Targeting autophagy to reduce inflammasome-mediated inflammation and immune dysfunction in HIV and methamphetamine use

Project Summary/Abstract Methamphetamine (MA), a potent addictive psychostimulant, is highly prevalent in HIV-infected individuals. Even for individuals with suppressive anti-retroviral therapy (ART), MA abuse has been linked to increased viral load, accelerated disease progression, and higher mortality rates in people living with HIV (PLWH). Despite well-documented evidence of MA's adverse effects on the central nervous system (CNS) and cognitive function, its effects on immunity remain unclear. Further research is needed to determine the molecular mechanisms of MA on the immune system, which could lead to targeted therapeutic interventions. Previous reports and our studies showed that MA could impair mitochondria function and exacerbate inflammasome activation and chronic inflammation during HIV infection. Autophagy, a homeostatic cellular mechanism involved in disposal of damaged organelles and intracellularly pathogens, has been reported to negatively regulate inflammasome activation. Our recent studies indicate that autophagy inducers such as rapamycin can induce autophagy, improve mitochondria function, reduce inflammasome activation and chronic inflammation in HIV infected humanized mice. We also observed improved anti-viral T cell immunity, reduced viral reservoir and lower viral rebound after ART withdrawal in rapamycin treated mice, suggesting its therapeutic potentials. In addition, we found that cannabis major components trans-Δ9-tetrahydrocannabinol (THC) and cannabidiol(CBD) can potently induce autophagy and reduce inflammasome activation in stimulated macrophages. Therefore, we hypothesize that inducing autophagy through rapamycin or THC/CBD may offer therapeutic benefits in reducing inflammasome-mediated inflammation in both the periphery and CNS in individuals with HIV infection and MA use. This, in turn, could enhance anti-viral immunity and decrease viral reservoirs. We will study the following aims: 1) Determine the effects of methamphetamine on inflammasome activation and T cell dysfunction during HIV infection with or without ART; 2) Examine the therapeutic potential of targeting autophagy to reduce excessive inflammasome activation and restore T cell function during HIV infection and methamphetamine abuse; 3) Investigate the effects of MA and autophagy induction on HIV- associated CNS inflammation.