PROJECT SUMMARY Globally, 2.7 million children are living with HIV and over 90% of them live in sub-Saharan Africa where HIV subtypes A, C and D are predominant. In adults, HIV subtypes differ in virulence and transmissibility, but whether the same is true in children is unknown. We have shown that viral fitness as measured by viral replication capacity (VRC) is correlated with markers of clinical disease progression, CD4+T cell loss, proviral HIV DNA load and inflammation in adults. Moreover, an HIV subtype hierarchy in VRC exists that is consistent with reported differences in the rate of disease progression. The role of viral specific features on immunologic and clinical outcomes in children with perinatal HIV (CPHIV), and on proviral DNA reservoir size, the main target in HIV cure strategies, are unknown and a significant gap in our knowledge of pediatric HIV pathogenesis. Perinatal HIV progresses much faster than acute HIV in adults, but a small portion of children with perinatal HIV (CPHIV) maintain healthy CD4 levels in the presence of viremia and have been termed pediatric nonprogressors (PNP). Study of this unique population of CPHIV may provide clues into the pathogenic factors that drive rapid disease progression or intrinsic viral or host factors that slow disease progression. The goal of our proposed study is to determine whether viral subtypes and VRC shape immune profiles and clinical outcomes in perinatal HIV. We will compare virologic and immunologic factors in PNP and slow progressors (SP) with pediatric progressors (PP) to elucidate pathogen- and host-specific mediators disease progression. We will leverage a biobank and corresponding immune database from the Pediatric Immune Activation (PIA) study that enrolled 156 CPHIV (including a subset of SP and PNP) and 82 children who were unexposed to HIV between 2011-2012 in Kenya. In Aim 1 we will identify viral subtypes and quantify VRC in viremic participants and determine associations with markers of HIV disease progression and proviral reservoir size. In Aim 2 we will probe whether viral subtypes and VRC are linked to inflammatory or exhausted immune profiles and HIV-specific T cell functions. In the last aim we will develop predictive mathematical models of perinatal HIV disease progression using individual virologic and immunologic profiles. Our paired virologic and immunologic measures and clinical outcome data combined with personalized computational models of clinical outcomes will identify protective viral and immune factors that mitigate perinatal HIV disease progression and proviral reservoir size. Our multidisciplinary research will fill fundamental knowledge gaps in how virologic factors shape pediatric HIV immunopathogenesis and disease progression and may stimulate innovative approaches towards HIV remission in children with perinatal HIV.