In lieu of a licensed vaccine, antivirals are being considered as an intervention to prevent congenital human cytomegalovirus (HCMV) infection. Ideally, antiviral therapies should undergo pre-clinical evaluation in an animal model prior to human use. Guinea pig cytomegalovirus (GPCMV) is the only small animal model for congenital CMV. However, GPCMV is not susceptible to the most commonly used HCMV antiviral, ganciclovir (GCV), rendering in vivo study of this agent problematic in the guinea pig model. Human cytomegalovirus (HCMV) susceptibility to GCV is linked to the UL97 gene. We hypothesized that GPCMV susceptibility to GCV could be improved by inserting the HCMV (Towne) UL97 gene into the GPCMV genome in place of the homolog, GP97. A chimeric GPCMV (GPCMV::UL97) expressed UL97 protein, and replicated efficiently in cell culture, with kinetics similar to wild-type GPCMV. In contrast, deletion of GP97 resulted in a virus (GPCMVdGP97) that grew poorly in culture. GPCMV::UL97 had substantially improved susceptibility to the inhibitory effects of GCV in comparison to wild-type GPCMV. Additionally, GPCMV::UL97 exhibited improved susceptibility to another antiviral undergoing clinical trials, maribavir (MBV; benzimidazole riboside 1263W94), which also acts through UL97.
Bibliographical noteFunding Information:
We are grateful to Don Coen (Harvard University) and Bill Britt (University of Alabama/Birmingham) for providing anti- UL97 and anti-GPCMV gB antisera, respectively. We thank Jodi Anderson (University of Minnesota, Minneapolis, MN), Greg Stroup and Nanette Huey (Cincinnati, OH) for technical assistance. This work was supported by National Institute of Health AI-65289, DC008651, HD38416-01, and March of Dimes Basic Research Grants 6-FY98/99-0416 and FY01-226. A.M. is a recipient of a Minnesota Medical Foundation Award.
- Antiviral therapy
- Bacterial artificial chromosome
- Congenital CMV infection
- Guinea pig cytomegalovirus