Abstract
People with HIV (PWH) on combination antiretroviral therapy have an elevated risk for aging-related non-AIDS comorbidities. We assess whether HIV infection accelerates biological aging in two independent cohorts of PWH using six organ-specific and three organism-wide aging clocks derived from plasma proteomics of healthy individuals. Proteomic age acceleration significantly correlates with DNA methylation age and is linked to comorbidities and mortality. HIV infection accelerates systemic biological aging, with Mendelian randomization demonstrating causality between organ aging and inflammatory or metabolic complications. Accelerated aging in PWH is further related to the total HIV reservoir, and specific antiretroviral drugs reduce age acceleration. These data reveal important causal effects between chronic HIV infection, antiretroviral medication, biological aging and age-associated diseases, highlighting targets for improving health span in PWH.