Doubly Active Protease

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Science  04 Mar 2005:
Vol. 307, Issue 5714, pp. 1377
DOI: 10.1126/science.307.5714.1377b

Evasion of host immune responses is a common defensive strategy used by viruses and is clearly illustrated by the ability of hepatitis C virus (HCV) to cause chronic liver infection. HCV achieves evasion, in part, through expression of the NS3/4A protease, which interrupts the induction of α/β interferon (IFN) gene expression by interferon regulatory factor 3 (IRF3).

Two studies identify the targets of NS3/4A, and both pathways are shown to be pivotal in IRF3 induction. Li et al. observed that the Toll-like receptor 3 (TLR3) adapter protein TRIF was cleaved by NS3/4A in an in vitro assay system. This was sufficient to prevent the induction of IFN-β by an activating ligand of TLR3. Furthermore, compromising TLR3 signaling was found to be sufficient to permit the cellular replication of HCV RNA. Foy et al. determined that the retinoic acid-inducible gene I (RIG-I) signaling pathway was disrupted by NS3/4A, again leading to loss of IRF3 induction of IFN-β The development of NS3/4A inhibitors may help guide improved therapeutic intervention in HCV infection. — SJS

Proc. Natl. Acad. Sci. U.S.A. 102, 2992; 2986 (2005).

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