Targeting the NLRP3 Inflammasome to Mitigate Neuroinflammation and HIV Persistence in the CNS: Mechanisms and Therapeutic Strategies

About This Grant

PROJECT SUMMARY Even with effective antiretroviral therapy (ART) that suppresses viral replication, individuals with HIV frequently experience chronic neuroinflammation and immune activation, leading to increased risk of neurocognitive disorders and other health complications. The connection between persistent HIV reservoirs in the central nervous system (CNS) and ongoing neuroinflammation remains poorly understood. This project investigates the role of the NLRP3 inflammasome in HIV-induced neuroinflammation, with a particular focus on how inflammasome activation contributes to blood-brain barrier (BBB) dysfunction and the persistence of HIV latency in the CNS. The research team, with expertise spanning HIV biology, inflammasome pathways, CNS model systems, and advanced data analysis, is uniquely equipped to address this critical gap in knowledge. Aim 1: This aim seeks to elucidate the link between HIV-1 infection and NLRP3 inflammasome activation in the CNS. We will use advanced brain organoid models and humanized mouse models to study how HIV-1 triggers inflammasome activation in microglia and contributes to BBB breakdown, providing insights into the mechanisms that sustain neuroinflammation and HIV persistence. Aim 2: This aim investigates the impact of NLRP3 inflammasome activation on the establishment and maintenance of HIV latency in the CNS. By examining how inflammasome activation influences the behavior of latent HIV reservoirs, the study will explore potential pathways that could be targeted to disrupt latency and reduce inflammation. Aim 3: This aim focuses on developing and evaluating therapeutic strategies to mitigate neuroinflammation and HIV persistence. Using innovative lineage tracing techniques and advanced in vivo models, we will test small molecule inhibitors and other therapeutic interventions to assess their efficacy in reducing inflammasome-driven inflammation and preserving CNS function. This project is expected to yield significant advancements in understanding the mechanisms driving HIV-associated neuroinflammation and latency. The findings from this project will provide crucial insights into the role of the NLRP3 inflammasome in sustaining HIV persistence, identify novel therapeutic targets, and potentially pave the way for a functional cure for HIV, ultimately leading to improved treatment strategies and quality of life for people living with HIV.