Efficacy of CCR5 Antagonist Maraviroc in Reducing the Early, Ritonavir Induced, Atherogenesis and the Advanced Plaque Progression in Mice
Background—CCR5 plays an important role in atherosclerosis and ischemic cardiovascular diseases, as well as in HIV replication and diffusion. HIV infection is characterized by a high burden of cardiovascular diseases, particularly in subjects exposed to ritonavir-boosted protease inhibitors. Maraviroc, a CCR5 antagonist antiretroviral drug, might provide benefit for M-tropic HIV infections patients at high risk for cardiovascular diseases.
Methods and Results—Exposure to maraviroc limits the evolution and the associated systemic inflammation of ritonavir-induced atherosclerotic in an ApoE-/- mice and inhibits plaques development in a late model of atherosclerosis in which dyslipidemia plays the main pathogenic role. In ritonavir treated mice, maraviroc reduced the plaque areas and macrophage infiltration, down-regulated the local expression of VCAM-1, ICAM-1, MCP-1 and IL-17A and reduced TNF-α, RANTES. Moreover, maraviroc counter-regulated the ritonavir-induced lipoatrophy and IL-6 gene expression in epididymal fat, along with the splenic pro-inflammatory profile and expression of CD36 in blood monocytes. In the late model, maraviroc inhibited atherosclerotic progression by reducing macrophage infiltration and lowering the expression of adhesion molecules and RANTES inside the plaques. Yet, limited systemic inflammation was observed.
Conclusions—In a mouse model of genetic dyslipidemia maraviroc reduced the atherosclerotic progression by interfering with inflammatory cell recruitment into plaques. Moreover, in mice characterized by a general ritonavir-induced inflammation, maraviroc reversed the pro-inflammatory profile. Being so, maraviroc could benefit HIV positive patients with residual chronic inflammation, who are at a high risk of acute coronary disease, despite a suppressive antiretroviral therapy. In order to determine these benefits, large clinical studies are needed.
- Received January 21, 2013.
- Revision received April 16, 2013.
- Accepted April 19, 2013.