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Journal of Virology, June 2008, p. 5527-5535, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02047-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Virion Host Shutoff Attenuates Establishment of the Antiviral State{triangledown} ,{dagger}

Tracy Jo Pasieka,1 Betty Lu,1 Seth D. Crosby,2 Kristine M. Wylie,3 Lynda A. Morrison,3 Diane E. Alexander,1 Vineet D. Menachery,1 and David A. Leib1,4*

Departments of Ophthalmology and Visual Sciences,1 Genetics,2 Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110,4 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri 631043

Received 14 September 2007/ Accepted 14 March 2008

Herpes simplex virus mutants lacking the vhs protein are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties, viruses with vhs deleted have been proposed as live-attenuated vaccines. Despite these findings and their implications for vaccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficient viruses replicate to reduced levels in interferon (IFN)-primed cells and that this deficit has both IFN-dependent and IFN-independent components. Furthermore, vhs-defective viruses induce increased and physiologically active levels of IFN, increased amounts of IFN-stimulated transcripts, and more phosphorylated eIF2{alpha}. In addition, we demonstrate greater accumulation of viral RNAs following infection with a vhs-deficient virus. This leads to the hypothesis that attenuation of viruses lacking vhs may be attributed to increased levels of double-stranded RNA, a potent pathogen-associated molecular pattern. Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as a critical determinant of viral pathogenesis.

* 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

{triangledown} Published ahead of print on 26 March 2008.

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

Journal of Virology, June 2008, p. 5527-5535, Vol. 82, No. 11
0022-538X/08/$08.00+0     doi:10.1128/JVI.02047-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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