Investigational Antiviral Therapy Models for the Prevention and Treatment of Congenital Cytomegalovirus Infection during Pregnancy

Hamilton ST, Marschall M, Rawlinson WD (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Antimicrobial Agents and Chemotherapy American Society for Microbiology

Book Volume: 65

Journal Issue: 1

DOI: 10.1128/AAC.01627-20

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 postinfection (dpi) showed an EC50 of 21 mu M for aciclovir, 0.0007 mu M for letermovir, 0.11 mu M for maribavir, and 0.29 mu M for cidofovir, relative to 0.42 mu M for ganciclovir. Antivirals added at 10 mu M showed no cytotoxic effects and did not affect trophoblast cell proliferation (P > 0.9999). Multiple-round HCMV replication measured at 7 dpi showed letermovir, maribavir, and cidofovir treatment inhibited immediate early, early, and true late viral protein expression as assayed on Western blots. 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 trialed HCMV antivirals letermovir and maribavir were 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.

Authors with CRIS profile

Manfred Marschall Lehrstuhl für Klinische und Molekulare Virologie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

None - None A088: Regulatory interaction btw. cyclins and cytomegalovirus kinase pUL97: focus on pUL97 drug resistance mutations Feb. 1, 2020 - July 31, 2023

Involved external institutions

Prince of Wales Hospital (POWH) AU Australia (AU)

How to cite

APA:

Hamilton, S.T., Marschall, M., & Rawlinson, W.D. (2021). Investigational Antiviral Therapy Models for the Prevention and Treatment of Congenital Cytomegalovirus Infection during Pregnancy. Antimicrobial Agents and Chemotherapy, 65(1). https://doi.org/10.1128/AAC.01627-20

MLA:

Hamilton, Stuart T., Manfred Marschall, and William D. Rawlinson. "Investigational Antiviral Therapy Models for the Prevention and Treatment of Congenital Cytomegalovirus Infection during Pregnancy." Antimicrobial Agents and Chemotherapy 65.1 (2021).

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