PROJECT SUMMARY An estimated 15 million children worldwide are living with perinatal HIV and antiretroviral (ARV) exposure, but are HIV-uninfected (PHEU). Recent studies reveal cognitive challenges, mental health problems, and increased rates of risk-taking behaviors including substance use among youth with PHEU (YPHEU). Existing, cross-sectional neuroimaging studies indicate disrupted brain development among YPHEU, yet the underlying neural mechanisms, particularly related to prenatal HIV and ARV exposure, are not well understood. Dysfunction of networks supporting emotional regulation has been linked with childhood psychopathologies and risk-taking behavior in youth, yet we know little in YPHEU despite increased risk behaviors. We propose a longitudinal investigation to address these gaps in our current understanding. Our central hypothesis is that disruption of networks supporting emotion regulation, and interaction with other developmental risks, are key to understanding deficits in mental health, cognition and behavior in YPHEU. We will assess brain network development, mental health, self-regulation and other cognitive domains, and risk-taking behavior, utilizing functional and structural neuroimaging, clinical and computer-based assessments and tasks, in 190 YPHEU (10-14 years) at baseline, and 2 years later. Participants will be recruited from the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicity Study (SMARTT). Aim 1 will leverage harmonized age- and gender-matched neuroimaging and behavioral data from the NIH funded ABCD study on over 10,000 children age 9-10 years followed yearly, to compare with trajectories of brain network development, cognition and behavior, as well as their relationships among YPHEU. Aim 2 will examine the impact of type and timing of perinatal ARVs and other perinatal exposures such as substance use on brain network development within YPHEU. We will also examine social and structural factors that may have independent effects on brain development or interact with perinatal exposures. To further our understanding of lifetime implications of perinatal exposures, exploratory Aim 3 will explore long-term brain network and behavioral consequences, and their effect on transition to adult independence, in 50 young adults with PHEU and 50 with perinatally acquired HIV (PHIV), age 22-29, enrolled in the PHACS Adolescent Master Protocol-Up (AMP Up) study. We will leverage harmonized age- and gender-matched healthy young adult neuroimaging and behavioral data from the NIH funded Human Connectome Project to compare outcomes. Recognizing significant public health implications of the effects of ARV exposure on long-term cognitive and behavioral outcomes among YPHEU, this project, leveraging multiple NIH-supported multicenter studies and established collaborations, will identify mechanisms driving cognitive and behavioral outcomes, critical data for informing much needed prevention and intervention ...