NLRP3 Activation and Impaired TGF-β Anti-Inflammatory Pathways Predict Vascular Risk in PWH on ART
Year: 2026
Type: preprint
Study design: Observational Study
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: These findings suggest that imbalance between inflammasome-driven inflammation and impaired immune regulation contributes to residual cardiovascular risk in treated HIV.
Source: medRxiv
Authors: Alton S. Barbehenn, Caroline H. Sheikhzadeh, Sonia Savur, Erik Lundgren, Sannidhi Sarvadhavabhatla, Vivian Pae, Maria Sophia Donaire, Alejandro Schuler, Xiuping Chu, Colin T. Maguire, Senay Topal, Anuradha Ganesan, Joseph M. Yabes, Derek T. Larson, Tahaniyat Lalani, Evan C. Ewers, Rhonda E. Colombo, Jeffrey A. Tomalka, Priscilla Y. Hsue, Rafick P. Sekaly, Brian K. Agan, Sulggi A. Lee
Institutions: University of California, San Francisco, University of California, Berkeley, Henry M. Jackson Foundation, Uniformed Services University of the Health Sciences, University of Utah, Walter Reed National Military Medical Center, Brooke Army Medical Center, Naval Medical Center San Diego, Naval Medical Center Portsmouth, Tripler Army Medical Center, Madigan Army Medical Center, Emory University, University of California, Los Angeles
Language: English
Subfield: Emergency Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1286242323, G1381013786, G196326787, G2528852203, G3637497573, G3971585873, G4525180912, G6222268797, G8075513919, G8126863376, G8452773626, G9000276756, CTSA UM1 Program at University of Utah, Host genetic predictors of plasma IL-1b levels and pharmacogenomics of in vivo IL-1b blockade during treated HIV disease
OpenAlex ID: W7202097432