Investigating the role of nicotine and the NRLP3 Inflammasome in HIV-1-Associated CNS Inflammation

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT People with HIV (PWH) often experience chronic systemic inflammation and are at risk for cognitive impairment due to neuroinflammation and blood-brain barrier (BBB) breakdown. Tobacco use exacerbates neuroinflammation and is associated with poor outcomes, such as increased risk of virologic rebound, poorer response to ART, and increased mortality. NLRP3 inflammasome activation, a key feature of neuroinflammation and BBB dysregulation, is influenced by both HIV and nicotine. Nicotine and HIV-1 have been shown to promote activation of the NLRP3 inflammasome in the periphery, leading to chronic inflammation, inflammatory cytokine release (including IL-1β), and pyroptosis. Periodic reactivation of dormant provirus within microglia is thought to be associated with inflammatory signaling, including NLRP3-induced IL- 1β secretion. However, specific mechanisms underlying the combined effect of HIV and nicotine on NLRP3- driven inflammation in the CNS remain largely undefined. Previous work in the Swartz laboratory demonstrated that HIV-1 infection activates the NLRP3 inflammasome in myeloid cells in a human tonsil explant model, and recent data suggest that this is potentiated by nicotine. The Swartz lab and collaborators recently reported on a novel humanized mouse model incorporating HIV infection of engrafted induced pluripotent stem cell (iPSC)- derived microglia to study HIV infection and latency in the CNS at a single-cell level. My underlying hypothesis is that the combined effect of HIV and nicotine drives NLRP3 activation, which promotes proinflammatory signaling in HIV-infected microglia, compromises BBB integrity and incites viral reactivation in latently infected cells. The Chen laboratory’s enhanced HIV-induced lineage tracing system (E-HILT) will allow me to test nicotine’s impact on latency establishment and maintenance by tracking productively and latently infected cells in both in vivo and in vitro. By probing the role of nicotine interactions with the BBB and its influence on inflammatory pathways using in vitro BBB models and a humanized mouse model, I aim to characterize its role in modulating neuroinflammation (Aim 1), BBB functionality (Aim 2), and viral latency (Aim 3). My findings will provide novel insights into the mechanism of nicotine’s impact on the pathogenesis of HIV-1-associated neurodegeneration, informing possibilities for future therapeutic development. This work will uncover novel connections between HIV and nicotine-associated inflammatory pathways, leading to an improved understanding of the complex effects of substance use on the BBB in PWH. This training at the Icahn School of Medicine at Mount Sinai will support my development as a scientist and prepare me to become a well-rounded principal investigator in the fields of neuroimmunology, virology, and substance use.