PROJECT SUMMARY/ABSTRACT Adolescent girls and young women (AGYW) remain at very high risk of HIV acquisition in sub-Saharan Africa and this increased risk is tied to social and interpersonal factors. Few studies in low- and middle-income countries have collected stress-responsive biomarkers to understand biological processes, such as the physiological stress response, that may underlie the increased risk of HIV infection observed among AGYW. Evidence is mounting for the association between social determinants of health and the physiological effects of stress in the United States and Europe, but it is lacking in sub-Saharan Africa. Stress has been associated with social determinants of health and with adverse outcomes in individuals with HIV; however, these studies are among adults and with small sample sizes and evidence is limited regarding incident HIV infection. The overarching objective of the proposed project is to generate preliminary evidence examining the relationships between psychosocial stressors; biological stress; and HIV prevention, care, and treatment in AGYW in South Africa. The project objective will be met through three Specific Aims: Using an existing and unique data source (HIV Prevention Trials Network 068 study) with information on psychosocial stressors, stress responsive biomarkers, and HIV incidence among a cohort of 2,533 AGYW that have been followed for 9 years in South Africa, in Aim 1 we will assess associations between acute (physical and sexual intimate partner violence, traumatic events) and chronic (food insecurity, depression, and low parental support) psychosocial stressors with stress-responsive immune biomarkers (C-reactive protein [CRP] titers, herpes simplex virus type 1 (HSV-1) titers, and cytomegalovirus (CMV)) among AGYW. We will use data from 1,517 AGYW with biomarker information available at the 2018/19 visit and will explore effect modification by HIV status and correlations with perceived stress. In Aim 2 we will conduct a case-cohort study of 849 AGYW to estimate the association between stress-responsive biomarkers during adolescence with sexual behavior and incident HIV infection at later time points. We will retrospectively test existing, stored biospecimens for cases and controls to assess these relationships. In Aim 3 we will estimate associations between stress- responsive biomarkers and antiretroviral therapy (ART) adherence and viral load among AGYW with HIV. We will use data from 164 AGYW with HIV along with information available about stress-responsive biomarkers, viral load, and ART from the 2018/19 visit. This study will provide preliminary data for an R34 application to develop and pilot an intervention mitigating the effects of physiological stress among AGYW to prevent HIV and improve access to care and treatment. The research aligns with the NIH HIV/AIDS research priority to advance cross-cutting areas of research and the Maternal and Pediatric Infectious Disease Branch (MPIDB) priorit...