Chronic Delta-9-Tetrahydrocannabinol (THC) Treatment Counteracts SIV-induced Modulation of Proinflammatory microRNA Cargo in Basal-ganglia-derived Extracellular- Vesicles

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Abstract Background:Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (1, 2), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (3, 4). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (5, 6), whether BG produces EVs and the effect of HIV and/or the phytocannabinoid― delta-9-tetrahydrocannabinol (THC) on BG-EVs and HIV neuropathogenesis remain unknown. Methods:We used simian immunodeficiency virus (SIV) model of HIV and THC treatment in rhesus macaques (7) to demonstrate for the first time that BG contains EVs (BG-EVs), and that BG-EVs cargo and function are modulated by SIV and THC. We also used primary astrocytes from the brains of wild type (WT) and CX3CR1+/GFP mice to investigate the significance of BG-EVs in CNS cells.Results:Significant changes in BG-EV associated miRNA specific to SIV infection and THC treatment were observed. BG-EVs from SIV infected rhesus macaques (SIV EVs) contain 11 significantly downregulated miRNA. Remarkably, intervention with THC led to significant upregulation of 37 miRNAs in BG-EVs (SIV-THC EVs). Most of these miRNAs regulate pathways related to inflammation/immune regulation, TLR signaling, Neurotrophin TRK receptor signaling, and cell death/response. BG-EVs activated WT and CX3CR1+/GFP astrocytes and reprogrammed astrocyte transcriptome in an EV and CX3CR1 dependent manners. Conclusions:Our findings reveal a role for BG-EVs as a vehicle with potential to disseminate HIV and THC induced changes within the CNS.

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