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Journal of Virology, April 2003, p. 4626-4634, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4626-4634.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vivo Replication of an ICP34.5 Second-Site Suppressor Mutant following Corneal Infection Correlates with In Vitro Regulation of eIF2{alpha} Phosphorylation

Stephen L. Ward,1 Donalyn Scheuner,2 Jeremy Poppers,3 Randal J. Kaufman,2 Ian Mohr,3 and David A. Leib1,4*

Departments of Ophthalmology and Visual Sciences,1 Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110,4 Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109,2 Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 100163

Received 17 September 2002/ Accepted 14 January 2003

In animal models of herpes simplex virus type 1 (HSV-1) infection, ICP34.5-null viruses are avirulent and also fail to grow in a variety of cultured cells due to their inability to prevent RNA-dependent protein kinase (PKR)-mediated inhibition of protein synthesis. We show here that the inability of ICP34.5 mutants to grow in vitro is due specifically to the accumulation of phosphorylated eIF2{alpha}. Mutations suppressing the in vitro phenotype of ICP34.5-null mutants have been described which map to the unique short region of the HSV-1 genome, resulting in dysregulated expression of the US11 gene. Despite the inability of the suppressor mutation to suppress the avirulent phenotype of the ICP34.5-null parental virus following intracranial inoculation, the suppressor mutation enhanced virus growth in the cornea, trigeminal ganglia, and periocular skin following corneal infection compared to that with the ICP34.5-null virus. The phosphorylation state of eIF2{alpha} following in vitro infection with the suppressor virus was examined to determine if in vivo differences could be attributed to differential regulation of eIF2{alpha} phosphorylation. The suppressor virus prevented accumulation of phosphorylated eIF2{alpha}, while the wild-type virus substantially reduced eIF2{alpha} phosphorylation levels. These data suggest that US11 functions as a PKR antagonist in vivo, although its activity may be modulated by tissue-specific differences in translation regulation.

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

Journal of Virology, April 2003, p. 4626-4634, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4626-4634.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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