PROJECT SUMMARY/ABSTRACT An estimated 37 million people worldwide are infected with human immunodeficiency virus (HIV). Combined antiretroviral therapy (ART) has turned HIV into a chronic infection with significantly longer life expectancy. New health issues have surfaced as HIV patients live longer. Specifically, 50% of HIV-infected (HIV+) individuals exhibit neurocognitive impairment, termed HIV-associated neurocognitive disorder (HAND). A key event leading to HAND is persistent low-level chronic inflammation resulting in neuronal damage and cell death. A major contributor to HIV-induced neuroinflammation is activated monocytes, which are significantly elevated in patients’ with HIV-associated dementia (HAD). A hallmark of HIV infection is chronic, systemic inflammation in part through translocation of microbial derived products from the gut which, activates monocytes and promote migration across the blood-brain barrier (BBB). Upon entry, activated monocytes release neurotoxic and proinflammatory factors (e.g., IL-1), which are thought to contribute to HAND. Recently, evidence has emerged implicating the importance of inflammasome activation as a contributing mechanism to neuroinflammation and HAND. Preliminary results presented in this application show that inflammasome activation in monocytes, as evidenced by IL-1 secretion, promotes astroglial cell inflammation. These findings support a critical role for inflammasome activation in monocytes as a mechanism driving neuroinflammation. In particular, immunohistocytochemistry of brain tissue from post-mortem HIV patients with HAD showed significant infiltration of proinflammatory CD16+ monocytes. By contrast, cannabinoid exposure displays anti-inflammatory properties in HIV-infected patients, which we and others have reported. The anti- inflammatory properties of cannabis are attributed largely to the canonical ligand, ∆9-tetrahydrocannabinol (THC), which exerts psychotropic activity through cannabinoid receptor (CB) 1 and the non-psychotropic- mediating CB2, while cannabidiol (CBD) does not act through CB1/CB2. Likewise, the CB2 selective agonist, JWH-015, represents a potential strategy for understanding the role of CB2 in limiting HIV-associated neuroinflammation. In fact, preliminary results demonstrate that a CB2 selective agonist impairs monocyte secretion of IL-1, a hallmark of inflammation and inflammasome activation. Mechanistic studies are proposed to test the hypothesis: CD16+ monocytes from non-cannabis using HIV+ subjects exhibit greater inflammasome formation and subsequent astrocyte activation compared to cannabis using HIV+ subjects, which is associated with the frequency of cannabis use.