NLRP3 Activation and Impaired TGF-β Anti-Inflammatory Pathways Predict Vascular Risk in PWH on ART

Abstract

Importance: The immune mechanisms driving vascular disease remain incompletely understood. People with HIV (PWH), even during effective antiretroviral therapy (ART), exhibit persistent immune activation and inflammation, which may contribute to higher rates of vascular disease and mortality compared with people without HIV (PWoH). Leveraging a cohort of U.S. military personnel followed from HIV diagnosis through long-term ART suppression, we sought to identify immunologic pathways underlying increased vascular risk. Objective: To identify plasma biomarkers reflecting distinct immune mechanisms that predict incident vascular outcomes in ART-suppressed PWH. Design: Case-cohort study within the U.S. Military HIV Natural History Study. Setting: Longitudinal, multicenter observational cohort. Participants: A total of 1,002 ART-suppressed PWH (HIV RNA Results: : Cytokine clusters reflecting NLRP3 inflammasome activation and persistent inflammation (IL-18, IL-6) and individual markers (IL-18: HR=1.89, q=0.007; TGF-β2: HR=0.74, q=0.026) were associated with increased ASCVD risk. IL-18 remained nominally significant after adjusting for traditional risk factors (pConclusions: and Relevance: NLRP3 inflammasome activation and reduced TGF-β2, indicating loss of anti-inflammatory and repair mechanisms, may contribute to atherogenesis in ART-suppressed PWH. These findings highlight potential interventional targets for mitigating inflammation-driven vascular risk and warrant validation in larger cohorts to inform novel therapeutic strategies.