Abstract
Background: Early invasion of the central nervous system (CNS) by human immunodefciency virus (HIV) (Gray et al.
in Brain Pathol 6:1–15, 1996; An et al. in Ann Neurol 40:611–6172, 1996), results in neuroinfammation, 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 efect of HIV and/or the phytocannabinoid–delta-9-tetrahydrocannabinol (THC) on
BG-EVs and HIV neuropathogenesis remain unknown.
Methods: We used the simian immunodefciency 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 frst 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 signifcance of BG-EVs in CNS cells.
Results: Signifcant changes in BG-EV-associated miRNA specifc to SIV infection and THC treatment were observed.
BG-EVs from SIV-infected rhesus macaques (SIV EVs) contained 11 signifcantly downregulated miRNAs. Remarkably,
intervention with THC led to signifcant upregulation of 37 miRNAs in BG-EVs (SIV–THC EVs). Most of these miRNAs are
predicted to regulate pathways related to infammation/immune regulation, TLR signaling, Neurotrophin TRK recep‑
tor 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 fndings 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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