Nicotine and NLRP3 Inflammasome in HIV-1-Associated CNS Inflammation

PROJECT SUMMARY Human immunodeficiency virus type 1 (HIV-1) infection remains incurable, with over 38 million people affected worldwide. While HIV-1 is known to enter the brain within the first two weeks of infection, it is estimated that 20- 50% of people with HIV-1 will develop HIV-associated neurocognitive disorder (HAND). Neuroinflammation is thought to play a key role in HIV-1 persistence, and substance use disorders, including smoking, may further contribute to inflammation and cognitive decline. In this study, we aim to investigate the impact of nicotine, a key component of tobacco smoking, on NLRP3 inflammasome activation in the central nervous system of people with HIV-1 and substance use disorders. Our research addresses a critical gap in understanding how inflammation contributes to HIV-1 persistence and cognitive decline in smokers with HIV-1. We will investigate how HIV-1 infection and nicotine exposure interact to activate the inflammasome and increase inflammation in human tonsil explants and iPSC-derived microglia to achieve our goals. We will use a newly developed xenograft humanized mouse model to track inflammasome differential expression and activation in brain regions, specifically in latent and productively infected and bystander cells. Finally, we will analyze post-mortem brain samples from individuals with HIV-1 and compare the expression of markers associated with NLRP3 inflammasome activation in smokers versus non-smokers. The proposed research will provide crucial insights into the mechanisms underlying neuroinflammation and cognitive decline in people with HIV-1 and substance use disorders. Our work will elucidate the role of NLRP3 inflammasome activation in HIV-1-associated inflammation and identify potential therapeutic targets to address this issue. By advancing our understanding of inflammation and the immune response to HIV-1 in smokers, we hope to develop novel treatments for this population's cognitive decline and immune dysregulation.