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Journal of Virology, February 2006, p. 1110-1120, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1110-1120.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Activated MEK Suppresses Activation of PKR and Enables Efficient Replication and In Vivo Oncolysis by {Delta}{gamma}134.5 Mutants of Herpes Simplex Virus 1

Kerrington D. Smith,1 James J. Mezhir,1 Kai Bickenbach,1 Jula Veerapong,1 Jean Charron,2 Mitchell C. Posner,1 Bernard Roizman,3 and Ralph R. Weichselbaum4*

Departments of Surgery,1 Radiation and Cellular Oncology,4 The Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, Chicago, Illinois,3 Centre de Recherché en Cancérologie de l'Université Laval, L'Hotel-Dieu de Quebec, Quebec, Canada2

Received 1 September 2005/ Accepted 8 November 2005

Herpes simplex virus mutants lacking the {gamma}134.5 gene are not destructive to normal tissues but are potent cytolytic agents in human tumor cells in which the activation of double-stranded RNA-dependent protein kinase (PKR) is suppressed. Thus, replication of a {Delta}{gamma}134.5 mutant (R3616) in 12 genetically defined cancer cell lines correlates with suppression of PKR but not with the genotype of RAS. Extensive analyses of two cell lines transduced with either dominant negative MEK (dnMEK) or constitutively active MEK (caMEK) indicated that in R3616 mutant-infected cells dnMEK enabled PKR activation and decreased virus yields, whereas caMEK suppressed PKR and enabled better viral replication and cell destruction in transduced cells in vitro or in mouse xenografts. The results indicate that activated MEK mediates the suppression of PKR and that the status of MEK predicts the ability of {Delta}{gamma}134.5 mutant viruses to replicate in and destroy tumor cells.

* Corresponding author. Mailing address: Department of Radiation and Cellular Oncology, The University of Chicago Hospitals, Center for Advanced Medicine, Room 1329, Mail Code 9006, 5758 South Maryland Avenue, Chicago, IL 60637. Phone: (773) 702-0817. Fax: (773) 834-7233. E-mail: rrw{at}rover.uchicago.edu.

Journal of Virology, February 2006, p. 1110-1120, Vol. 80, No. 3
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.3.1110-1120.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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