Long-Term Low-Dose Delta-9-Tetrahydrocannbinol (THC) Administration to Simian Immunodeficiency Virus (SIV) Infected Rhesus Macaques Stimulates the Release of Bioactive Blood Extracellular Vesicles (EVs) that Induce Divergent Structural Adaptations and Signaling Cues.
Blood extracellular vesicles (BEVs) carry bioactive cargo (proteins, genetic materials, lipids, licit, and illicit drugs) that regulate diverse functions in target cells. The cannabinoid drug delta-9-tetrahydrocannabinol (THC) is FDA approved for the treatment of anorexia and weight loss in people living with HIV. However, the effect of THC on BEV characteristics in the setting of HIVSIV infection needs to be determined. Here, we used the SIV-infected rhesus macaque model of AIDS to evaluate the longitudinal effects of THC (THCSIV) or vehicle (VEHSIV) treatment in HIVSIV infection on the properties of BEVs. While BEV concentrations increased longitudinally (pre-SIV (0), 30, and 150 days post-SIV infection (DPI)) in VEHSIV macaques, the opposite trend was observed with THCSIV macaques. SIV infection altered BEV membrane properties and cargo composition late in infection, since i) the electrostatic surface properties (zeta potential, ζ potential) showed that RM BEVs carried negative surface charge, but at 150 DPI, SIV infection significantly changed BEV ζ potential ii) BEVs from the VEHSIV group altered tetraspanin CD9 and CD81 levels compared to the THCSIV group. Furthermore, VEHSIV and THCSIV BEVs mediated divergent changes in monocyte gene expression, morphometrics, signaling, and function. These include altered tetraspanin and integrin β1 expression altered levels and distribution of polymerized actin, FAKpY397 FAK, pERK12, cleaved caspase 3, proapoptotic Bid and truncated tBid and altered adhesion of monocytes to collagen I. These data indicate that HIVSIV infection and THC treatment result in the release of bioactive BEVs with potential to induce distinct structural adaptations and signaling cues to instruct divergent cellular responses to infection.