Opioid-induced transcriptional reprogramming of cerebrospinal fluid immune cells drives neuroinflammation in SIV-infected rhesus macaques.

Background: Opioid use is disproportionately high among People with HIV (PWH). Although combined anti-retroviral therapy (ART) can dampen HIV-associated dementia, a large fraction of PWH continue to experience neurocognitive deficits which are further exacerbated by opioid use. In the present study, we performed single cell transcriptomic profiling of cerebrospinal fluid (CSF) immune cells to explore their functional characteristics in opioid mediated neurological disorders among PWH using the SIV/rhesus macque model. Methods: In this study, we utilized CSF cells from morphine- and saline-administered, SIV-infected, ART-treated rhesus macaques (RMs). The CSF scRNA-Seq was performed longitudinally at baseline, post ramp-up with morphine (pre-infection), during acute infection, and after suppression of viremia to profile cell-specific transcriptomic signatures that mirror the CNS pathogenesis observed in opioid-dependent PWH. Results: We observed the presence of all major immune cells in CSF, including CD4 + T Conclusion: Chronic opioid exposure reprograms CSF monocytes toward a DAM state that persists despite ART-mediated viral suppression, driving maladaptive immune-glial crosstalk and progressive neurocognitive dysfunction in morphine-dependent macaques with possible implications for neuroinflammation and neurodegenerative disorders that are observed in PWH.