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Journal of Virology, September 1998, p. 7005-7011, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Second-Site Mutation in the Herpes Simplex Virus Recombinants Lacking the gamma 134.5 Genes Precludes Shutoff of Protein Synthesis by Blocking the Phosphorylation of eIF-2alpha

Kevin A. Cassady,1 Martin Gross,2 and Bernard Roizman1,*

The Marjorie B. Kovler Viral Oncology Laboratories1 and Department of Pathology,2 The University of Chicago, Chicago, Illinois 60637

Received 23 March 1998/Accepted 21 May 1998

In cells infected with the herpes simplex virus 1 (HSV-1) recombinant R3616 lacking both copies of the gamma 134.5 gene, the double-stranded protein kinase R (PKR) is activated, eIF-2alpha is phosphorylated, and protein synthesis is shut off. Although PKR is also activated in cells infected with the wild-type virus, the product of the gamma 134.5 gene, infected-cell protein 34.5 (ICP34.5), binds protein phosphatase 1alpha and redirects it to dephosphorylate eIF-2alpha , thus enabling sustained protein synthesis. Serial passage in human cells of a mutant lacking the gamma 134.5 gene yields second-site, compensatory mutants lacking various domains of the alpha 47 gene situated next to the US11 gene (I. Mohr and Y. Gluzman, EMBO J. 15:4759-4766, 1996). We report the construction of two recombinant viruses: R5103, lacking the gamma 134.5, US8, -9, -10, and -11, and alpha 47 (US12) genes; and R5104, derived from R5103 and carrying a chimeric DNA fragment containing the US10 gene and the promoter of the alpha 47 gene fused to the coding domain of the US11 gene. R5104 exhibited a protein synthesis profile similar to that of wild-type virus, whereas protein synthesis was shut off in cells infected with R5103 virus. Studies on the wild-type parent and mutant viruses showed the following: (i) PKR was activated in cells infected with parent or mutant virus but not in mock-infected cells, consistent with earlier studies; (ii) lysates of R3616, R5103, and R5104 virus-infected cells lacked the phosphatase activity specific for eIF-2alpha characteristic of wild-type virus-infected cells; and (iii) lysates of R3616 and R5103, which lacked the second-site compensatory mutation, contained an activity which phosphorylated eIF-2alpha in vitro, whereas lysates of mock-infected cells or cells infected with HSV-1(F) or R5104 did not phosphorylate eIF-2alpha . We conclude that in contrast to wild-type virus-infected cells, which preclude the shutoff of protein synthesis by causing rapid dephosphorylation of eIF-2alpha , in cells infected with gamma 134.5- virus carrying the compensatory mutation, eIF-2alpha is not phosphorylated. The activity made apparent by the second-site mutation may represent a more ancient mechanism evolved to preclude the shutoff of protein synthesis.

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

Journal of Virology, September 1998, p. 7005-7011, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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