Abstract
Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of viral and cellular substrates. A hierarchy of functional importance of individual pUL97-mediated phosphorylation events has been discussed; however, the most pronounced pUL97-dependent phenotype could be assigned to viral nuclear egress, as illustrated by deletion of the UL97 gene or pharmacological pUL97 inhibition. Despite earlier data pointing to a cyclin-independent functionality, experimental evidence increasingly emphasized the role of pUL97-cyclin complexes. Consequently, the knowledge about pUL97 involvement in host interaction, viral nuclear egress and additional replicative steps led to the postulation of pUL97 as an antiviral target. Indeed, validation experiments in vitro and in vivo confirmed the sustainability of this approach. Consequently, current investigations of pUL97 in antiviral treatment go beyond the known pUL97-mediated ganciclovir prodrug activation and henceforward include pUL97-specific kinase inhibitors. Among a number of interesting small molecules analyzed in experimental and preclinical stages, maribavir is presently investigated in clinical studies and, in the near future, might represent a first kinase inhibitor applied in the field of antiviral therapy.
Highlights
Human cytomegalovirus (HCMV), the prototypic β-herpesvirus, represents a major human pathogen and is characterized by a multifaceted mode of virus-host interaction
In the cytoplasmic virion assembly complex, capsids are assembled with tegument proteins, before fully enveloped virus particles of approximately 150–200 nm are formed in the trans-Golgi network and released from the cell by final transition through the cytoplasmic membrane [2,6,7]
In addition to highly productive lytic infection of major target cells, such as fibroblasts, smooth muscle cells, endothelial and epithelial cells [8,9,10,11,12], HCMV causes life-long persistence by latent infection of minor target cells, such as monocytes/macrophages and CD34+ hematopoietic stem cells, in which latent HCMV may undergo reactivation resulting from immune insult, allogenic stimulation or differential signals
Summary
HCMV, the prototypic β-herpesvirus, represents a major human pathogen and is characterized by a multifaceted mode of virus-host interaction. Viral genomic DNA replication takes place in the nucleus and the double-stranded viral genome is packaged into capsids, which undergo nuclear egress and budding through the nuclear membranes [4,5]. In the cytoplasmic virion assembly complex (cVAC), capsids are assembled with tegument proteins, before fully enveloped virus particles of approximately 150–200 nm are formed in the trans-Golgi network and released from the cell by final transition through the cytoplasmic membrane [2,6,7]. In addition to highly productive lytic infection of major target cells, such as fibroblasts, smooth muscle cells, endothelial and epithelial cells [8,9,10,11,12], HCMV causes life-long persistence by latent infection of minor target cells, such as monocytes/macrophages and CD34+ hematopoietic stem cells, in which latent HCMV may undergo reactivation resulting from immune insult, allogenic stimulation or differential signals (reviewed in [13])
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