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Journal of Virology, July 2009, p. 6652-6663, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00260-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Type 1 Suppresses RNA-Induced Gene Silencing in Mammalian Cells{triangledown}

Zetang Wu,1,§ Yali Zhu,2 David M. Bisaro,1,3 and Deborah S. Parris1,2*

Graduate Program in Molecular, Cellular, and Developmental Biology,1 Department of Molecular Virology, Immunology, and Medical Genetics,2 Department of Molecular Genetics and Plant Biotechnology Center, Ohio State University, Columbus, Ohio 432103

Received 5 February 2009/ Accepted 9 April 2009

RNA-induced silencing is a potent innate antiviral defense strategy in plants, and suppression of silencing is a hallmark of pathogenic plant viruses. However, the impact of silencing as a mammalian antiviral defense mechanism and the ability of mammalian viruses to suppress silencing in natural host cells have remained controversial. The ability of herpes simplex virus type 1 (HSV-1) to suppress silencing was examined in a transient expression system that employed an imperfect hairpin to target degradation of transcripts encoding enhanced green fluorescent protein (EGFP). HSV-1 infection suppressed EGFP-specific silencing as demonstrated by increased EGFP mRNA levels and an increase in the EGFP mRNA half-life. The increase in EGFP mRNA stability occurred despite the well-characterized host macromolecular shutoff functions of HSV-1 that globally destabilize mRNAs. Moreover, mutant viruses defective in these functions increased the stability of EGFP mRNA even more than did the wild-type virus in silenced cells compared to results in control cells. The importance of RNA silencing to HSV-1 replication was confirmed by a significantly enhanced virus burst size in cells in which silencing was knocked down with small inhibitory RNAs directed to Argonaute 2, an integral component of the silencing complex. Given that HSV-1 encodes several microRNAs, it is possible that a dynamic equilibrium exists between silencing and silencing suppression that is capable of modulating viral gene expression to promote replication, to evade host defenses, and/or to promote latency.

* Corresponding author. Mailing address: Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, 2198 Graves Hall, 333 West Tenth Avenue, Columbus, OH 43210. Phone: (614) 292-0735. Fax: (614) 292-9805. E-mail: parris.1{at}osu.edu

{triangledown} Published ahead of print on 15 April 2009.

§ Present address: Department of Neurology, University of Michigan, Room 5258 RSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109.

Journal of Virology, July 2009, p. 6652-6663, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00260-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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