The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection.

Natalia Landázuri,Ylva Terelius,Fredrik Öberg,Koon Chu Yaiw,Cecilia Söderberg-Nauclér,Jennifer Gorwood,Afsar Rahbar

doi:10.3390/cells10113072

Natalia Landázuri, Ylva Terelius + Show 5 more

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https://doi.org/10.3390/cells10113072

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Abstract

Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection.

Highlights

Human cytomegalovirus (HCMV) is a ubiquitous, opportunistic double-strandedDNA virus of the herpesviridae family [1]
We first assessed if macitentan, its metabolite ACT-132577, bosentan, ambrisentan, the ETBR-specific chemical compound BQ788, and ganciclovir affected cellular viability in human umbilical vein endothelial cells (HUVECs), MRC5 and RPE-1 cells (Figure 1A)
We found that macitentan compared equal or slightly better than letermovir at tested concentrations to inhibit HCMV infection in vitro, wherefore this drug may provide one additional option for treatment of patients infected with ganciclovir-resistant HCMV strains

Summary

Introduction

Human cytomegalovirus (HCMV) is a ubiquitous, opportunistic double-strandedDNA virus of the herpesviridae family [1]. Depending on geographical location and socioeconomic status, 40% to >90% of the population is infected with HCMV [1]. After a primary HCMV infection, which is typically asymptomatic, the virus establishes lifelong latency and persistence. In immunocompromised individuals, such as AIDS patients and transplant patients, reactivation of HCMV can lead to significant morbidity and mortality [1]. HCMV establishes latency in myeloid lineage progenitor cells and can be transferred from donors to recipients of solid organ and bone marrow transplants [2,3]. Transplant recipients can acquire a primary infection from an HCMV-positive donor [2,3,7]

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