PBMCs from people with HIV imprint diet-sensitive hepatic inflammation and lipid remodeling in NSG mice 2260261

Abstract

Abstract Introduction People living with HIV (PLWH) exhibit a twofold higher risk of cardiovascular disease (CVD) compared to people without HIV (PWoH), likely due to chronic immune activation. Although inflammation is linked to CVD in PLWH, the immune mechanisms driving this risk remain poorly defined. We hypothesized that PBMCs from PLWH contain immune and metabolic signals that impose an HIV-associated cardiometabolic phenotype in vivo. To test this, we employed an immunocompromised mouse model. Methods PBMC from PLWH and PWoH were adoptively transferred into NOD scid gamma (NSG) mice and divided into two groups: high-fat diet (HFD) or standard chow diet (SCD). Body weight was monitored biweekly. Transcriptomic assessments of the liver were conducted via bulk RNA sequencing. The lipid profile was assessed by liquid chromatography-tandem mass spectrometry. Results Gene-set enrichment revealed consistent upregulation of epithelial—mesenchymal transition pathways in PLWH-PBMC recipient mice versus PWoH. On SCD, PLWH-PBMC livers had 104 DEGs compared to PWoH-PBMC (58 up/46 down), with increased inflammatory signaling, including the IL6-Jak-stat3 pathway. On HFD, differences were smaller but converged on calcium-handling/ contractile-structural programs, suggesting altered hepatic Ca²+/cytoskeletal regulation. Lipidomic analysis on HFD showed a shift toward lysosomal and storage/pro-inflammatory species in PLWH-PBMC livers compared to NSG control mice, increased bis(monoacylglycerol)phosphate, triacylglycerols, phosphatidylcholine, phosphatidylmethanol, and sphingolipid SHexCer, accompanied by reductions in mitochondrial membrane lipids (cardiolipin, monolysocardiolipin) and anti-inflammatory lipids (N-acylethanolamines, lysophosphatidylethanolamine, lysophosphatidylglycerol). Conclusion These data suggest that circulating immune cells transmit HIV-associated cardiometabolic features to target tissues in a diet-dependent manner, implicating immune lipid and calcium handling pathways as potential therapeutic targets. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)