. In this Review, we highlight the host genetic factors, the viral genetic factors and the immunological factors that are associated with the controller phenotype, we discuss emerging methodological approaches that could facilitate a better understanding of spontaneous HIV-1 immune control in the future, and we delineate implications for a 'functional cure' of HIV-1 infection.