Chronic delta-9-tetrahydrocannabinol (THC) treatment counteracts SIV-induced modulation of proinflammatory microRNA cargo in basal ganglia-derived extracellular vesicles

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“Background: Early invasion of the central nervous system (CNS) by human immunodeficiency virus (HIV) (Gray et al. in Brain Pathol 6:1-15, 1996; An et al. in Ann Neurol 40:611-6172, 1996), results in neuroinflammation, potentially through extracellular vesicles (EVs) and their micro RNAs (miRNA) cargoes (Sharma et al. in FASEB J 32:5174-5185, 2018; Hu et al. in Cell Death Dis 3:e381, 2012). Although the basal ganglia (BG) is a major target and reservoir of HIV in the CNS (Chaganti et al. in Aids 33:1843-1852, 2019; Mintzopoulos et al. in Magn Reson Med 81:2896-2904, 2019), 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 the simian immunodeficiency virus (SIV) model of HIV and THC treatment in rhesus macaques (Molina et al. in AIDS Res Hum Retroviruses 27:585-592, 2011) 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) contained 11 significantly downregulated miRNAs. Remarkably, intervention with THC led to significant upregulation of 37 miRNAs in BG-EVs (SIV-THC EVs). Most of these miRNAs are predicted to 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 altered the expression of CD40, TNFα, MMP-2, and MMP-2 gene products in primary mouse astrocytes 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.”

“In summary, the findings of this study suggest that HIV/SIV infection reprograms the BG leading to the release of pathogenic EVs that may potentially promote CNS inflammation and toxicity. However, cannabinoid mediated modulation of EV cargo composition as shown in this study maybe a mechanism for the regulation of HIV/SIV-induced changes. This is significant, because exploration of the potential of THC EVs in a preclinical animal model may be logical to investigate whether the clinical advantages of THC EVs will result in beneficial outcomes. The findings of this study also pave the way for investigation into the effects of the combined administration of THC:CBD [1:1 or 1:3 ratio] on neuroinflammation and their effects on BG-EV composition and function. The implication of our findings goes beyond HIV-induced inflammation. Glia cells (microglia and astrocytes) are involved in the pathogenesis of pain. Activated/reactive astrocytes play a role in neuropathic pain, inflammatory pain, as well as bone cancer pain. Activated astrocytes are also involved in Parkinson’s disease, spinal cord injury, and traumatic brain injury. In line with their role in the pathogenesis of pain, studies are warranted to assess the effect of CNS EVs in mediating the development and maintenance of pain.”

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