Opioid-induced immunosuppression of brain myeloid cells in SIV-infected rhesus macaques.

Microglia and CNS-associated macrophages (CAMs) are the primary targets of human immunodeficiency virus (HIV-1) in humans and simian immunodeficiency virus (SIV) infection in nonhuman primates, contributing to HIV-associated neurocognitive disorders and establishment of a persistent viral reservoir in the central nervous system (CNS). Despite antiretroviral therapy (ART), neurocognitive and other neurological disorders persist in people with HIV (PWH). Opioid users can suffer exacerbated disease progression and neurological complications. However, the impact of ART-treated infection and opioids on brain myeloid cells, the main targets for HIV/SIV in the brain, remains poorly understood. Using an SIV-infected rhesus macaque model and single-cell multi-omic sequencing, we show that ART promotes the restoration of homeostatic microglial states, while morphine exerts immunosuppressive effects on brain myeloid cells. Consistent with this immunosuppression, in morphine-treated, SIV-infected ART-suppressed macaques we found that myeloid cells exhibited reduced antiviral gene expression, including downregulation of MHC class II and interferon-stimulated genes, as well as decreased activity of AP-1 and ETS transcription factors. Furthermore, through the integration of single-cell data from PWH, we found that homeostatic microglial signatures were also evident in ART-treated PWH, although the microglia from PWH exhibited more activated/inflammatory phenotypes than those from the macaque model. These findings reveal distinct effects of ART and morphine on brain myeloid cell dynamics during SIV infection, indicating potential mechanisms underlying worsened neurocognitive outcomes in opioid-using PWH.