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Journal of Virology, January 1999, p. 474-481, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Hepatitis B Virus RNA-Binding Proteins Associated with Cytokine-Induced Clearance of Viral RNA from the Liver of Transgenic Micedagger

Tilman Heise,1,2 Luca G. Guidotti,1 Victoria J. Cavanaugh,1 and Francis V. Chisari1,*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,1 and Institut für Biochemie und Molekulare Zellbiologie, Georg-August-Universität Göttingen, D-37073 Göttingen, Germany2

Received 20 July 1998/Accepted 7 October 1998

Hepatitis B virus (HBV) gene expression is downregulated in the liver of HBV transgenic mice by a posttranscriptional mechanism that is triggered by the local production of gamma interferon (IFN-gamma ) and tumor necrosis factor alpha (TNF-alpha ) during intrahepatic inflammation (hepatitis). The molecular basis for this antiviral effect is unknown. In this study, we identified three HBV RNA-binding liver nuclear proteins (p45, p39, and p26) the relative abundance of which correlates with the abundance of HBV RNA in response to the induction of IFN-gamma and TNF-alpha . All three proteins bind to a 91-bp element located at the 5' end of a previously defined posttranscriptional regulatory element that is thought to mediate the nuclear export of HBV RNA. The presence of p45 correlates directly with the presence of HBV RNA, being detectable under baseline conditions when the viral RNA is abundant and undetectable when the viral RNA disappears in response to IFN-gamma and TNF-alpha . In contrast, p26 is inversely related to HBV RNA, being detectable only when the viral RNA disappears following cytokine activation. Finally, p39 is constitutively expressed, and its abundance and mobility appear to be slightly increased by cytokine activation. These results suggest a model in which hepatocellular HBV RNA content might be controlled by the stabilizing and/or destabilizing influences of these RNA-binding proteins whose activity is regulated by cytokine-induced signaling pathways.

* Corresponding author. Mailing address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (619) 784-8228. Fax: (619) 784-2160. E-mail: fchisari{at}scripps.edu.

dagger Manuscript no. 11630-MEM from The Scripps Research Institute.

Journal of Virology, January 1999, p. 474-481, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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