Over 60,000 young adults are living with HIV in the US today, many of whom acquired HIV at birth. This group of adults with perinatally acquired HIV (pHIV) has not seen improvements in the prevalence of HIV- related co-morbidities, including poor cognitive outcomes. Despite this trend, little is known about the prognosis and pathogenesis of pHIV-related cognitive impairment in adulthood. Cognitive dysfunction occurs in up to half of individuals living with HIV, and is directly associated with immune activation in adults with horizontally acquired HIV (hHIV). In contrast, CD8+ T-cell and monocyte activation in our cohort of children with pHIV in Southeast Asia correlates with better cognitive scores suggesting an adapted immune-host response in those who are long-term survivors of pHIV. This adapted state has not been well studied. The goal of our proposed study is to address key gaps in our understanding of 1) cognitive trajectories and 2) biomarkers of cognitive resilience in adults with pHIV, through a recently initiated longitudinal cohort study of adults with pHIV in Connecticut. We will evaluate 1) cognitive performance and 2) interactions between peripheral and cerebrospinal fluid (CSF) immunologic markers, neuroimaging and cognition using a novel analytic method, group based trajectory modeling. This study will determine the prognosis of cognitive impairment and further characterize the biologic underpinnings of cognitive resilience as potential neuroprotective targets in adults with pHIV. The candidate is a pediatric neurologist with specialized training in neuro-infectious diseases. Dr. Patel is committed to improving our understanding of the pathogenesis of and treatment for poor neurologic outcomes following pHIV. The proposal will capitalize on Dr. Patel's prior training and mentored research experience in group based trajectory analysis of longitudinal cognitive data in children with pHIV, while enabling her to build expertise in 1) flow cytometry methods and analyses, 2) utilizing diffusion tensor imaging as a research tool, and 3) dual trajectory analysis, a complex modeling technique to assess contemporaneous changes in longitudinally acquired biomarker and cognitive data. Dr. Patel has assembled a mentorship committee comprised of leaders in the pathogenesis of neurologic injury in adults with hHIV (Serena Spudich, MD, primary mentor), biomarkers of disease progression in pHIV (Elijah Paintsil, MBChB, co-mentor), and biostatistics and imaging markers of cognitive impairment in pHIV (Robert Paul, PhD, co-mentor). The knowledge and experience gained from this proposal will allow Dr. Patel to successfully compete for R01 funding to further evaluate the pathogenesis and prevention of pHIV-related neurologic morbidity. Her future R01 applications will focus on cerebral HIV compartmentalization in adults with pHIV and analyzing cellular subsets identified in the proposed study as linked to cognitive resilience in CSF using mass cytometry.

PROJECT NARRATIVE Due to advances in combination antiretroviral therapy, individuals with perinatal HIV are living into adulthood and are subject to long-term complications of HIV-associated neurologic injury. The prognosis and pathogenesis of cognitive impairment related to perinatal HIV, including its relationship to immune activation, is unknown. The objective of this proposal is to understand the immunologic mechanisms that underlie cognitive impairment and resilience in adults with perinatal HIV.