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J Virol, August 1998, p. 6710-6715, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Human Thymidine Kinase Can Functionally Replace Herpes Simplex
Virus Type 1 Thymidine Kinase for Viral Replication in Mouse Sensory
Ganglia and Reactivation from Latency upon Explant
Shun-Hua
Chen,
W. James
Cook,
Kristie L.
Grove, and
Donald M.
Coen*
Department of Biological Chemistry and
Molecular Pharmacology, Harvard Medical School, Boston,
Massachusetts 02115
Received 19 March 1998/Accepted 11 May 1998
Herpes simplex virus type 1 thymidine kinase exhibits a strikingly
broad substrate specificity. It is capable of phosphorylating deoxythymidine and deoxyuridine as does human thymidine kinase, deoxycytidine as does human deoxycytidine kinase, the cytosolic kinase
whose amino acid sequence it most closely resembles, and thymidylate as does human thymidylate kinase. Following peripheral inoculation of mice, viral thymidine kinase is ordinarily required for
viral replication in ganglia and for reactivation from latency following ganglionic explant. To determine which activity of the viral
kinase is important for replication and reactivation in mouse ganglia,
recombinant viruses lacking viral thymidine kinase but expressing
individual human kinases were constructed. Each recombinant virus
expressed the appropriate kinase activity with early kinetics
following infection of cultured cells. The virus expressing
human thymidine kinase exhibited thymidine phosphorylation activity equivalent to ~5% of that of wild-type virus in a
quantitative plaque autoradiography assay. Nevertheless, it
was competent for ganglionic replication and reactivation following
corneal inoculation of mice. The virus expressing human thymidylate
kinase was partially competent for these activities despite failing to
express detectable thymidine kinase activity. The virus expressing
human deoxycytidine kinase failed to replicate acutely in
neurons or to reactivate from latency. Therefore, it appears that low
levels of thymidine phosphorylation suffice to fulfill the role of the
viral enzyme in ganglia and that this role can be partially fulfilled
by thymidylate kinase activity alone.
*
Corresponding author. Mailing address: Department of
Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, 250 Longwood Ave., Boston, MA 02115. Phone: (617) 432-1691. Fax: (617) 432-3833. E-mail:
dcoen{at}warren.med.harvard.edu.

Present address: Millennium Pharmaceuticals, Inc., Cambridge,
MA 02139.
J Virol, August 1998, p. 6710-6715, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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