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J. Biol. Chem., Vol. 282, Issue 14, 10792-10803, April 6, 2007

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Functional and Therapeutic Analysis of Hepatitis C Virus NS3·4A Protease Control of Antiviral Immune Defense^*

From the Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Chronic hepatitis C virus (HCV) infection is a major global public health problem. HCV infection is supported by viral strategies to evade the innate antiviral response wherein the viral NS3·4A protease complex targets and cleaves the interferon promoter stimulator-1 (IPS-1) adaptor protein to ablate signaling of interferon / immune defenses. Here we examined the structural requirements of NS3·4A and the therapeutic potential of NS3·4A inhibitors to control the innate immune response against virus infection. The structural composition of NS3 includes an amino-terminal serine protease domain and a carboxyl-terminal RNA helicase domain. NS3 mutants lacking the helicase domain retained the ability to control virus signaling initiated by retinoic acid-inducible gene-I (RIG-I) or melanoma differentiation antigen 5 and suppressed the downstream activation of interferon regulatory factor-3 (IRF-3) and nuclear factor B (NF-B) through the targeted proteolysis of IPS-1. This regulation was abrogated by truncation of the NS3 protease domain or by point mutations that ablated protease activity. NS3·4A protease control of antiviral immune signaling was due to targeted proteolysis of IPS-1 by the NS3 protease domain and minimal NS4A cofactor. Treatment of HCV-infected cells with an NS3 protease inhibitor prevented IPS-1 proteolysis by the HCV protease and restored RIG-I immune defense signaling during infection. Thus, the NS3·4A protease domain can target IPS-1 for cleavage and is essential for blocking RIG-I signaling to IRF-3 and NF-B, whereas the helicase domain is dispensable for this action. Our results indicate that NS3·4A protease inhibitors have immunomodulatory potential to restore innate immune defenses to HCV infection.

Received for publication, November 7, 2006 , and in revised form, February 8, 2007.

^* This work was supported by National Institutes of Health Grants R01AI060389 and U19AI40035 Project 4 (to M. G.) and a Medical Scientist Training Program grant (to C. L. J. and D. M. O.), the Burroughs-Wellcome fund, and a gift from Mr. and Mrs. R. Batcheldor (to M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A Nancy C. and Jeffrey A. Marcus Scholar in Medical Research in honor of Dr. Bill S. Vowell. To whom correspondence should be addressed: Dept. of Microbiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd. NA6.308, Dallas, TX 75390-9048. Tel.: 214-648-5940; Fax: 214-648-5905; E-mail: Michael.Gale{at}UTSouthwestern.edu.

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