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Journal of Virology, September 2009, p. 8463-8469, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00751-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Inhibition of Intrahepatic Gamma Interferon Production by Hepatitis C Virus Nonstructural Protein 5A in Transgenic Mice {triangledown}

Tatsuo Kanda,1,{dagger} Robert Steele,1 Ranjit Ray,2,3 and Ratna B. Ray1,2,3*

Departments of Pathology,1 Internal Medicine,2 Liver Center, Saint Louis University, St. Louis, Missouri3

Received 12 April 2009/ Accepted 18 June 2009

Hepatitis C virus (HCV) utilizes strategies to suppress or evade the host immune response for establishment of persistent infection. We have shown previously that HCV nonstructural protein 5A (NS5A) impairs tumor necrosis factor alpha (TNF-{alpha})-mediated apoptosis. In this study, we have examined the immunomodulatory role of HCV NS5A protein in transgenic mouse (NS5A-Tg) liver when mice were challenged with an unrelated hepatotropic adenovirus as a nonspecific stimulus. Hepatotropic adenovirus was introduced intravenously into NS5A-Tg mice and control mice, and virus clearance from liver was compared over a time course of 3 weeks. The differential mRNA expression levels of 84 cytokine-related genes, signal pathway molecules, transcription factors, and cell surface molecules were determined using real-time reverse transcription-PCR array. NS5A-Tg mice failed to clear adenovirus from liver up to 3 weeks postinfection while control mice cleared virus within 1 to 2 weeks. Subsequent study revealed that gamma interferon (IFN-{gamma}) expression is inhibited at both the mRNA and protein levels in NS5A-Tg mice, and an inverse expression of transcription factors Gata-3 and Tbx21 is observed. However, TNF-{alpha} mRNA and protein expression were elevated in both NS5A-Tg and control mice. Together, our results suggested that HCV NS5A acts as an immunomodulator by inhibiting IFN-{gamma} production and may play an important role toward establishment of chronic HCV infection.

* Corresponding author. Mailing address: Department of Pathology, Saint Louis University, 1100 S. Grand Blvd., DRC-207, St. Louis, MO 63104. Phone: (314) 977-7822. Fax: (314) 771-3816. E-mail: rayrb{at}slu.edu

{triangledown} Published ahead of print on 24 June 2009.

{dagger} Present address: Chiba University, School of Medicine, Chiba, Japan.

Journal of Virology, September 2009, p. 8463-8469, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00751-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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