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Journal of Virology, November 1998, p. 9131-9141, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The PK Domain of the Large Subunit of Herpes Simplex Virus Type 2 Ribonucleotide Reductase (ICP10) Is Required for Immediate-Early Gene Expression and Virus Growth

C. C. Smith,1 T. Peng,1,dagger M. Kulka,1 and L. Aurelian1,2,*

Virology/Immunology Laboratories1 and Departments of Pharmacology and Experimental Therapeutics and Microbiology,2 University of Maryland School of Medicine, Baltimore, Maryland 21201

Received 30 March 1998/Accepted 7 July 1998

The large subunit of herpes simplex virus (HSV) ribonucleotide reductase (RR), RR1, contains a unique amino-terminal domain which has serine/threonine protein kinase (PK) activity. To examine the role of the PK activity in virus replication, we studied an HSV type 2 (HSV-2) mutant with a deletion in the RR1 PK domain (ICP10Delta PK). ICP10Delta PK expressed a 95-kDa RR1 protein (p95) which was PK negative but retained the ability to complex with the small RR subunit, RR2. Its RR activity was similar to that of HSV-2. In dividing cells, onset of virus growth was delayed, with replication initiating at 10 to 15 h postinfection, depending on the multiplicity of infection. In addition to the delayed growth onset, virus replication was significantly impaired (1,000-fold lower titers) in nondividing cells, and plaque-forming ability was severely compromised. The RR1 protein expressed by a revertant virus [HSV-2(R)] was structurally and functionally similar to the wild-type protein, and the virus had wild-type growth and plaque-forming properties. The growth of the ICP10Delta PK virus and its plaque-forming potential were restored to wild-type levels in cells that constitutively express ICP10. Immediate-early (IE) genes for ICP4, ICP27, and ICP22 were not expressed in Vero cells infected with ICP10Delta PK early in infection or in the presence of cycloheximide, and the levels of ICP0 and p95 were significantly (three- to sevenfold) lower than those in HSV-2- or HSV-2(R)-infected cells. IE gene expression was similar to that of the wild-type virus in cells that constitutively express ICP10. The data indicate that ICP10 PK is required for early expression of the viral regulatory IE genes and, consequently, for timely initiation of the protein cascade and HSV-2 growth in cultured cells.

* Corresponding author. Mailing address: Virology/Immunology Laboratories, University of Maryland School of Medicine, 10 S. Pine St., Baltimore, MD 21201. Phone: (410) 706-3895. Fax: (410) 706-2513. E-mail: laurelia{at}umaryland.edu.

dagger Present address: Department of Microbiology, School of Medicine. University of Pennsylvania, Philadelphia, Pa.

Journal of Virology, November 1998, p. 9131-9141, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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