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Journal of Virology, September 2005, p. 10968-10977, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.10968-10977.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis A Virus Suppresses RIG-I-Mediated IRF-3 Activation To Block Induction of Beta Interferon

Volker Fensterl, Dajana Grotheer, Iris Berk, Stefanie Schlemminger,{dagger} Angelika Vallbracht, and Andreas Dotzauer*

Department of Virology, University of Bremen, D-28359 Bremen, Germany

Received 4 April 2005/ Accepted 2 June 2005

Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of double-stranded RNA (dsRNA)-induced beta interferon (IFN-ß) gene expression. In this report, we show that this is due to an interaction of HAV with the intracellular dsRNA-induced retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway upstream of the kinases responsible for interferon regulatory factor 3 (IRF-3) phosphorylation (TBK1 and IKK{varepsilon}). In consequence, IRF-3 is not activated for nuclear translocation and gene induction. In addition, we found that HAV reduces TRIF (TIR domain-containing adaptor inducing IFN-ß)-mediated IRF-3 activation, which is part of the Toll-like receptor 3 signaling pathway. As IRF-3 is necessary for IFN-ß transcription, inhibition of this factor results in efficient suppression of IFN-ß synthesis. This ability of HAV seems to be of considerable importance for HAV replication, as HAV is not resistant to IFN-ß, and it may allow the virus to establish infection and preserve the sites of virus production in later stages of the infection.

* Corresponding author. Mailing address: Department of Virology, University of Bremen, Leobener Str. / UFT, D-28359 Bremen, Germany. Phone: 49 421 218 4354. Fax: 49 421 218 4266. E-mail: dotzauer{at}uni-bremen.de.

{dagger} Present address: Klinik I für Innere Medizin, University of Cologne, Cologne, Germany.

Journal of Virology, September 2005, p. 10968-10977, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.10968-10977.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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