Project Summary Globally, 2.7 million children are living with HIV and 270,000 new infections occur annually. With antiretroviral therapy (ART) that suppresses viremia these children are surviving through adolescence into adulthood, but ART may not fully restore immunologic health and inflammation may persist despite early ART initiation. In adults living with HIV (ALHIV) inflammation has been associated with higher incidence of cardiovascular, metabolic and neurocognitive age-related comorbidities than persons without HIV. Because immunologic and neurologic development occur alongside exposure to HIV and ART in children with perinatal HIV (CPHIV), the long-term consequences of inflammation may differ from adults and is largely unknown. In a cross-sectional study of Kenyan CPHIV, we previously reported that inflammation persists despite viral suppression on ART. The proposed research leverages this cohort in a 10-year follow up study to determine whether viral suppression on prolonged ART dampens immune activation, the pathogenic mediators of inflammation and the consequences of sustained inflammation with a global assessment of immunologic, cardiovascular, metabolic and neurocognitive outcomes. The follow up cohort will include 80 persons with perinatal HIV (PPHIV) on ART for ~11 years and 82 persons unexposed to HIV (HU). In Aim 1, the durability of inflammation and immune dysregulation in PPHIV on long-term ART with viral suppression will be assessed by comparing monocyte (sCD14, sCD163), T cell (CD38, HLA-DR) and plasma (hsCRP, TNF-α, IL-6) inflammatory markers and innate and adaptive immune cell subsets between baseline (T0, 2012 PIA study) and 10-year follow-up (T1) levels. The pathogenic role of viral reservoir size and replicative capacity and intestinal permeability on immune activation will also be assessed. In Aim 2 we will examine whether early (T0) or concurrent (T1) inflammatory markers correlate with clinical outcomes including 1) cardiovascular measures of myocardial function by echocardiogram and endothelial dysfunction by endothelial peripheral arterial tonometry (EndoPAT), 2) metabolic measures of insulin resistance by HOMA-IR and pancreatic beta cell function and stress by HOMA-B and proinsulin/C-peptide ratios and 3) neurocognitive assessments using NeuroScreen, a tablet-based tool that evaluates six neuropsychological domains most affected by HIV. The proposed study will be among the first to comprehensively examine multisystemic immunologic, cardiovascular, metabolic and neurocognitive outcomes in PPHIV in sub-Saharan Africa after prolonged viral suppression. Our research will fill fundamental knowledge gaps in understanding the role of early childhood inflammation in durable health outcomes of PPHIV, with potential to identify screening biomarkers and implement preventative interventions that mitigate HIV-related comorbidities so PPHIV can thrive as adults.