With the elucidation of host antiviral response mechanisms, it has become evident that replication-competent viruses are equipped to counteract the antiviral mechanisms. It is well known that acutely infecting viruses, which undergo a lytic infection, selectively inhibit host macromolecular syntheses collectively known as shut off. Apart from this nonspecific blockade, viruses encode inhibitory proteins, which target specific processes of the antiviral signaling.
V proteins of paramyxoviruses bind to MDA5 and inhibit its signaling (Andrejeva et al. 2004; Yoneyama et al. 2005). V protein of Sendai virus specifically binds to MDA5 but neither interaction nor blockade was observed with RIG-I; however, in light of the fact that paramyxoviruses are specifically detected by RIG-I, as evidenced by RIG-I knockout mice, its physiological relevance is controversial.
Hepatitis C virus (HCV) is known to be poorly adaptable to tissue culture for replication. One reason is its high sensitivity to IFN-mediated reaction: HCV replication requires host cell mutations that inactivate RIG-I signaling (Sumpter et al. 2005). HCV encodes a protein complex, NS3/4A, which acts as RNA heli-case and protease. NS3/4A protease cleaves IPS-1 at its cytoplasmic domain, thus releasing it from mitochondria (Lin et al. 2006; Loo et al. 2006; Meylan et al. 2005). As IPS-1 is an essential adaptor for both RIG-I and MDA5 signaling and its association with mitochondria is obligatory, this cleavage completely blocks RIG-I/MDA5 signaling. Indeed, IPS-1 mutation at the cleavage motif or NS3/4A protease inhibitor restores the activation cascade stimulating the IFN genes.
NS1 protein of influenza A virus has been implicated in the inhibition of IFN gene activation. Using influenza A virus with NS1 mutation and RIG-I knockout mice, it was shown that NS1 blocks the signaling cascade triggered by RIG-I (Kato et al. 2006). NS1 is a dsRNA binding protein, thus sequestration of RIG-I from its ligand is one mechanism; however, the dsRNA-binding-deficient mutant of NS1 remains inhibitory (Donelan et al. 2003), suggesting multiple actions of this protein.
Ebola virus VP35 protein is another dsRNA binding protein inhibiting RIG-I-mediated signaling (Cardenas et al. 2006). Like NS1 of influenza A virus, VP35 may have dual inhibitory functions: in addition to dsRNA sequestration, it may be inhibiting steps downstream of IPS-1and IRF-3 kinases.
Since RIG-I and MDA5 are IFN-inducible and positive feedback is an important trait of the system, inhibition of IFN action, including IFN-R, by the JAK-STAT pathway remotely inhibits RIG-I and MDA5. In this regard, viral proteins that target IFN action are also inhibitory for IFN production.
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