Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Circulating monocytes pre-disposed to form atherogenic foam cells are characterised by distinct transcriptional changes in people with HIV.

Abstract

BACKGROUND: People with HIV (PWH) have a 2-fold increased risk of cardiovascular disease despite antiretroviral therapy (ART) and adjustment for traditional risk factors. Monocytes play a key role in early atherosclerotic events and have a 'pro-atherogenic' phenotype in PWH, as evidenced by an enhanced formation of lipid-laden foam cells ex vivo. METHODS: To elucidate the contributing mechanisms, we analysed the transcriptome of monocytes from virologically suppressed PWH who exhibited a high degree of foam cell formation ex vivo (HIV FC_High), and compared them to PWH and HIV-seronegative individuals with low monocyte atherogenic activity (HIV_FC Low and NEG, respectively, n = 10 per group, all male, median age 51 years [range 39-62]). RESULTS: Monocytes from HIV FC_High individuals exhibited substantial transcriptomic alterations including 3477 and 47 differentially expressed genes compared to the NEG and HIV FC_Low groups, respectively (adjusted p < 0.05). Genes significantly upregulated in HIV FC_High vs HIV FC_Low groups included those related to lipid synthesis (LIPI), cell structure/cytoskeleton and adhesion (XIRP1 and 2, LRFN5, CLDN4), extracellular matrix remodelling (FN1, PRELP, IGTA11), metalloproteinase activity (ADAMTS2, PAPPA) and members of the olfactory receptor family (OR52N1 and OR1L8). Gene set enrichment analysis identified 24 pathways significantly over-represented in monocytes from the HIV FC_High group compared with the HIV FC_Low group. These pathways included coagulation, fatty acid metabolism, glycolysis as well as TGFbeta signalling and epithelial mesenchymal transition, together suggesting a fibrocyte-like phenotype. CONCLUSIONS: Our findings indicate that monocytes from PWH without elevated traditional cardiovascular risk factors exhibit significant transcriptional changes which are associated with heightened atherosclerosis-promoting activity.