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Journal of Virology, March 2004, p. 2853-2862, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2853-2862.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Roscovitine, a Cyclin-Dependent Kinase Inhibitor, Prevents Replication of Varicella-Zoster Virus

Shannon L. Taylor,1 Paul R. Kinchington,2 Andrew Brooks,3 and Jennifer F. Moffat1*

Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse,1 DNA Core Facility, University of Rochester, Rochester, New York,3 Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania2

Received 12 August 2003/ Accepted 7 November 2003

Understanding the interactions between varicella-zoster virus (VZV) and host cells can be addressed by using small molecule inhibitors of cellular enzymes. Roscovitine (Rosco) is a purine derivative that inhibits cyclin-dependent kinase 1 (cdk1), cdk2, cdk5, cdk7, and cdk9, which are key regulators of the cell cycle and transcription. Herpesviruses are known to interact with cell cycle proteins; thus, the antiviral effects of Rosco on VZV growth were evaluated. In a plaque reduction assay, 25 µM Rosco prevented VZV replication, and the antiviral effect was reversible for at least up to 24 h posttreatment. Rosco also reduced expression of the major transactivator, IE62, over 48 h. Confocal microscopy studies indicated that Rosco caused the immediate-early proteins ORF4 and IE62 to abnormally localize in infected cells and prevented cell-cell spread of VZV over 48 h. Rosco was found to inhibit VZV DNA synthesis as measured by real-time PCR, and this technique was used to estimate the 50% effective concentration (EC50) of 14 µM. This value was close to the EC50 estimate of 12 µM determined from plaque reduction assays. At 25 µM, Rosco was not cytotoxic over 48 h in a neutral red uptake assay, and proliferation was slowed as the cells accumulated in a G2-like state. These results demonstrate the importance of cdk's in VZV replication and suggest that cdk inhibitors could serve as useful VZV antivirals.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, SUNY Upstate Medical University, 750 East Adams St., Syracuse, NY 13210. Phone: (315) 464-5454. Fax: (315) 464-4417. E-mail: moffatj{at}upstate.edu.

Journal of Virology, March 2004, p. 2853-2862, Vol. 78, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.6.2853-2862.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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