Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir

Abstract

Summary 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.

Two isoforms of the protein kinase pUL97 of human cytomegalovirus are differentially regulated in their nuclear translocation

“…An indirect nuclear transport mechanism could result from interaction of pUL97 with a nuclear cellular protein, such as the retinoblastoma protein (Rb) which contains a strong importin-a-driven NLS (Fontes et al, 2003). However, although motifs involved in the regulation of Rb phosphorylation through pUL97 were described (Gill et al, 2009;Prichard, 2009;Prichard et al, 2008), a direct binding of Rb to pUL97 has not been demonstrated yet. Another factor impacting on the regulation of nuclear translocation may be provided through the pronounced autophosphorylation activity of pUL97.…”

“…HCMV replication is restricted to specific host-cell types and is dependent on the balance of interactions between viral and cellular proteins. In this regard, various virus-or cell-encoded protein kinases display crucial functions during HCMV replication and are interlinked in several aspects of their regulatory properties (Prichard, 2009;Lee & Chen, 2010). The serine/threoninetype protein kinase pUL97 is an important determinant of efficient HCMV replication.…”

Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection

“…Infection with the prevalent β-herpes virus human cytomegalovirus (HCMV) induces increased levels of protein phosphorylation and markedly alters host cell signal transduction pathways (1). A portion of the phosphorylation changes induced by HCMV infection are attributed to the Ser/ Thr kinase encoded by the viral genome, pUL97 (2), and others may derive from cellular kinase(s) packaged into virions (3) or from cellular kinases known to be activated by HCMV (4).…”

Management of multidrug‐resistant viruses in the immunocompromised host

“…The lead compound in this group is maribivir (5,6-dichloro-2-(isopropyl)amino-1-(l-ribofuranosyl)benzimidazole), which is a highly specific inhibitor of the UL97 kinase. Evidence suggests that inhibition of UL97 results in defective viral encapsidation, hinting at a possible role for this kinase at the stage of nuclear egress (Krosky et al, 2003), although the functions of the UL97 kinase appear to be numerous (Prichard, 2009). Plaque reduction assays have shown that maribavir has five-fold greater activity against viral replication in some laboratory strains of CMV when compared with GCV .…”