Figure 1.

The effect of HIV infection on monocyte- and inflammation-mediated mechanisms of foam cell formation. HIV infection causes systemic monocyte activation (I) due to factors unresolved by ART including residual HIV viremia, CMV reactivation, elevated bacterial ligands and oxidative stress. Gut bacterial ligands (eg., lipopolysaccharide; LPS) activate classical and intermediate monocytes via CD14/TLR4 receptor while viral ligands activate non-classical monocytes via TLR7/8 (144). Unresolved inflammation also activates the endothelium (II) which secrete chemokines to attract different monocyte subsets (not illustrated) via specific chemokine receptors, CCR2, CCR5, and CX3CR1 (99). Intermediate monocytes in particular exhibit increased pro-atherogenic properties (127). Activation of the endothelium and of monocytes results in greater monocyte adherence, rolling, firm adhesion and extravasation, the last via either paracellular, or transcellular mechanisms (III) [reviewed in (145)]. Cholesterol accumulates in the intima due in part to ART-induced dyslipidemia and to increased traditional risk factors in PLWH (IV). This is oxidized by the activated myeloid and endothelial cells which produce reactive oxygen intermediates (ROS) (V). Monocytes that have migrated into the intima ingest LDL and oxLDL via LDL receptor and CD36/SR-A1/II (131), respectively and either mature into monocyte–derived dendritic cells (VI) and reverse migrate out of the intima or mature into immobile foam cells (VII). Changes in monocytes, including decreased ABCA1 expression (126), favors pathway (VII) over pathway (VI). Oxidation of HDL (VIII) that also occurs in virologically suppressed PLWH impairs the protective function of this lipoprotein and further increases the risk of atherosclerotic plaque formation. Direct infection of macrophages in the intima also induces an atherogenic phenotype promoting foam cell formation (IX).