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Journal of Virology, June 2002, p. 5646-5653, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5646-5653.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cytokine-Sensitive Replication of Hepatitis B Virus in Immortalized Mouse Hepatocyte Cultures{dagger}

Valérie Pasquetto,1,2 Stefan F. Wieland,1 Susan L. Uprichard,1 Marco Tripodi,2 and Francis V. Chisari1*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,1 Fondazione ‘Istituto Pasteur-Cenci Bolognetti,' Dipartimento di Biotechnologie Cellulari ed Ematologi, Università La Sapienza, and I.N. Malattie Infettive, I.R.C.C.S. "L. Spallanzani," Rome, Italy2

Received 5 December 2001/ Accepted 12 February 2002

We have previously shown that alpha/beta interferon (IFN-{alpha}/ß) and gamma interferon (IFN-{gamma}) inhibit hepatitis B virus (HBV) replication by eliminating pregenomic RNA containing viral capsids from the hepatocyte. We have also shown that HBV-specific cytotoxic T lymphocytes that induce IFN-{gamma} and tumor necrosis factor alpha (TNF-{alpha}) in the liver can inhibit HBV gene expression by destabilizing preformed viral mRNA. In order to further study the antiviral activity of IFN-{alpha}/ß, IFN-{gamma}, and TNF-{alpha} at the molecular level, we sought to reproduce these observations in an in vitro system. Accordingly, hepatocytes were derived from the livers of HBV-transgenic mice that also expressed the constitutively active cytoplasmic domain of the human hepatocyte growth factor receptor (c-Met). Here, we show that the resultant well-differentiated, continuous hepatocyte cell lines (HBV-Met) replicate HBV and that viral replication in these cells is efficiently controlled by IFN-{alpha}/ß or IFN-{gamma}, which eliminate pregenomic RNA-containing capsids from the cells as they do in the liver. Furthermore, we demonstrate that IFN-{gamma}, but not IFN-{alpha}/ß, is capable of inhibiting HBV gene expression in this system, especially when it acts synergistically with TNF-{alpha}. These cells should facilitate the analysis of the intracellular signaling pathways and effector mechanisms responsible for these antiviral effects.

* Corresponding author. Mailing address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8228. Fax: (858) 784-2160. E-mail: fchisari{at}scripps.edu.

{dagger} This is manuscript no. 14574-MEM from the Scripps Research Institute.

{ddagger} Present address: ViaCell, Worcester, MA 01605.

Journal of Virology, June 2002, p. 5646-5653, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5646-5653.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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