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Journal of Virology, March 2005, p. 2689-2699, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2689-2699.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulating Intracellular Antiviral Defense and Permissiveness to Hepatitis C Virus RNA Replication through a Cellular RNA Helicase, RIG-I{dagger}

Rhea Sumpter Jr.,1 Yueh-Ming Loo,1 Eileen Foy,1 Kui Li,2 Mitsutoshi Yoneyama,3 Takashi Fujita,3 Stanley M. Lemon,2 and Michael Gale Jr.1*

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas,1 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas,2 Department of Tumor Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan3

Received 13 October 2004/ Accepted 18 October 2004

Virus-responsive signaling pathways that induce alpha/beta interferon production and engage intracellular immune defenses influence the outcome of many viral infections. The processes that trigger these defenses and their effect upon host permissiveness for specific viral pathogens are not well understood. We show that structured hepatitis C virus (HCV) genomic RNA activates interferon regulatory factor 3 (IRF3), thereby inducing interferon in cultured cells. This response is absent in cells selected for permissiveness for HCV RNA replication. Studies including genetic complementation revealed that permissiveness is due to mutational inactivation of RIG-I, an interferon-inducible cellular DExD/H box RNA helicase. Its helicase domain binds HCV RNA and transduces the activation signal for IRF3 by its caspase recruiting domain homolog. RIG-I is thus a pathogen receptor that regulates cellular permissiveness to HCV replication and, as an interferon-responsive gene, may play a key role in interferon-based therapies for the treatment of HCV infection.

* Corresponding author. Mailing address: Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9048. Phone: (214) 648-5940. Fax: (214) 648-5905. E-mail: michael.gale{at}UTSouthwestern.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, March 2005, p. 2689-2699, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.2689-2699.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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