HIV-infected individuals are living longer in the antiretroviral therapy (ART) era, but remain at high risk for non-AIDS-associated diseases typically associated with aging and continue to have a markedly shorter life expectancy than the general population. The mechanisms mediating this increased risk of death remain unknown. While soluble inflammatory markers predict earlier mortality in this setting, no study has assessed whether T cell senescence predicts death among HIV-infected individuals maintaining treatment-mediated viral suppression. The goal of this proposal is to assess the relative contributions of persistent inflammation and immune senescence in early mortality in this setting. To address these issues, we propose a nested case control study within the Study of the Ocular Complications of AIDS (SOCA), a cohort of over 2,200 HIV-infected individuals who initiated antiretroviral therapy with a diagnosis of AIDS (CD4 count<200 or an opportunistic disease) and have been followed for nearly 12,000 person-years. Over 1000 participants are maintaining plasma HIV RNA levels <400 copies/ml on ART and 92 of these participants subsequently died from non-traumatic causes with a most recent plasma HIV RNA level <400 copies/ml. We will sample cryopreserved peripheral blood mononuclear cells (PBMC) and plasma from the last timepoint prior to death in these in these participants and match each case to 2 controls by duration of viral suppression, age, gender, and nadir CD4 count. We will compare soluble markers of inflammation and microbial translocation as well as levels of T cell activation, senescence, and proliferative capacity between cases and controls. We will also measure CMV-specific CD8 responses as asymptomatic CMV co-infection has been associated with T cell senescence and mortality in elderly HIV-uninfected individuals. We hypothesize that higher CMV-specific CD8 responses will be associated with greater T cell senescence, which will predict earlier mortality independent of plasma inflammatory markers. This study will be the first to assess whether T cell senescence predicts earlier mortality in HIV-infected individuals maintaining treatment-mediated viral suppression, potentially identifying targets for future interventions. PUBLIC HEALTH RELEVANCE: HIV-infected individuals are living longer in the antiretroviral therapy (ART) era, but remain at high risk for non-AIDS-associated diseases typically associated with aging and continue to have a markedly shorter life expectancy than the general population. The mechanisms mediating this increased risk of death remain unknown. While soluble inflammatory markers predict earlier mortality in this setting, no study has assessed whether T cell senescence predicts death among HIV-infected individuals maintaining treatment-mediated viral suppression. The goal of this proposal is to assess the relative contributions of persistent inflammation and immune senescence in early mortality in this setting.