PROJECT ABSTRACT/SUMMARY. The proposed R01 is built upon the premise that: 1) Cognitive impairment (CI) persists even in the context of HIV viral suppression; 2) women living with HIV (WLWH) experience disproportionate burden of CI and have higher rates of, and stronger associations with, many of the underlying biopsychosocial risk factors for CI, as well as unique sex-specific risk factors; 3) immune activation persists in the context of viral suppression; 4) immune activation (e.g., Interleukin[IL]-6, sCD163) is a consistent risk factor of CI in HIV; 5) neurobiological pathways affecting cognitive functions are activated by HIV directly and indirectly through immune activation; 6) psychosocial factors such as stigma/discrimination, depression, and substance use impair cognitive functions and are associated with heightened immune activation, likely both directly and indirectly through reduced ART levels. By leveraging the strong infrastructure of the Women's Interagency HIV Study (WIHS), including existing behavioral data and specimen, the current longitudinal study will fill significant gaps in the field by examining the role of the neurobiological pathways whereby chronic immune activation leads to CI phenotypes in a large phenotypically well-defined group of WLWH. In a highly cost-effective approach, we will use existing biospecimen to assess biomarkers of chronic immune activation and neurobiological pathways and link them to existing neuropsychological assessments among N=500 WLWH aged 26 and older (Median age = 50) at 3 time points, to assess the following aims: Aim 1. To examine neurobiological pathways mediating the link between chronic immune activation and CI phenotypes in WLWH. Aim 2. To identify psychosocial factors affecting immune activation and neurobiological pathways. Aim 3. To examine the role of ART hair levels in mediating the effect of psychosocial factors in Aim 2 on immune activation and neurobiological pathway biomarkers. Impact. The results of this study will have several important clinical implications for the prevention and treatment of CI in WLWH, including behavioral and pharmacological therapies. Understanding the unique impact of biomarkers on cognitive outcomes will provide guidance on clinical intervention targets (e.g., immune therapy, dopamine reuptake inhibitors). Understanding the role of psychosocial factors in modulating immune activation and neurobiological pathways and the mediating role of ART adherence level, will inform behavioral intervention strategies (e.g., resilience, social support). Psychosocial factors may be particularly ideal intervention targets to curb the inflammatory cascade leading to CI.

PROJECT NARRATIVE Even in the context of viral suppression, WLWH have higher rates of cognitive impairment (CI) and stronger associations with many of the underlying CI biopsychosocial risk factors as well as unique sex-specific risk factors. We aim to examining putative biological pathways involving immune activation and neurobiological pathways (i.e., depletion of neurotransmitters, increased neurotoxic metabolites, and neuronal damage) to identify the markers that can be tightly linked to the clinical course of CI phenotypes in WLWH. This project examines also the role of psychosocial factors in impairing cognitive functions by exacerbating immune activation and neurobiological pathways directly and indirectly through ART levels adherence among WLWH.