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Journal of Virology, September 2009, p. 9151-9162, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00886-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Increased eIF2{alpha} Phosphorylation Attenuates Replication of Herpes Simplex Virus 2 vhs Mutants in Mouse Embryonic Fibroblasts and Correlates with Reduced Accumulation of the PKR Antagonist ICP34.5{triangledown}

Kristine M. Wylie, Jane E. Schrimpf, and Lynda A. Morrison*

Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 63104

Received 1 May 2009/ Accepted 29 June 2009

Herpes simplex virus 2 (HSV-2) strains containing mutations in the virion host shutoff (vhs) protein are attenuated for replication compared with wild-type virus in mouse embryonic fibroblasts (MEFs). However, HSV-2 vhs mutants replicate to near wild-type levels in the absence of the RNA-activated protein kinase (PKR). PKR is one of several kinases that phosphorylates the eukaryotic initiation factor 2{alpha} (eIF2{alpha}) to inhibit translation initiation, and we previously found that more of the phosphorylated form of eIF2{alpha} accumulates in MEFs infected with HSV-2 vhs mutants than with wild-type virus. Here, we show that this increase in phosphorylated eIF2{alpha} is primarily PKR dependent. Using MEFs expressing nonphosphorylatable eIF2{alpha}, we demonstrate that phosphorylated eIF2{alpha} is the primary cause of attenuated replication of HSV-2 vhs mutants and that attenuation correlates with decreased accumulation of viral proteins. Normally, HSV antagonizes eIF2{alpha} phosphorylation through the action of ICP34.5, which redirects protein phosphatase 1{alpha} (PP1{alpha}) to dephosphorylate eIF2{alpha} during infection. We show that ICP34.5 does not accumulate efficiently in MEFs infected with HSV-2 vhs mutant viruses, suggesting that the accumulation of phosphorylated eIF2{alpha} and the attenuated phenotype of HSV-2 vhs mutants in MEFs result from a deficiency in ICP34.5.

* Corresponding author. Mailing address: Saint Louis University School of Medicine, Department of Molecular Microbiology and Immunology, 1100 South Grand Boulevard, St. Louis, MO 63104. Phone: (314) 977-8874. Fax: (314) 977-8717. E-mail: morrisla{at}slu.edu

{triangledown} Published ahead of print on 8 July 2009.

Journal of Virology, September 2009, p. 9151-9162, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00886-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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