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Journal of Virology, October 2008, p. 9900-9916, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.00928-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Transactivation of Cellular Genes Involved in Nucleotide Metabolism by the Regulatory IE1 Protein of Murine Cytomegalovirus Is Not Critical for Viral Replicative Fitness in Quiescent Cells and Host Tissues{triangledown}

Vanessa Wilhelmi,1 Christian O. Simon,1 Jürgen Podlech,1 Verena Böhm,1 Torsten Däubner,1 Simone Emde,1 Dennis Strand,2 Angélique Renzaho,1 Niels A. W. Lemmermann,1 Christof K. Seckert,1 Matthias J. Reddehase,1* and Natascha K. A. Grzimek1

Institute for Virology, Johannes Gutenberg-University, Mainz, Germany,1 Department of Internal Medicine, Medical Centre Mainz, Mainz, Germany2

Received 5 May 2008/ Accepted 29 July 2008

Despite its high coding capacity, murine CMV (mCMV) does not encode functional enzymes for nucleotide biosynthesis. It thus depends on cellular enzymes, such as ribonucleotide reductase (RNR) and thymidylate synthase (TS), to be supplied with deoxynucleoside triphosphates (dNTPs) for its DNA replication. Viral transactivation of these cellular genes in quiescent cells of host tissues is therefore a parameter of viral fitness relevant to pathogenicity. Previous work has shown that the IE1, but not the IE3, protein of mCMV transactivates RNR and TS gene promoters and has revealed an in vivo attenuation of the mutant virus mCMV-{Delta}IE1. It was attractive to propose the hypothesis that lack of transactivation by IE1 and a resulting deficiency in the supply of dNTPs are the reasons for growth attenuation. Here, we have tested this hypothesis with the mutant virus mCMV-IE1-Y165C expressing an IE1 protein that selectively fails to transactivate RNR and TS in quiescent cells upon transfection while maintaining the capacity to disperse repressive nuclear domains (ND10). Our results confirm in vivo attenuation of mCMV-{Delta}IE1, as indicated by a longer doubling time in host organs, whereas mCMV-IE1-Y165C replicated like mCMV-WT and the revertant virus mCMV-IE1-C165Y. Notably, the mutant virus transactivated RNR and TS upon infection of quiescent cells, thus indicating that IE1 is not the only viral transactivator involved. We conclude that transactivation of cellular genes of dNTP biosynthesis is ensured by redundancy and that attenuation of mCMV-{Delta}IE1 results from the loss of other critical functions of IE1, with its function in the dispersal of ND10 being a promising candidate.

* Corresponding author. Mailing address: Institute for Virology, Johannes Gutenberg-University, Hochhaus am Augustusplatz, 55101 Mainz, Germany. Phone: 49-6131-39-33650. Fax: 49-6131-39-35604. E-mail: Matthias.Reddehase{at}uni-mainz.de

{triangledown} Published ahead of print on 6 August 2008.

Journal of Virology, October 2008, p. 9900-9916, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.00928-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Bohm, V., Simon, C. O., Podlech, J., Seckert, C. K., Gendig, D., Deegen, P., Gillert-Marien, D., Lemmermann, N. A. W., Holtappels, R., Reddehase, M. J. (2008). The Immune Evasion Paradox: Immunoevasins of Murine Cytomegalovirus Enhance Priming of CD8 T Cells by Preventing Negative Feedback Regulation. J. Virol. 82: 11637-11650 [Abstract] [Full Text]  


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