PROJECT SUMMARY/ABSTRACT Chronic, immune activation is one of the major hallmarks of HIV in the modern era, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. This chronic immune activation is largely mediated by myeloid-lineage cells, including monocytes, macrophages, and microglia. This demonstrates a critical need to develop new anti-inflammatory strategies that are effective in inhibiting myeloid activation in the context of chronic HIV infection and treatment. Cannabinoids, particularly the phytocannabinoid cannabidiol (CBD) is among the most promising new anti-inflammatory drug. However, the impact of CBD on HIV/SIV associated inflammation is not clear because there have been no studies assessing the anti-inflammatory properties of cannabidiol (CBD) in the SIV/macaque model of HIV. There is a pressing need to better counteract HIV- associated inflammation in the ART era. Given the gap in our knowledge regarding the immunomodulatory effects of cannabinoids, we propose studies on CBD administration in a virally suppressed rhesus macaque model (ART-SIV). Resident tissue macrophages express functional CB1, CB2, and GPR55, though there is variable expression among the organs. Our data show that stimulating these receptors inhibits endogenous and LPS-induced pro-inflammatory and anti-viral genes, while increasing potent anti-inflammatory cytokines. We determined that these cytokines were a source of chronic inflammation in the periphery and CNS in our SIV-ART model. Thus, we propose to 1) evaluate the impact of CBD on myeloid immune activation, 2) determine the effect of CBD on myeloid antiviral signatures, and 3) define the impact of CBD on the monocytic and microglial neuroinflammatory and neuroprotective transcriptome. We anticipate our work will provide insight into the mechanisms by which CBD exerts anti-inflammatory properties, both peripherally and in the brain. Additionally, our findings will fill a critical gap in knowledge regarding the inflammatory mechanisms underlying CNS dysfunction in the current ART era.