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Journal of Virology, May 2002, p. 5251-5259, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.5251-5259.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Blockade of Interferon Induction and Action by the E3L Double-Stranded RNA Binding Proteins of Vaccinia Virus

Ying Xiang,1 Richard C. Condit,2 Sangeetha Vijaysri,3 Bertram Jacobs,3 Bryan R. G. Williams,1 and Robert H. Silverman1*

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio,1 Department of Molecular Genetics, Center for Mammalian Genetics, University of Florida, Gainesville, Florida 32610-0266,2 Department of Microbiology, Graduate Program in Molecular and Cellular Biology, Arizona State University, Tempe, Arizona 85287-27013

Received 4 January 2002/ Accepted 19 February 2002

The vaccinia virus E3L gene encodes two double-stranded RNA binding proteins that promote viral growth and pathogenesis through suppression of innate immunity. To explore how E3L enables vaccinia virus to evade the interferon system, cells and mice deficient in the principal interferon-regulated antiviral enzymes, PKR and RNase L, were infected with wild-type vaccinia virus and strains of vaccinia virus from which E3L had been deleted (E3L-deleted strains). While wild-type virus was unaffected by RNase L and PKR, virus lacking E3L replicated only in the deficient cells. Nevertheless, E3L-deleted virus failed to replicate to high titers or to cause significant morbidity or mortality in triply deficient mice lacking RNase L, PKR, and Mx1. To investigate the underlying cause, we determined the effect of E3L on interferon regulatory factor 3 (IRF3), a transcription factor required for viral induction of subtypes of type I interferons. Results showed that IRF3 activation and interferon-ß induction occurred after infections with E3L-deleted virus but not with wild-type virus. These findings demonstrate that E3L plays an essential role in the pathogenesis of vaccinia virus by blocking the interferon system at multiple levels. Furthermore, our results indicate the existence of an interferon-mediated antipoxvirus pathway that operates independently of PKR, Mx1, or the 2-5A/RNase L system.

* Corresponding author. Mailing address: Department of Cancer Biology, NB40, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44195. Phone: (216) 445-9650. Fax: (216) 445-6269. E-mail: silverr{at}ccf.org.

Journal of Virology, May 2002, p. 5251-5259, Vol. 76, No. 10
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.10.5251-5259.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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