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

ABSTRACT Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of double-stranded RNA (dsRNA)-induced beta interferon (IFN-β) 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 IKKε). 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-β)-mediated IRF-3 activation, which is part of the Toll-like receptor 3 signaling pathway. As IRF-3 is necessary for IFN-β transcription, inhibition of this factor results in efficient suppression of IFN-β synthesis. This ability of HAV seems to be of considerable importance for HAV replication, as HAV is not resistant to IFN-β, and it may allow the virus to establish infection and preserve the sites of virus production in later stages of the infection.

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