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Journal of Virology, February 2002, p. 942-949, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.942-949.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Second-Site Mutation Outside of the US10-12 Domain of {Delta}{gamma}134.5 Herpes Simplex Virus 1 Recombinant Blocks the Shutoff of Protein Synthesis Induced by Activated Protein Kinase R and Partially Restores Neurovirulence

Kevin A. Cassady,1,2 Martin Gross,3 G. Yancey Gillespie,4 and Bernard Roizman1*

The Marjorie B. Kovler Viral Oncology Laboratories,1 Division of Clinical Virology,2 Department of Pathology, The University of Chicago, Chicago, Illinois 60637,3 Division of Neurosurgery, The University of Alabama at Birmingham, Birmingham, Alabama 352334

Received 16 May 2001/ Accepted 25 October 2001

Earlier studies have shown that herpes simplex virus type 1 (HSV-1) activated protein kinase R (PKR) but that the product of the product of the {gamma}134.5 gene binds and redirects the host phosphatase 1 to dephosphorylate the {alpha} subunit of eukaryotic translation initiation factor 2 (eIF-2{alpha}). In consequence, the {gamma}134.5 gene product averts the threatened shutoff of protein synthesis caused by activated PKR. Serial passages of {Delta}{gamma}134.5 mutants in human cells led to isolation of two classes of second-site, compensatory mutants. The first, reported earlier, resulted from the juxtaposition of the {alpha} promoter of the US12 gene to the coding sequence of the US11 gene. The mutant blocks the phosphorylation of eIF-2{alpha} but does not restore the virulence phenotype of the wild-type virus. We report another class of second-site, compensatory mutants that do not map to the US10-12 domain of the HSV-1 genome. All mutants in this series exhibit sustained late protein synthesis, higher yields in human cells, and reduced phosphorylation of PKR that appears to be phosphatase dependent. Specific dephosphorylation of eIF-2{alpha} was not demonstrable. At least one mutant in this series exhibited a partial restoration of the virulence phenotype characteristic of the wild-type virus phenotype. The results suggest that the second-site mutations reflect activation of fossilized functions designed to block the interferon response pathways in cells infected with the progenitor of present HSV.

* Corresponding author. Mailing address: The Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, 910 East 58th St., Chicago, IL 60637. Phone: (773) 702-1898. Fax: (773) 702-1631. E-mail: Bernard{at}cummings.uchicago.edu.

Journal of Virology, February 2002, p. 942-949, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.942-949.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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