Corticostriatal glial and peripheral immune mechanisms of polysubstance use and associated comorbidities

About This Grant

Project Summary/Abstract Human immunodeficiency virus (HIV) and substance use are ongoing public health dilemmas throughout the United States and worldwide. Drugs such as cocaine and opioids can potentiate the pathophysiology of HIV within the central nervous system (CNS), exacerbating HIV-induced neurocognitive impairment among people living with HIV (PLWH) on antiretroviral therapy (ART). The recent sharp rise in cocaine overdose deaths is largely driven by co-use of synthetic opioids such as fentanyl. Polysubstance use (PSU) is very common among PLWH who use drugs, particularly PSU of cocaine and opioids. Nevertheless, very little is known regarding how cocaine and opioids interact to dysregulate reward learning and motivation, especially in the context of HIV. Taken together, identifying the unique cellular mechanisms underlying drug seeking and relapse-like behavior in the context of HIV and PSU is imperative for developing targeted and effective treatment strategies for substance use among PLWH. This proposal aims to elucidate the contribution of central and peripheral immune mechanisms to HIV-induced dysregulation of reward seeking, with the goal of identifying novel treatment targets for PLWH who use drugs. Our work thus far has revealed that mice infected with the chimeric HIV construct, EcoHIV, display potentiated cocaine-seeking behavior, impaired extinction learning, as well as dysregulated peripheral immune function. Moreover, our work has revealed a potential role of microglia and astrocytes in facilitating these deficits as well as independent and interactive effects of ART and EcoHIV on striatal neuroimmune function. Corticostriatal neural circuitry crucially mediates extinction learning and facilitates adaptive changes in behavior in response to changes in environmental contingencies. Moreover, corticostriatal dysfunction is heavily implicated in HIV at both the clinical and preclinical levels. Both cocaine and opioids disrupt peripheral immune function and homeostasis of corticolimbic glial cells, but no studies to date have interrogated how co-use of these drugs interact with HIV and ART to impair central and peripheral immune function. During the K99 phase of this proposal (Aims 1 & 2), I will leverage quantitative imaging and morphometric analysis of microglia and astrocytes to characterize the impact of opioid-cocaine PSU on the structural plasticity and reactivity of corticostriatal glial cells in the context of EcoHIV infection and ART. In parallel, I will also examine proinflammatory activation of peripheral lymphocytes and macrophages via flow cytometry and multiplex cytokine arrays. Transitioning to independence in the R00 phase, I will combine my training in flow cytometry and quantitative cellular imaging with my expertise in systems neuroscience to study the functional contributions of corticostriatal microglia to neurocircuit function in the context of HIV and PSU (Aim 3). This research has the potential to reveal novel, clinically-translational insights into the unique neuroimmune consequences of PSU in the context of HIV and ART treatment, which will help identify new treatment targets for comorbid HIV and PSU.