Human cytomegalovirus encodes an unusual
protein kinase, UL97, that activates the established
antiviral drug ganciclovir and is specifically inhibited by a new
antiviral drug,
maribavir. We used
maribavir and a UL97 null mutant, which is severely deficient in viral replication, to determine what stage of
virus infection critically requires UL97. Compared with wild-type virus, there was little or no decrease in immediate-early gene expression,
viral DNA synthesis, late gene expression, or packaging of
viral DNA into nuclease-resistant structures in mutant-infected or
maribavir-treated cells under conditions where the virus yield was severely impaired. Electron microscopy studies revealed similar proportions of various capsid forms, including
DNA-containing capsids, in the nuclei of wild-type- and mutant-infected cells. However, capsids were rare in the cytoplasm of mutant-infected or
maribavir-treated cells; the magnitudes of these decreases in cytoplasmic capsids were similar to those for virus yield. Thus, genetic and pharmacological evidence indicates that UL97 is required at the stage of
infection when nucleocapsids exit from the nucleus (nuclear egress), and this poorly understood stage of
virus infection can be targeted by
antiviral drugs. Understanding UL97 function and
maribavir action should help elucidate this interesting biological process and help identify new
antiviral drug targets for an important pathogen in immunocompromised patients.