PROJECT SUMMARY/ABSTRACT People living with HIV experience neurologic dysfunction, including encephalitis, depression, anxiety, and cognitive deficits. Chronic inflammation is a major hallmark of HIV disease today and contributes to the development of neurologic dysfunction in up to 50% of people living with the virus. These neurologic deficits result in poorer daily functioning, decreased quality of life, and have become more prevalent due to the survival benefits of antiretroviral therapy (ART). Thus, chronic inflammation and its consequent effect on neurologic health represents a major public health issue. Microglia are an integral underlying mediator of this chronic inflammation through production of inflammatory cytokines, chemokines, and antiviral responses. Together, these components promote neuroinflammation that persists despite ART and contributes to neurologic impairment through demyelination, pruning, and destruction of neurons. There is a pressing need to develop adjunct therapies to limit deleterious effects on neurologic health. Cannabinoids are emerging as an important modulator of inflammation. Phytocannabinoids, including cannabidiol (CBD), are known to modulate inflammation through activation of canonical and extended endocannabinoid system receptors. While canonical endocannabinoid receptors (CB1 and CB2) are the most well studied, less studied extended endocannabinoid receptors (TRPV2 and PPAR-a) also possess immune modulating functions. The research goal of this F31 proposal is to evaluate expression, function, and immunomodulatory potential of endocannabinoid receptors, and CBD, in microglia in the context of HIV. Our preliminary data determine that macrophage/microglia express both canonical and extended endocannabinoid receptors. Of note, they express TRPV2 and PPAR-a more than any other brain cell type, including neurons, astrocytes, endothelial cells, and pericytes. We determined that endocannabinoid receptor pharmacologic agonists modulate myeloid cell inflammation following exposure to potent bacterial moiety, lipopolysaccharide, an example of a strong inflammatory agent. Together, these preliminary data suggest endocannabinoid receptors are present on myeloid cells and have the capacity to modulate chronic, myeloid derived inflammation. We hypothesize that 1) CB1, CB2, TRPV2, and PPAR-a are present on macrophage/microglia, are selectively impacted by HIV infection, and that they 2) mechanistically contribute to modulation of HIV inflammatory responses. We will systematically test this hypothesis by evaluating the impact of HIV on expression and function of these receptors. We will also use CBD and agonists to evaluate the mechanistic contribution of receptors to modulating microglial inflammation. Successful completion of these research goals along with the proposed mentorship and training provided through this F31 award will propel me forward in accomplishing my long-term goal of becoming a public health research sc...