Inflammation-associated lipidomic signatures prior to carotid artery atherosclerosis in people living with HIV

Lipid metabolism plays an important role in HIV-associated atherosclerosis. However, the interplay between lipid metabolism, uncontrolled inflammation and subclinical carotid atherosclerosis (SCA) in HIV infection remains poorly understood. This study aimed to characterize lipidome signatures that, togetherwith inflammatory patterns, may predispose HIV-positive individuals to incident SCA. A nested case-control study was conducted within the Comparative HIV and Aging Research Cohort in Taizhou, China, including 115 HIV-positive individuals with incident SCA, 112 age and sex comparable HIV-positive normal controls, and 117 HIV-negative normal controls. Untargeted lipidomic profiling and inflammatory marker assessments were performed at baseline and follow-up. 649 plasma lipid species were annotated and 20 plasma inflammatory markers were quantified. Three distinct baseline lipidomic signatures were identified: one upregulated in HIV infection, one downregulated and one upregulated in HIV-associated SCA (showing a decreasing or increasing trend from HIV-negative NCs to HIV-positive NCs to SCA cases). The latter two signatures were p enriched in glycerophospholipid metabolism, particularly involving lysophospholipids (LPL) and short-chain fatty acyls (SCFA). Lipid species within each signature exhibited distinct correlation patterns with subsets of inflammatory proteins, a pattern that persisted after onset of SCA. Network analysis revealed that IL-18 was the only inflammatory protein showing divergent associations across lipidomic signatures, displaying positive correlations in the HIV-associated SCA-upregulated lipidomic signature and negative correlations in the other two. Our findings underscore specific lipidomic-inflammatory networks that may underlie the heightened risk of atherosclerosis in HIV infection. The differential involvement of IL-18 suggests a central role of NLRP3 inflammasome activation in HIV-associated vascular inflammation. The observed alterations in LPL and SCFA metabolism warrant further mechanistic investigation as potential mediators of HIV-related atherogenesis.