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Antimicrobial Agents and Chemotherapy, August 1999, p. 1941-1946, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Acyclovir Is Phosphorylated by the Human Cytomegalovirus UL97 Protein

Christine L. Talarico,1,* Thimysta C. Burnette,2 Wayne H. Miller,3 Sheila L. Smith,1 Michelle G. Davis,1 Sylvia C. Stanat,1 Teresa I. Ng,4,dagger Zuwen He,5 Donald M. Coen,5 Bernard Roizman,4 and Karen K. Biron1

Department of Virology,1 Division of Bioanalysis and Drug Metabolism,2 and Department of Biochemistry,3 Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 27709; The Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, Chicago, Illinois 60637;4 and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 021155

Received 4 November 1998/Returned for modification 16 March 1999/Accepted 24 May 1999

Acyclovir (ACV) has shown efficacy in the prophylactic suppression of human cytomegalovirus (HCMV) reactivation in immunocompromised renal transplant patients without the toxicity associated with ganciclovir (GCV). The HCMV UL97 gene product, a protein kinase, is responsible for the phosphorylation of GCV in HCMV-infected cells. This report provides evidence for the phosphorylation of ACV by UL97. Anabolism studies with the HCMV wild-type strain AD169 and with recombinant mutants derived from marker transfer experiments performed by using mutant UL97 DNA from both clinical isolates and a laboratory-derived strain resistant to GCV showed that mutations in the UL97 gene cripple the ability of recombinant virus-infected cells to anabolize both GCV and ACV. These mutant UL97 recombinant viruses were less susceptible to both GCV and ACV than was the wild-type strain. A recombinant herpes simplex virus type 1 strain, in which the thymidine kinase gene is deleted and the UL13 gene is replaced with the HCMV UL97 gene, was able to induce the phosphorylation of ACV in infected cells. Finally, purified UL97 phosphorylated both GCV and ACV to their monophosphates. Our results indicate that UL97 promotes the selective activity of ACV against HCMV.

* Corresponding author. Mailing address: Glaxo Wellcome, Inc., P.O. Box 13398, Research Triangle Park, NC 27709. Phone: (919) 483-9147. Fax: (919) 315-5243. E-mail: clt39226{at}glaxowellcome.com.

dagger Present address: Antiviral Research, Abbott Laboratories, Abbott Park, IL 60064.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1941-1946, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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