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Journal of Virology, August 2006, p. 7600-7612, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00333-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Functional Genomic Analysis of Herpes Simplex Virus Type 1 Counteraction of the Host Innate Response{dagger}

Tracy Jo Pasieka,1 Tracey Baas,2 Victoria S. Carter,2 Sean C. Proll,2 Michael G. Katze,2,3 and David A. Leib1,4*

Departments of Ophthalmology and Visual Sciences,1 Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110,2 Department of Microbiology, University of Washington School of Medicine,3 Washington National Primate Research Center, Seattle, Washington 981954

Received 15 February 2006/ Accepted 15 May 2006

Herpes simplex virus type 1 (HSV-1) mutants lacking the ICP34.5 gene are severely attenuated in mouse models and have a significant growth defect in confluent mouse embryo fibroblasts. Previously, ICP34.5 was demonstrated to have a crucial role in evading the innate immune response to infection by mediating the dephosphorylation of eIF2{alpha}, a translation initiation factor phosphorylated by PKR during the antiviral response. To further understand the role of ICP34.5 in evasion of the antiviral response, we used transcriptional profiling to examine host cell gene expression in both wild-type and ICP34.5-null virus-infected mouse embryo fibroblasts over a time course of infection. Our study revealed that cells responded to infection within 3 h through PKR-dependent eIF2{alpha} phosphorylation and that the majority of up-regulated genes at 3 h postinfection were involved in the antiviral response. HSV-1 counters this response through early expression of ICP34.5 and dephosphorylation of eIF2{alpha}. By 12 h postinfection, the differences between the number and functional classification of genes differentially up- and down-regulated between wild-type and ICP34.5-null virus-infected cells were maximal. Specifically, in wild-type virus-infected cells, the majority of changed genes were involved in metabolic and biosynthetic processes, while in ICP34.5-null virus-infected cells, mostly antiviral genes were up-regulated. Further, ICP34.5-null virus-infected cells produced greater amounts of beta interferon than wild-type virus-infected cells. These results indicate that ICP34.5 expression and function at early times postinfection have a pivotal role in the ability of HSV-1 to gain control of the host cell and maintain an environment for successful viral replication.

* Corresponding author. Mailing address: Washington University School of Medicine, Department of Ophthalmology and Visual Sciences, 660 South Euclid Ave., Box 8096, St. Louis, MO 63110. Phone: (314) 362-2689. Fax: (314) 362-3638. E-mail: leib{at}vision.wustl.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, August 2006, p. 7600-7612, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00333-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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