Effects of Medication for Opioid Use Disorder on Microglial Activation and Neurocognition in People Living with HIV

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to compare and contrasts the effects of different medications for opioid use disorder (MOUD) on driving abnormal immune activation in the central nervous system (CNS) in people living with HIV (PLWH) through the lens of epigenetic programming. Prior published research suggests that opioids and opioid receptor agonists lead to a proinflammatory state in the CNS through changes to myeloid cells. Conversely, pre- clinical studies suggest potential beneficial anti-neuroinflammatory effects of opioid antagonists. Cerebrospinal fluid (CSF) studies are a window into the CNS of PLWH, revealing a role for abnormal myeloid cell activation and persistent viral transcription in the CNS, despite apparent systemic viral suppression with ART. Our own single cell genomic studies of fresh CSF cells from PLWH have shown that a rare microglia-like myeloid cell population resides in the CSF in PLWH; that these cells are linked to HIV disease status; and are defined by a distinct epigenetic state consisting of alterations in chromatin accessibility of myeloid/microglia-like cell type specific proinflammatory genes. However, despite myeloid cells being recognized as crucial cellular mediators of CNS abnormalities in PLWH, the impact of different MOUD therapies on the epigenetic landscapes of CNS myeloid and other immune cells in PLWH remain uncharted. Our central hypothesis is that opioid antagonist MOUD (XR-naltrexone) suppresses myeloid cell activation by exerting anti-inflammatory epigenetic effects in CNS myeloid cells of PWH, thereby improving cognitive function; while, in contrast, opioid receptor full/partial agonists (methadone, buprenorphine) induce a pro-inflammatory epigenetic landscape increasing myeloid cell activation, and impairing cognitive function. This hypothesis will be tested in our established InSTRIDE Research MOUD program at Yale that includes a mobile health clinic to perform lumbar puncture and cognitive testing “on the road” meeting research participants in their own communities. We have assembled a multidisciplinary team with expertise in Neuro-HIV, addiction medicine including treatment of OUD, single cell epigenetics, HIV neuropsychology, and data science. In PLWH, we will longitudinally assess CSF biomarkers of neuroinflammation, neuronal injury, and myeloid cell activation over the course of either opioid antagonist or agonist MOUD treatment. Using single cell simultaneous profiling of epigenetic chromatin accessibility and gene expression from the same CSF cells, we will then ask whether there is damage to the epigenomes of CSF myeloid cells sustained during specific MOUD treatments that persists over time as epigenetic “scars”. Lastly, we will evaluate the effect of the different MOUD regimens on post-treatment cognitive trajectories and associations with post-MOUD CSF biomarker and single cell biological measures. The proposed work will significantly advance our understanding of how specific MOUD treatments interact at a molecular and cellular level in the CNS, potentially leading to improved treatments and outcomes for PLWH with opioid use disorder.