Potential mechanisms of heightened atherogenesis in HIV infection. Two primary risk factors of cardiovascular disease are chronically elevated plasma LDL and/or decreased HDL, and inflammation-driven activation of monocytes and vascular endothelium with heightened migration of monocytes into the atherogenic lesion and maturation into macrophages and lipid-rich foam cells. Plaque regression is associated with emigration of macrophages from the plaque [118], whereas chronic foam cell accumulation, together with their production of proatherogenic factors and their ultimate apoptosis and necrosis in a hypercholesterolemic patient, causes plaque expansion and plaque instability, ultimately resulting in cardiovascular event(s). HIV infection is likely to affect each stage of this process (indicated in red), thereby increasing risk of cardiovascular disease above the effects of traditional risk factors. Dyslipidemia: Specific antiretroviral drugs (e.g., PIs) are associated with dyslipidemia (increased plasma LDL and triglycerides, decreased HDL). HIV infection itself may also promote dyslipidemia as a result of changes in cholesterol metabolism. Systemic inflammation: Plasma levels of proinflammatory cytokines may be increased in viremic HIV-infected individuals, and HIV-associated microbial translocation across gut epithelium results in chronic endotoxemia [10]. Monocyte activation has been demonstrated in viremic HIV-infected individuals and is ameliorated only partially during virological suppression [42]. Whether viremia-induced IFN-α production and adaptive T cell responses have additional proatherogenic effects is not known. Macrophage egress: Reverse transendothelial migration of monocyte-derived macrophages from the plaque requires basal-to-apical migration across the vascular endothelium, which is defective in HIV-infected macrophages in vitro [109]. Accumulation of foam cells: Internalization of extracellular lipoprotein and development of lipid-laden foam cells are associated with reduced migratory capacity [120]; defective cholesterol efflux by HIV-infected macrophages is likely to promote foam cell accumulation in plaques [11]. Foam cells also produce proatherogenic factors such as chemokines, cytokines, and matrix metalloproteinases (MMPs), which promote plaque expansion and instability and can undergo apoptosis and/or necrosis in hypercholesterolemic settings.