Herpes simplex virus virion host shutoff attenuates establishment of the antiviral state

Tracy Jo Pasieka, Betty Lu, Seth D. Crosby, Kristine M. Wylie, Lynda A. Morrison, Diane E. Alexander, Vineet Menachery, David A. Leib

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58 Scopus citations

Abstract

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 eIF2α. 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.

Original languageEnglish (US)
Pages (from-to)5527-5535
Number of pages9
JournalJournal of Virology
Volume82
Issue number11
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Pasieka, T. J., Lu, B., Crosby, S. D., Wylie, K. M., Morrison, L. A., Alexander, D. E., Menachery, V., & Leib, D. A. (2008). Herpes simplex virus virion host shutoff attenuates establishment of the antiviral state. Journal of Virology, 82(11), 5527-5535. https://doi.org/10.1128/JVI.02047-07