Macrophage maturation from blood monocytes is altered in people with HIV, and is linked to serum lipid profiles and activation indices: A model for studying atherogenic mechanisms

Author summary People with HIV (PWH) are at greater risk for developing cardiovascular disease (CVD) than the general public, but the mechanisms underlying this increased risk are poorly understood. Macrophages play key roles in the pathogenesis of atherosclerosis, and are potential targets for therapeutic intervention. Here, we investigate phenotypic and functional abnormalities in monocyte-derived macrophages (MDMs) isolated from PWH that may drive CVD risk in this population. MDMs were differentiated in the presence of autologous serum, enabling us to explore the contributions of serum components (lipids, inflammatory cytokines, microbial products) as drivers of altered MDM function. We link serum levels of inflammatory biomarkers and CVD-associated lipid species to MDM activation. Our study provides new insight into drivers of pro-atherogenic MDM phenotype in PWH, and identifies directions for future study and potential intervention strategies to mitigate CVD risk. People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1 beta, TLR expression, PPAR beta delta) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNF alpha, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD.