Cyclic cidofovir (cHPMPC) prevents congenital cytomegalovirus infection in a guinea pig model

Mark R Schleiss,Jodi L Anderson,Alistair Mcgregor

doi:10.1186/1743-422x-3-9

Abstract

BackgroundCongenital cytomegalovirus (CMV) infection is a major public health problem. Antiviral therapies administered during pregnancy might prevent vertical CMV transmission and disease in newborns, but these agents have not been evaluated in clinical trials. The guinea pig model of congenital CMV infection was therefore used to test the hypothesis that antiviral therapy, using the agent agent cyclic cidofovir (cHPMPC), could prevent congenital CMV infection.ResultsPregnant outbred Hartley guinea pigs were challenged in the early-third trimester with guinea pig CMV (GPCMV) and treated with placebo, or the antiviral agent, cyclic cidofovir. To optimize detection of vertical infection, an enhanced green fluorescent protein (eGFP)-tagged virus was employed. Compared to placebo, cyclic cidofovir-treated dams and pups had reduced mortality following GPCMV challenge. The magnitude of GPCMV-induced maternal and fetal mortality in this study was reduced from 5/25 animals in the placebo group to 0/21 animals in the treatment group (p = 0.05, Fisher's exact test). By viral culture assay, antiviral therapy was found to completely prevent GPCMV transmission to the fetus. In control pups, 5/19 (26%) were culture-positive for GPCMV, compared to 0/16 of pups in the cyclic cidofovir treatment group (p < 0.05, Fisher's exact test).ConclusionAntiviral therapy with cyclic cidofovir improves pregnancy outcomes in guinea pigs, and eliminates congenital CMV infection, following viral challenge in the third trimester. This study also demonstrated that an eGFP-tagged recombinant virus, with the reporter gene inserted into a dispensable region of the viral genome, retained virulence, including the potential for congenital transmission, facilitating tissue culture-based detection of congenital infection. These observations provide support for clinical trials of antivirals for reduction of congenital CMV infection.

Highlights

Congenital cytomegalovirus (CMV) infection is a major public health problem
Characterization of vAM403: genome structure and virion polypeptides The details of construction of the enhanced green fluorescent protein (eGFP)-tagged recombinant guinea pig cytomegalovirus (GPCMV) used in this study, vAM403, have been previously described [11]
To experimentally characterize the protein profile of the vAM403 virus, radio-immunoprecipitation assays were performed with polyclonal anti-GPCMV antibodies, using polypeptides purified from 35S-labeled cells

Summary

Introduction

Congenital cytomegalovirus (CMV) infection is a major public health problem. Antiviral therapies administered during pregnancy might prevent vertical CMV transmission and disease in newborns, but these agents have not been evaluated in clinical trials. Treatment of the affected newborn with the anti-CMV nucleoside analogue, ganciclovir, improves the outcome of SNHL, but the response is incomplete, and significant sequelae may persist even following completion of antiviral therapy [2]. These observations provide support for studying the approach of administering antiviral agents administered prior to (page number not for citation purposes). Virology Journal 2006, 3:9 http://www.virologyj.com/content/3/1/9 delivery, with the goal of preventing acquisition of infection in utero Such therapy could potentially be employed in pregnant women in the setting of documented fetal CMV infection, as demonstrated by seroconversion to CMV, or by amniotic fluid analysis confirming the presence of CMV genome. This intervention has been attempted and described in a number of case reports [3,4,5], it is not clear whether in utero therapy for CMV is effective in interrupting vertical transmission, or reducing disease

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