Investigational antiviral therapy models for the prevention and treatment of congenital cytomegalovirus infection during pregnancy

Antimicrob Agents Chemother. 2020 Oct 19:AAC.01627-20. doi: 10.1128/AAC.01627-20. Online ahead of print.

ABSTRACT

Congenital cytomegalovirus (HCMV) infection may cause significant fetal malformation, lifelong disease and in severe cases fetal or neonatal death. Placental infection with HCMV is the major mechanism of mother to child transmission (MTCT) and fetal injury. Thus, any pharmaceutical antiviral interference to reduce viral load may reduce placental damage, MTCT, and fetal disease. However, there is currently no licensed HCMV antiviral for use during pregnancy. In this study aciclovir, and the HCMV-specific antivirals letermovir, maribavir and cidofovir were compared with ganciclovir, for antiviral effects in model systems of pregnancy including first trimester TEV-1 trophoblast cell cultures and third trimester ex vivo placental explant histocultures. HCMV-infected trophoblasts at 7 days post infection (dpi) showed an EC50 of 21μM for aciclovir, 0.0007μM for letermovir, 0.11μM for maribavir, and 0.29μM for cidofovir, relative to 0.42μM for ganciclovir. Antivirals added at 10μM showed no cytotoxic effects and did not affect trophoblast cell proliferation (p>0.9999). Multiple-round HCMV replication measured at 7dpi showed letermovir, maribavir, and cidofovir treatment inhibited immediate-early, early and true late viral protein expression on western blot. Antiviral treatment of HCMV-infected placental explants showed significant inhibition (p<0.05) of viral replication with letermovir (83.3%), maribavir (83.6%), cidofovir (89.3%), and ganciclovir (82.4%), but not aciclovir (p>0.9999). In ex vivo model systems, recently trialled HCMV antivirals letermovir and maribavir are effective at inhibiting HCMV replication. They partly fulfil requirements for use as safe and effective therapeutics during pregnancy to control congenital HCMV. Clinical trials of these newer agents would assist assessment of their utility in pregnancy.

PMID:33077661 | DOI:10.1128/AAC.01627-20