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Journal of Virology, November 2000, p. 10729-10736, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Comparison between Human Cytomegalovirus pUL97 and Murine Cytomegalovirus (MCMV) pM97 Expressed by MCMV and Vaccinia Virus: pM97 Does Not Confer Ganciclovir Sensitivity

Markus Wagner,1 Detlef Michel,2 Peter Schaarschmidt,2 Bianca Vaida,2 Stipan Jonjic,3 Martin Messerle,1 Thomas Mertens,2,* and Ulrich Koszinowski1

Max von Pettenkofer Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, Munich,1 and Abteilung Virologie, Institut für Mikrobiologie, Universität Ulm, Ulm,2 Germany, and Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia3

Received 26 June 2000/Accepted 18 August 2000

The UL97 protein (pUL97) of human cytomegalovirus (HCMV) is a protein kinase that also phosphorylates ganciclovir (GCV), but its biological function is not yet clear. The M97 protein (pM97) of mouse cytomegalovirus (MCMV) is the homolog of pUL97. First, we studied the consequences of genetic replacement of M97 by UL97. Using the infectious bacterial plasmid clone of the full-length MCMV genome (M. Wagner, S. Jonjic, U. H. Koszinowski, and M. Messerle, J. Virol. 73:7056-7060, 1999), we replaced the M97 gene with the UL97 gene and constructed an MCMV M97 deletion mutant and a revertant virus. In addition, pUL97 and pM97 were expressed by recombinant vaccinia virus to compare both for known functions. Remarkably, pM97 proved not to be the reason for the GCV sensitivity of MCMV. When expressed by the recombinant MCMV, however, pUL97 was phosphorylated and endowed MCMV with the capacity to phosphorylate GCV, thereby rendering MCMV more susceptible to GCV. We found that deletion of pM97, although it is not essential for MCMV replication, severely affected virus growth. This growth deficit was only partially amended by pUL97 expression. When expressed by recombinant vaccinia viruses, both proteins were phosphorylated and supported phosphorylation of GCV, but pUL97 was about 10 times more effective than pM97. One hint of the functional differences between the proteins was provided by the finding that pUL97 accumulates in the nucleus, whereas pM97 is predominantly located in the cytoplasm of infected cells. In vivo testing revealed that the UL97-MCMV recombinant should allow evaluation of novel antiviral drugs targeted to the UL97 protein of HCMV in mice.

* Corresponding author. Mailing address: Abteilung Virologie, Institut für Mikrobiologie, Universität Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany. Phone: 49 (0) 731 502 3340. Fax: 49 (0) 731 502 3337. E-mail: thomas.mertens{at}medizin.uni-ulm.de.

Journal of Virology, November 2000, p. 10729-10736, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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