title: Expression of the human cytomegalovirus UL97 gene in a chimeric guinea pig cytomegalovirus (GPCMV) results in viable virus with increased susceptibility to ganciclovir and maribavir.
abstract: 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.
authors.affiliation: Division of Pediatric Infectious Diseases, University of Minnesota Medical School, Center for Infectious Diseases and Microbiology Translational Research, 2001 6th Street SE, Minneapolis, MN 55455, United States. mcgre077@umn.edu
authors.forename: Alistair
authors.initials: A
authors.lastname: McGregor
authors.forename: K Yeon
authors.initials: KY
authors.lastname: Choi
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cui
authors.forename: Michael A
authors.initials: MA
authors.lastname: McVoy
authors.forename: Mark R
authors.initials: MR
authors.lastname: Schleiss
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial; D003587:Cytomegalovirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D004926:Escherichia coli / Q000235:genetics; D005347:Fibroblasts / Q000821:virology; D015774:Ganciclovir / Q000494:pharmacology*; D017353:Gene Deletion; D005818:Genetic Engineering; D006168:Guinea Pigs / Q000821:virology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D012263:Ribonucleosides / Q000494:pharmacology*; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D015774:Ganciclovir; D017853:Phosphotransferases (Alcohol Group Acceptor); D012263:Ribonucleosides; C075365:ganciclovir kinase; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole