PAR-20-221: NIDA Avant-Garde - Abstract Alex K. Shalek ABSTRACT HIV-1 prevention and cure strategies are urgently needed for people who inject drugs (PWID) with opioid use disorder (OUD) or polysubstance used disorder (PSUD) given substantial risk for, and incidence of, HIV-1 and others infection. Most prophylactic and therapeutic strategies under development for HIV-1 and other infections rely on modulating host immunity. Nevertheless, we do not have a working knowledge of how opioids—which, themselves, are immunomodulatory—and the lived experiences of those with OUD or PSUD (inclusive of exposure to contaminated equipment, community infections, and physical and social environmental factors) alter immune function in the absence or presence of HIV-1 infection and, thus, the efficacy of interventions against HIV-1 and other pathogens. We hypothesize that opioids and OUD/PSUD modulate baseline immune responses in the host (“function”), as well as immunity against other pathogens (“fitness”), impacting prevention and cure strategies. Here, we propose a pioneering program to define, at unprecedented resolution, the cellular and molecular impact of OUD and PSUD on immune function and response to pathogens, such as HIV-1. We will also develop and utilize an innovative “compressed’ screening platform to functionally test, in high-throughput, informed chemical and biological perturbations for prevention and cure strategies. More specifically, we will deploy—and, where necessary, develop—cutting-edge single-cell and bulk genomic profiling methods to generate functional hypotheses on how OUD and PSUD alter critical physiology associated with drug metabolism (liver), innate mucosal defense (gastrointestinal tract (GI)), and adaptive immune function in tissues of relevance to HIV-1 (liver, GI, and peripheral blood mononuclear cells (PBMCS)). We will explicitly characterize and contrast changes in the presence and absence of HIV-1 infection. To systematically test resulting hypotheses, we will create and implement “compressed” perturbation screens to examine simultaneously the individual impact of multiple chemical and biological perturbations on limited primary samples (e.g., PBMCs, tissue biopsies). This will enable us to delineate how factors associated with several aspects of OUD and PSUD intersect with HIV-1 infection. Given my lab’s broad and yet deep interdisciplinary expertise in developing and applying innovative experimental and computational technologies to obtain mechanistic insights into the cellular and molecular drivers of human health and disease, and our team of committed clinical collaborators in Boston and beyond, we are uniquely positioned to successfully execute this pioneering, transformative investigation of the impact of OUD and PSUD on immune function. Overall, our work will define the immunological landscape of OUD and PSUD, and inform strategies to improve baseline immunity and the efficacy of preventions and cures against HIV-1 and...