Chemokine receptor CCR5: from AIDS to atherosclerosis.
There is increasing recognition of an important contribution of chemokines and their receptors in the pathology of atherosclerosis and related cardiovascular disease. The chemokine receptor CCR5 was initially known for its role as a co-receptor for HIV infection of macrophages and is the target of the recently approved CCR5 antagonist maraviroc. However, evidence is now emerging supporting a role for CCR5 and its ligands CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) in the initiation and progression of atherosclerosis. Specifically, the CCR5 deletion polymorphism CCR5delta32, which confers resistance to HIV infection, has been associated with a reduced risk of cardiovascular disease and both CCR5 antagonism and gene deletion reduce atherosclerosis in mouse models of the disease. Antagonism of CCL5 has also been shown to reduce atherosclerotic burden in these animal models. Crucially, CCR5 and its ligands CCL3, CCL4 and CCL5 have been identified in human and mouse vasculature and have been detected in human atherosclerotic plaque. Not unexpectedly, CC chemokines have also been linked to saphenous vein graft disease, which shares similarity to native vessel atherosclerosis. Distinct roles for chemokine-receptor systems in atherogenesis have been proposed, with CCR5 likely to be critical in recruitment of monocytes to developing plaques. With an increased burden of cardiovascular disease observed in HIV-infected individuals, the potential cardiovascular-protective effects of drugs that target the CCR5 receptor warrant greater attention. The availability of clinically validated antagonists such as maraviroc currently provides an advantage for targeting of CCR5 over other chemokine receptors.
Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK.
K L
KL
Jones
J J
JJ
Maguire
A P
AP
Davenport
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D065100:CCR5 Receptor Antagonists; D018925:Chemokines / Q000276:immunology*; D006801:Humans; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology*
D065100:CCR5 Receptor Antagonists; D018925:Chemokines; D019713:Receptors, CCR5