Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression

Abstract

Incidences of cardiovascular diseases (CVD) are high among virologically suppressed HIV-infected individuals. Monocyte activation and trafficking are key mechanisms in the evolution of CVD. We studied the ability of cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and CCR5 antagonist, to influence the migration of monocytes from HIV-infected individuals on antiretroviral therapy (ART). Monocytes were derived from 23 ART-suppressed HIV-infected and 16 HIV-uninfected donors. In a trans-endothelial migration model, monocytes, and human aortic endothelial cells (HAoECs) were exposed to cenicriviroc and migrated monocytes, quantified. Expression of CCR2 and CCR5 on monocytes and adhesion molecules (E-selectin, ICAM-1, VCAM-1, PECAM-1, and CD99) on HAoECs were measured. The single antagonists, BMS-22 (CCR2), and maraviroc (CCR5), served as controls. When both HAoECs and monocytes together were exposed to the antagonists, cenicriviroc led to a greater decrease in monocyte migration compared to BMS-22 or vehicle in both HIV-infected and HIV-uninfected groups (P < 0.05), with maraviroc having no inhibitory effect. Cenicriviroc treatment of HAoECs alone decreased monocyte migration in the HIV-infected group when compared to vehicle (P < 0.01). Inhibition of migration was not evident when monocytes alone were exposed to cenicriviroc, BMS-22 or maraviroc. Incubation of HAoECs with cenicriviroc decreased E-selectin expression (P = 0.045) but had limited effects on the other adhesion molecules. Cenicriviroc inhibits monocyte trans-endothelial migration more effectively than single chemokine receptor blockade, which may be mediated via disruption of monocyte-endothelial tethering through reduced E-selectin expression. Cenicriviroc should be considered as a therapeutic intervention to reduce detrimental monocyte trafficking.

CCL5/CCR5 axis in human diseases and related treatments

“…In comparison to maraviroc, cenicriviroc possesses higher efficiency in disruption of links between cells. 171 Nowadays, cenicriviroc-related clinical trials have demonstrated that the drug has both antiviral and anti-fibrosis effects in the condition of infections, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC) (NCT02653625) and many other conditions. 172 , 173 …”

Pathogenesis of Aging and Age-related Comorbidities in People with HIV: Highlights from the HIV ACTION Workshop

“…Dysregulation of the immune system due to HIV itself, coinfections, or bystander mediators of inflammation may drive inappropriate activation and retention of immune cells within tissue sites such as blood vessels, liver, adipose tissues, and the central nervous system (CNS). Circulating immune cell populations that include activated monocytes expressing pro-coagulants (eg, tissue factor), as well as increased numbers of mature activated CD8 + T cells that can home to endothelial surfaces via expression of homing receptors including the fractalkine receptor (CX3CR1), lymphocyte function-associated antigen 1 (LFA-1), macrophage-1 antigen (Mac-1) [19,20], C-C chemokine receptor type 2 (CCR2), and type 5 (CCR5) [21], are detected in PWH, and may be linked to development of CVD and other comorbidities [22][23][24][25][26]. Altered migration of activated immune cells to, and retention within, these tissues may also influence development of other end-organ diseases.…”

Fibrin Strands Will Grow from Soluble Fibrin and Hang Up In an ex vivo Microcirculatory Viscoelastic Model: Is This a Major Cause of Covid-19 Associated Coagulopathy?

“…At least some of the molecules that attract macrophages to the site of virally damaged cells have been identified [35]. The I-SPY-Covid-19 Trial is investigating the clinical utility of Cenicriviroc against macrophage attractant molecules CCR-2 and CCR-5 [36]. Preventing macrophages from gathering in alveoli would likely be most effective in the several days before SF levels rise.…”