Identification of opioid-induced innate immune dysregulation among people living with HIV

Project Summary Highly active antiretroviral therapy (ART) has dramatically improved survival and reduced progression to AIDS for people-living-with-HIV (PWH). However, PWH remain at significantly increased risk for diseases associated with chronic systemic inflammation, such as coronary artery disease, stroke, cognitive disorders, and some malignancies. Substance-use-disorders (SUD) are associated with HIV-disease progression, regardless of ART use. Understanding if and how opioids impact immunity among PWH is important due to the increased risk of opioid-use-disorder (OUD) among PWH, and the vulnerability of PWH to co-morbidities driven by immune dysregulation. This proposal aims to determine if chronic opioid exposure (COE) among PWH who are experiencing OUD is a driver of dysregulated innate immunity. Our published work and preliminary data demonstrate that monocytes are vulnerable to opioid-associated disruption of both pro- and anti-inflammatory functions among PWH, regardless of HIV viral load. In this dissertation proposal, I will address my hypothesis that COE among PWH results in increased reliance on glycolysis during a resting state, disruption of mTORC1 signaling, and impaired metabolic plasticity in response to stimulation that compromises both pro- and anti- inflammatory monocyte functions. Findings from this proposal will open the door for therapeutics that ameliorate opioid-induced monocyte dysregulation and advance our understanding of the off-target effects of long term opioid-exposure.