Hepatitis C virus (HCV) is a hepatotropic virus that belongs to the family Flaviviridae. Chronic HCV infection can result in fibrosis, cirrhosis, and hepatocellular carcinoma (1). It is estimated that approximately 2% of the world population (ϳ170 million people) is infected with HCV, making it a major world health concern (2-6). The HCV genome consists of a positive-strand RNA molecule of approximately 9,600 nucleotides encoding both structural and nonstructural proteins. Nonstructural proteins 3 (NS3) and 5B (NS5B) have serine protease and RNA-dependent RNA polymerase functions, respectively, which are essential for proteolytic processing of the nonstructural-protein region of the HCV polyprotein and for viral RNA replication.Because the HCV polymerase and protease are necessary for the viral replication cycle, both have been attractive targets for anti-HCV drug development (7). Several inhibitors of the NS3 · 4A protease (e.g., Incivek In addition to being essential for proteolytic cleavage of the viral polyprotein, the HCV NS3 · 4A protease has also been shown to suppress the innate immune response by cleaving beta interferon (IFN-␤) stimulator 1 (IPS-1) (13) and Toll/interleukin 1 (IL-1) receptor domain-containing adapter inducing IFN-␤ (TRIF) (14) in cultured cells. In response to viral replication intermediates, such as viral RNA and proteins, IPS-1 and TRIF adaptor protein act as signaling intermediates in retinoic acidinducible gene (Rig-I) and/or Toll-like receptor 3 (TLR3) pathways (15-17). Activation of these pathways induces IRF3 activation and subsequent transcriptional activation of type I