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Journal of Virology, January 2007, p. 964-976, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.02076-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

GB Virus B Disrupts RIG-I Signaling by NS3/4A-Mediated Cleavage of the Adaptor Protein MAVS{triangledown}

Zihong Chen,1,2 Yann Benureau,3,{dagger} Rene Rijnbrand,1,2,{dagger},{ddagger} Jianzhong Yi,1,2 Ting Wang,1,2,4 Lucile Warter,3 Robert E. Lanford,5 Steven A. Weinman,2,4 Stanley M. Lemon,1,2 Annette Martin,3 and Kui Li1,2*

Departments of Microbiology & Immunology,1 Neuroscience and Cell Biology,4 Center for Hepatitis Research, Institute for Human Infections & Immunity, University of Texas Medical Branch, Galveston, Texas,2 Unité de Génétique Moléculaire des Virus Respiratoires, CNRS URA 1966, Institut Pasteur, Paris, France,3 Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas5

Received 21 September 2006/ Accepted 25 October 2006

Understanding the mechanisms of hepatitis C virus (HCV) pathogenesis and persistence has been hampered by the lack of small, convenient animal models. GB virus B (GBV-B) is phylogenetically the closest related virus to HCV. It causes generally acute and occasionally chronic hepatitis in small primates and is used as a surrogate model for HCV. It is not known, however, whether GBV-B has evolved strategies to circumvent host innate defenses similar to those of HCV, a property that may contribute to HCV persistence in vivo. We show here in cultured tamarin hepatocytes that GBV-B NS3/4A protease, but not a related catalytically inactive mutant, effectively blocks innate intracellular antiviral responses signaled through the RNA helicase, retinoic acid-inducible gene I (RIG-I), an essential sensor molecule that initiates host defenses against many RNA viruses, including HCV. GBV-B NS3/4A protease specifically cleaves mitochondrial antiviral signaling protein (MAVS; also known as IPS-1/Cardif/VISA) and dislodges it from mitochondria, thereby disrupting its function as a RIG-I adaptor and blocking downstream activation of both interferon regulatory factor 3 and nuclear factor kappa B. MAVS cleavage and abrogation of virus-induced interferon responses were also observed in Huh7 cells supporting autonomous replication of subgenomic GBV-B RNAs. Our data indicate that, as in the case of HCV, GBV-B has evolved to utilize its major protease to disrupt RIG-I signaling and impede innate antiviral defenses. These data provide further support for the use of GBV-B infection in small primates as an accurate surrogate model for deciphering virus-host interactions in hepacivirus pathogenesis.

* Corresponding author. Mailing address: 4.168A Medical Research Building, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019. Phone: (409) 772-4934. Fax: (409) 772-5065. E-mail: kuli{at}utmb.edu.

{triangledown} Published ahead of print on 8 November 2006.

{dagger} Y.B. and R.R. contributed equally to this work.

{ddagger} Present address: Immusol, 10790 Roselle Street, San Diego, CA 92121.

Journal of Virology, January 2007, p. 964-976, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.02076-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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