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Journal of Virology, July 1999, p. 5663-5670, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Recombinant Human Cytomegalovirus with a Large Deletion in UL97 Has a Severe Replication Deficiency

Mark N. Prichard,1,* Ning Gao,1,dagger Sanju Jairath,1 Gilbert Mulamba,2 Paula Krosky,2 Donald M. Coen,2 Breck O. Parker,1,Dagger and Gregory S. Pari1,§

Hybridon, Cambridge, Massachusetts 02139,1 and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 021152

Received 30 November 1998/Accepted 24 March 1999

Human cytomegalovirus encodes a protein kinase (UL97) that confers sensitivity to ganciclovir by phosphorylating it to the monophosphate. The function of this unusual kinase in viral replication is unknown. We constructed two independent isolates of a recombinant virus, RCDelta 97, that contain large deletions in this gene and carry a 4.8-kb insertion containing a selectable genetic marker. These mutant viruses were isolated by using a population of primary cells (HEL97) that express this gene from integrated copies of a defective retroviral vector. The recombinant viruses were severely impaired in their ability to replicate in primary fibroblasts, attaining virus titers that were 2 to 3 orders of magnitude lower than those produced by the parent virus. Despite the severe replication deficit, both of these viruses retained the ability to form small, slowly growing plaques in primary fibroblasts, demonstrating that UL97 is not absolutely essential for replication in cell culture. The replication deficit was relieved when UL97 was provided in trans in the complementing cell line, showing that the phenotype was due to a deficiency in UL97. Thus, the UL97 gene product plays a very important role in viral replication in tissue culture and may be a good target for antiviral chemotherapy.

* Corresponding author. Present address: Iconix Pharmaceuticals Inc., 850 Maude Ave., Mountain View, CA 94043. Phone: (650) 567-5515. Fax: (650) 526-3034. E-mail: mprichard{at}iconixpharm.com.

dagger Present address: Astra Research Center Boston, Cambridge, MA 02139.

Dagger Present address: Schleicher & Schuell, Inc., Keene, NH 03431.

§ Present address: Department of Microbiology and Nevada State Health Laboratory, School of Medicine, University of Nevada, Reno, NV 89557.

Journal of Virology, July 1999, p. 5663-5670, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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