Despite significant advancements in understanding HIV pathogenesis, a vaccine has not been discovered. Findings from the MRKAd5 and RV144 HIV vaccine trials suggest that other components of the host immune response, specifically innate immunity, need to be investigated. Immune activation is an important element of the host’s response to pathogens; however, chronic immune activation may promote HIV replication and co-receptor expression. Natural killer (NK) cells are key actors in innate host immune responses through early viral control and may promote the development of adaptive immune responses. Thus, it is plausible that pre-existing levels of immune activation and NK cell function are associated with HIV acquisition. Immune responses among highly exposed, seronegative (HESN) individuals provide a unique opportunity to study correlates of protection that are associated with a natural resistance to HIV infection. We propose a case-control study nested within an HIV-discordant couples cohort in Nairobi, Kenya, which will compare HESN partners who seroconvert to those who do not. The overall goal of this project is to determine whether host immune activation state and NK cell activity influence susceptibility to HIV. Understanding the factors conferring protection against HIV will provide useful information that may be used for the development and design of new vaccines.