Given the high prevalence of cannabis use among people with HIV (PWH) and its potential to modulate immune responses and reduce inflammation, this systematic review examines preclinical evidence on how tetrahydrocannabinol (THC), a key compound in cannabis, affects gene and micro-RNA expression in simian immunodeficiency virus (SIV)-infected macaques and HIV-infected human cells. Through a comprehensive search, 19 studies were identified, primarily involving SIV-infected macaques, with a pooled sample size of 176, though methodological quality varied across the studies.

Pathway analysis of differentially expressed genes (DEGs) and miRNAs associated with THC revealed enrichment in pathways related to inflammation, epithelial cell proliferation, and adhesion. Notably, some DEGs were targets of the differentially expressed miRNAs, suggesting that epigenetic regulation may contribute to THC’s effects on gene function. These findings indicate that THC may help mitigate chronic immune activation in HIV infection by altering gene and miRNA expression, suggesting its potential immunomodulatory role. However, the evidence is constrained by small sample sizes and inconsistencies across studies. Further research employing advanced methodologies and larger cohorts is essential to confirm THC’s potential as a complementary therapy for PWH and fully elucidate the underlying mechanisms, which could inform targeted interventions to harness its immunomodulatory effects.