Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir.
The serine/threonine kinase expressed by human cytomegalovirus from gene UL97 phosphorylates the antiviral drug ganciclovir, but its biological function is the phosphorylation of its natural viral and cellular protein substrates which affect viral replication at many levels. The UL97 kinase null phenotype is therefore complex, as is the mechanism of action of maribavir, a highly specific inhibitor of its enzymatic activity. Studies that utilise the drug corroborate results from genetic approaches and together have elucidated many functions of the UL97 kinase that are critical for viral replication. The kinase phosphorylates eukaryotic elongation factor 1delta, the carboxyl terminal domain of the large subunit of RNA polymerase II, the retinoblastoma tumour suppressor and lamins A and C. Each of these is also phosphorylated and regulated by cdc2/cyclin-dependent kinase 1, suggesting that the viral kinase may perform a similar function. These and other activities of the UL97 kinase appear to stimulate the cell cycle to support viral DNA synthesis, enhance the expression of viral genes, promote virion morphogenesis and facilitate the egress of mature capsids from the nucleus. In the absence of UL97 kinase activity, viral DNA synthesis is inefficient and structural proteins are sequestered in nuclear aggresomes, reducing the efficiency of virion morphogenesis. Mature capsids that do form fail to egress the nucleus as the nuclear lamina are not dispersed by the kinase. The critical functions performed by the UL97 kinase illustrate its importance in viral replication and confirm that the kinase is a target for the development of antiviral therapies.
Prichard
Mark N
MN
Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama 35233, USA. mprichard@peds.uab.edu
D000595:Amino Acid Sequence; D001562:Benzimidazoles / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects / Q000502:physiology; D012263:Ribonucleosides / Q000494:pharmacology*; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
D001562:Benzimidazoles; D004279:DNA, Viral; D017853:Phosphotransferases (Alcohol Group Acceptor); D012263:Ribonucleosides; D014764:Viral Proteins; C075365:ganciclovir kinase; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole