| Summary: | HIV/SIV-associated oral mucosal disease/dysfunction (HAOMD) (gingivitis/periodontitis/salivary adenitis) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Using a systems biology approach, we investigated molecular changes (mRNA/microRNA) underlying HAOMD and its modulation by phytocannabinoids (delta-9-tetrahydrocannabinol (∆<sup>9</sup>-THC)) in uninfected (<i>n</i> = 5) and SIV-infected rhesus macaques untreated (VEH-untreated/SIV; <i>n</i> = 7) or treated with vehicle (VEH/SIV; <i>n</i> = 3) or ∆<sup>9</sup>-THC (THC/SIV; <i>n</i> = 3). Relative to controls, fewer mRNAs were upregulated in THC/SIV compared to VEH-untreated/SIV macaques. Gene enrichment analysis showed differential enrichment of biological functions involved in anti-viral defense, Type-I interferon, Toll-like receptor, RIG-1 and IL1R signaling in VEH-untreated/SIV macaques. We focused on the anti-ER-stress anterior gradient-2 (<i>AGR2</i>), epithelial barrier protecting and anti-dysbiotic WAP Four-Disulfide Core Domain-2 (<i>WFDC2</i>) and glucocorticoid-induced anti-inflammatory <i>TSC22D3</i> (TSC22-domain family member-3) that were significantly downregulated in oropharyngeal mucosa (OPM) of VEH-untreated/SIV macaques. All three proteins localized to minor salivary gland acini and secretory ducts and showed enhanced and reduced expression in OPM of THC/SIV and VEH/SIV macaques, respectively. Additionally, inflammation associated miR-21, miR-142-3p and miR-29b showed significantly higher expression in OPM of VEH-untreated/SIV macaques. <i>TSC22D3</i> was validated as a target of miR-29b. These preliminary translational findings suggest that phytocannabinoids may safely and effectively reduce oral inflammatory responses in HIV/SIV and other (autoimmune) diseases.
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