Pilot Awards for Investigators New to HIV

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) affects approximately 18% of HIV/TB co-infected patients starting antiretroviral therapy, with a mortality rate exceeding 3%. Despite its clinical significance, the precise mechanisms underlying TB-IRIS remain incompletely understood. Our research has uncovered a novel pathway: Mycobacterium tuberculosis (Mtb)-specific antibodies complexed with Mtb can stimulate NLRP3 inflammasome assembly, triggering excessive inflammation through IL-1β release. Our preliminary data demonstrates that this antibody-mediated inflammasome activation is protective in early TB infection but paradoxically exacerbates established disease. This pilot study will investigate the role of antibody-mediated NLRP3 inflammasome activation in TB-IRIS through two specific aims. First, we will mechanistically dissect how Mtb/antibody immune complexes induce NLRP3 inflammasome activation in primary human macrophages, determining NLRP3 dependence and identifying required Fc receptor signaling pathways. Second, using a well-characterized cohort of HIV/TB patients who did or did not develop TB-IRIS, we will evaluate the clinical correlation between inflammasome activation potential and TB-IRIS development, enabling biomarker discovery. This research provides a novel perspective on TB-IRIS pathophysiology by integrating humoral, innate, and cell-mediated immunity. Identifying specific biomarkers and mechanisms could lead to targeted interventions that effectively prevent TB-IRIS without broad immunosuppression, significantly improving outcomes for HIV/TB co-infected patients.