PROJECT SUMMARY HIV/SIV infects microglia and astrocytes in the CNS during acute infection establishing viral reservoirs and causing CNS inflammation mediated by activation of inflammasomes. Prior to ART, severe HIV-associated dementia (HAD) occurred in approximately one-third of infected patients. Although ART has led to marked decrease in HAD, milder forms of HIV-associated neurocognitive disorders (HAND) are still diagnosed in 50% of infected ART-treated individuals. Although ART reduced the incidence of HIV-related morbidity and mortality, there is evidence that chronic inflammatory diseases occur more frequently and/or at earlier ages in HIV- infected individuals. The pathogenesis of HAND is unclear, though chronic inflammation induced by long-term infection and drug abuse may be contributing factors. Inflammation associated with viral infections is caused by activation of inflammasomes. Inflammasome assembly results in recruitment and activation of caspase-1 and cleavage of the pro-forms of IL-1β and IL-18 into active, secreted cytokines. IL-1β and IL-18 are proinflammatory cytokines known to mediate inflammation. However, the role of elevated IL-18 in HIV CNS disease is not clear, especially in the context of chronic drug abuse. The effects of commonly used drugs of abuse, cocaine and morphine, on inflammasome activation in brain during HIV/SIV infection have not been rigorously examined. We propose to examine effects of cocaine and morphine on activation of inflammasomes and viral infection in the SIVmac251 infected rhesus macaque model with and without ART. Our studies suggest cocaine and morphine affect inflammasome activation in SIV infection. Long-term exposure to cocaine or morphine before/after SIV infection leads to elevated levels of IL-18 in CSF compared to infected animals without drugs. We propose to study the effects of chronic cocaine and chronic morphine exposure on CNS inflammasome activation in ART suppressed SIV infected macaques. We also propose to examine, for the first time, effects of inflammasome activation during acute infection and the effects of cocaine and morphine on the seeding of SIV infection in brain. We hypothesize that SIV infection in brain results in high levels of inflammasome activation, and that chronic exposure to cocaine or morphine will modulate inflammasome activation in brain. Specific Aim 1 will determine if chronic cocaine or morphine administration alters SIV- induced inflammasome activation in the CNS. Specific Aim 2 will determine if chronic morphine or cocaine administration in ART-suppressed SIV-infected macaques affects inflammasome activation. Specific Aim 3 will examine whether chronic cocaine or morphine treatment alters the progression of SIV infection and/or the establishment of/or maintenance of viral reservoirs in brain.