Viral and Cell Cycle–Regulated Kinases in Cytomegalovirus-Induced Pseudomitosis and Replication

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Abstract
A process of pseudomitosis occurs during human cytomegalovirus infection that appears similar to cellular mitosis but involves the formation of multiple spindle poles, abnormal condensation, and mislocalization of chromosomal DNA. The relationship of this process to viral replication and cell cycle regulation during infection has been poorly understood. Pseudomitosis consistently peaks at late times of infection in all viral strains examined but at overall highest frequencies (30% to 35% of cells) using one common laboratory strain variant (AD169varATCC). Cyclin-dependent kinase 1 (Cdk1) plays a crucial role in pseudomitosis, mirroring its role in conventional mitosis. Dominant negative Cdk1 inhibits and wild-type Cdk1 stimulates this process; however, viral yields remain the same regardless of pseudomitosis levels. Broad inhibition of cell cycle−regulated kinases (Cdk1/Cdk2/Cdk5/Cdk9) with indirubin-3′-monoxime substantially decreases viral yields and synergizes with the viral UL97 kinase inhibitor, maribavir. Thus, Cdk1 is necessary and sufficient to drive pseudomitosis, whereas a combination of viral and cell cycle−regulated kinases is important during viral replication. The human herpesvirus cytomegalovirus, which infects most people worldwide, orchestrates a stimulatory effect on cell growth and division, creating an environment that appears similar to many cancer-causing viruses that may be important in viral disease. In previous work, we discovered that viral infection stimulates cells to proceed to an abnormal state mimicking cell division or mitosis but blocks the formation of daughter cells. Here the abnormal state (pseudomitosis) is shown to depend on viral events that drive high levels of the cellular enzyme cyclin-dependent kinase 1 (Cdk1), normally associated with progression through cell division. Although Cdk1 by itself exerts no detectable influence on viral replication levels, host cell cyclin-dependent kinases play an overlapping role with the virus-encoded protein kinase (UL97) in viral replication. Specific inhibitors of these host and viral kinases are used to demonstrate that Cdk1 is necessary and sufficient to drive pseudomitosis; however, viral as well as cell cycle−regulated kinases are important for efficient viral replication.

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