Efficacy of the CCR5 Antagonist Maraviroc in Reducing Early, Ritonavir-Induced Atherogenesis and Advanced Plaque Progression in Mice

Abstract

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 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 ritonavirinduced 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.

Effects of Therapy with Maraviroc on the Carotid Intima Media Thickness in HIV-1/HCV Co-infected Patients

“…HIV CCR5 co-receptor, which plays a crucial role in HIV viral entry, is also involved in many inflammatory pathways (1)(2)(3)(4)(5). MVC is the only available CCR5 antagonist currently used in clinical practice for treating HIV infection.…”

“…CCR5 expression on monocytes/macrophage and T-cells and both endothelial and vascular smooth muscle cells suggests a key role in the atherosclerotic process. Several studies demonstrated that inhibition of this co-receptor produces an anti-inflammatory and anti-atherogenic effect (1)(2)(3)(4)(5). A body of evidence has documented that in patients with HIV, atherosclerosis is accelerated and chronic inflammatory processes are activated (6)(7)(8)(9); furthermore, certain evidence indicates that hepatitis C (HCV) co-infection can augment the risk of cardiovascular events (10,11).…”

Pretreatment with a combination of ligustrazine and berberine improves cardiac function in rats with coronary microembolization

“…IL-1β increases dynamically following CME and is associated with impaired cardiac function [37] . RANTES has been identified as a specific marker for unstable angina pectoris by several studies [38][39] . The adhesion molecule, ICAM-1, also represents a marker of slow coronary flow caused by microvascular dysfunction [40][41] .…”

Off-label use of maraviroc in clinical practice

“…So, there are good evidences that linked CCR5 to liver diseases (e.g., hepatocellular carcinoma and liver steatosis), [3][4][5][6] autoimmune disorders (e.g., rheumatoid arthritis), [7] pulmonary diseases (e.g., pulmonary arterial hypertension and sarcoidosis), [8,9] organ rejection (e.g., stem cell transplant), [10] malignancies (e.g., colorectal cancer), [11] and vascular diseases (e.g., endothelial dysfunction and atherogenesis). [12,13] Therefore, we wonder if CCR5 antagonist could be an attractive therapeutic option to prevent and/or treat different inflammatory and/or malignant diseases. Indeed, the absence of functional CCR5 is well tolerated in humans homozygous for the CCR5Δ32 mutation.…”

“…In this regard, interesting data have been obtained with MVC from studies using murine models designed to prevent liver cancer [5] or nonalcoholic fatty liver disease, [6] or treating atherogenesis, [13] or pulmonary arterial hypertension, [9] were also very relevant because this drug was effective preventing the rejection. [22] Nonetheless, not always the use of MVC supports its use as a therapeutic strategy.…”