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

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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 <50 copies/mL) were included, with N=135 vascular event (VE) cases and N=702 controls. Cases encompassed atherosclerotic cardiovascular disease (ASCVD) – coronary artery disease (CAD), myocardial infarction (MI), stroke (CVA), peripheral artery disease (PAD) – and venous thrombotic events (VTE) – deep vein thrombosis (DVT) and pulmonary embolism (PE). Exposures Thirty-three soluble plasma analytes quantified using a high-sensitivity multiplex assay from samples collected ≥1 year after ART suppression. Main Outcomes and Measures The primary outcome was incident ASCVD. Associations between cytokine concentrations (individual and clustered) and vascular risk were evaluated using unsupervised clustering, Cox proportional hazards models, and causal inference (to estimate 5-year ASCVD risk under hypothetical cytokine alterations). Mediation analyses assessed direct and indirect effects of key inter-related cytokines. Secondary outcome included any VE (ASCVD plus VTE). Covariates included traditional cardiovascular risk factors, HIV clinical variables, and demographics. False discovery rate (FDR) adjustment was applied using the Benjamini-Hochberg method. 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 (p<0.05) but did not meet FDR significance (q<0.05). Conclusions 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. Key Points Question Which inflammatory immune pathways are associated with incident atherosclerotic cardiovascular disease in ART-suppressed people with HIV? Findings In this longitudinal case-cohort study of 1,002 ART-suppressed people with HIV, elevated IL-18 and reduced TGF-β2 were associated with incident ASCVD. Associations were specific to arterial rather than venous events, and IL-18-related risk was partly mediated through IL-6. Meaning These findings suggest that imbalance between inflammasome-driven inflammation and impaired immune regulation contributes to residual cardiovascular risk in treated HIV.

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