Integrated neuroimmune model of problematic substance use and depression in people living with HIV

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PROJECT SUMMARY Despite major advances in the treatment of HIV, people living with HIV (PLWH) experience greater burdens of multiple aging-related chronic diseases compared to people without HIV. Substance use, depression, and systemic inflammation are risk factors for aging-related chronic diseases and occur at higher rates among PLWH. Research is needed to identify factors that drive substance use, depression, and systemic inflammation among PLWH in young adulthood, at ages when chronic disease prevention is still feasible. The brain’s central executive network (CEN) plays a key role in exerting self-control, reappraising stressful stimuli, and managing intrusive thoughts. These skills are critical for managing negative emotions when facing stressful life circumstances. Lower CEN function may thus increase susceptibility to stress-related mental health outcomes, such as depression and substance use. Among people living with HIV, greater substance use and depression may reduce adherence to antiretroviral therapy (ART). Reduced ART adherence may lead to greater systemic inflammation. Greater systemic inflammation may lead to lower CEN function. Lower CEN function, in turn, may further increase susceptibility to problematic substance use and depression. PLWH may therefore be at risk of falling into a vicious cycle of increased depressive symptoms, increased substance use, lower ART adherence, increased systemic inflammation, and reduced CEN function. This project will test an integrated neuroimmune model of problematic substance use and depression in a sample of young adults living with HIV (n=246) who are enrolled in RADAR, a cohort study of sexual and gender minority youth assigned male at birth (e.g., gay and bisexual men, trans women, non-binary individuals). This project has considerable clinical importance because previous research suggests that CEN function can be improved through interventions such as cognitive training, meditation, and neuromodulation. Improving CEN function may therefore prove to be an important new component of HIV care plans aimed at reducing substance use, improving mental health, maximizing ART adherence, and reducing systemic inflammation among PLWH. To make this novel project feasible, the applicant has assembled a team of mentors with expertise in neuroscience, clinical psychology, and HIV pathogenesis. The applicant’s primary career goal is to establish an independently funded research program on the neuroimmunology of substance use, mental health, and chronic aging-related diseases among people living with HIV (PLWH). To this end, the applicant will receive advanced training and research experience in three interrelated research domains relevant to his career goals: (1) Problematic substance use among PLWH, (2) Neuroimaging of brain connectivity, and (3) Chronic inflammation in PLWH. This project will also provide opportunities and formal training to further develop his skills in manuscript writing, grant development, and project management. Building proficiency in these key skills and research domains will equip the applicant to become an independently funded investigator in HIV research.