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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,
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.

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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