Persons with HIV on combination antiretroviral therapy (cART) are at increased risk of the premature development of age-associated non-communicable comorbidities (AANCC), including cardiovascular, chronic kidney, liver and pulmonary disease, diabetes mellitus, osteoporosis, non-AIDS associated malignancies, and neurocognitive impairment. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated ageing. The underlying pathogenesis is likely to be multifactorial and include sustained immune activation, both systemically and within the central nervous system.By building on an established infrastructure for conducting longitudinal HIV cohort studies in Amsterdam and London, we will provide a detailed, prospective evaluation of AANCC among HIV-infected patients suppressed on cART and appropriately chosen and comparable non-infected controls. In this way, we will provide a robust estimate of the effect of treated HIV infection on the prevalence, incidence and age of onset of AANCC, thus clearly establishing a link between HIV and AANCC.Through the “Human Immune System” (HIS) mouse model, experimental studies will permit us to differentiate the effects of HIV and cART on metabolic outcomes when applied under controlled conditions, thereby further elucidating the causative nature of the link between HIV and AANCC.To further clarify potential pathogenic mechanisms underlying this causative link, including the possible induction of an inflammation-associated accelerated ageing phenotype, biomarkers which reflect each of these mechanisms will be investigated in biomaterial obtained from HIS mice and humans, and subsequently validated in patients with HIV on cART.The successful execution of the experimental and clinical research outlined in this proposal will be ensured through a strong interdisciplinary collaboration between clinical, basic and translational scientists bridging the fields of HIV, AANCC and ageing.