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Efficacy of the CCR5 antagonist maraviroc in reducing early, ritonavir-induced atherogenesis and advanced plaque progression in mice.

AbstractBACKGROUND:
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 patients with M-tropic HIV infections at high risk for cardiovascular diseases.
METHODS AND RESULTS:
Exposure to maraviroc limits the evolution and associated systemic inflammation of ritonavir-induced atherosclerotic in 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 plaque areas and macrophage infiltration; downregulated the local expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-17A; and reduced tumor necrosis factor-α and RANTES (regulated on activation, normal T cell expressed, and secreted). Moreover, maraviroc counterregulated ritonavir-induced lipoatrophy and interlelukin-6 gene expression in epididymal fat, along with the splenic proinflammatory profile and expression of CD36 on 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. However, 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 proinflammatory profile. Therefore, 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. To determine these benefits, large clinical studies are needed.
AuthorsSabrina Cipriani, Daniela Francisci, Andrea Mencarelli, Barbara Renga, Elisabetta Schiaroli, Claudio D'Amore, Franco Baldelli, Stefano Fiorucci
JournalCirculation (Circulation) Vol. 127 Issue 21 Pg. 2114-24 (May 28 2013) ISSN: 1524-4539 [Electronic] United States
PMID23633271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Retroviral Agents
  • Apolipoproteins E
  • CCR5 Receptor Antagonists
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CCL5
  • Cyclohexanes
  • Interleukin-17
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Maraviroc
  • Ritonavir
Topics
  • Animals
  • Anti-Retroviral Agents (adverse effects)
  • Apolipoproteins E (deficiency, genetics)
  • Atherosclerosis (chemically induced, metabolism, prevention & control)
  • CCR5 Receptor Antagonists
  • Cell Movement
  • Chemokine CCL2 (metabolism)
  • Chemokine CCL5 (metabolism)
  • Cyclohexanes (therapeutic use)
  • Disease Models, Animal
  • Intercellular Adhesion Molecule-1 (metabolism)
  • Interleukin-17 (metabolism)
  • Macrophages (pathology)
  • Male
  • Maraviroc
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plaque, Atherosclerotic (chemically induced, metabolism, prevention & control)
  • Ritonavir (adverse effects)
  • Treatment Outcome
  • Triazoles (therapeutic use)
  • Tumor Necrosis Factor-alpha (metabolism)
  • Vascular Cell Adhesion Molecule-1 (metabolism)

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