Sunday, May 18, 2025
5/18/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).