title: Impact of a cytomegalovirus kinase inhibitor on infection and neuronal progenitor cell differentiation.
abstract: Human cytomegalovirus (HCMV) is the leading cause of congenital infections. Symptomatic newborns present with a range of sequelae including disorders of the CNS such as visual impairment, microcephaly, mental retardation and hearing loss. HCMV congenital infection causes gross changes in brain morphology and disturbances in glial and neuronal distribution, number and migration. In these studies, we have evaluated the effectiveness of the antiviral maribavir in inhibiting HCMV infections of ES cell-derived neuronal progenitor cells (NPC). We used EZ-spheres generated from H9 ES cells which are pre-rosette NPCs that retain long-term potential to differentiate into diverse central and peripheral neural lineages following directed differentiation. Our results demonstrate that the maribavir disrupts HCMV replication and viral yield in undifferentiated EZ-sphere-derived NPCs. In addition, we observed that maribavir limits HCMV replication and reduces the percentage of infected cells during differentiation of NPCs. Finally, early steps in differentiation are maintained during infection by treating with maribavir, likely an indirect effect resulting from decreased viral spread. Future studies of NPC proliferation and differentiation during infection treated with maribavir could provide the impetus for studying maribavir as an antiviral agent for congenital HCMV disease.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Tarin M
authors.initials: TM
authors.lastname: Bigley
authors.affiliation: Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Jered V
authors.initials: JV
authors.lastname: McGivern
authors.affiliation: Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Allison D
authors.initials: AD
authors.lastname: Ebert
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: sterhune@mcw.edu.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Terhune
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000821:virology; D006801:Humans; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology / Q000821:virology*; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology; D012263:Ribonucleosides / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D012263:Ribonucleosides; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole
keywords: Congenital infection; Differentiation; Human cytomegalovirus; Maribavir; Neuronal progenitor cells; Viral kinase