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Journal of Virology, March 2002, p. 2617-2621, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2617-2621.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interferon-Regulated Pathways That Control Hepatitis B Virus Replication in Transgenic Mice{dagger}

Luca G. Guidotti,1* Amber Morris,1 Heike Mendez,1 Rick Koch,1 Robert H. Silverman,2 Bryan R. G. Williams,2 and Francis V. Chisari1

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037 ,1 Department of Cancer Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 441952

Received 3 October 2001/ Accepted 5 December 2001

We previously showed that the intrahepatic induction of cytokines such as alpha/beta interferon (IFN-{alpha}/ß) and gamma interferon (IFN-{gamma}) inhibits hepatitis B virus (HBV) replication noncytopathically in the livers of transgenic mice. The intracellular pathway(s) responsible for this effect is still poorly understood. To identify interferon (IFN)-inducible intracellular genes that could play a role in our system, we crossed HBV transgenic mice with mice deficient in IFN regulatory factor 1 (IRF-1), the double-stranded RNA-activated protein kinase (PKR), or RNase L (RNase L) (IRF-1-/-, PKR-/-, or RNase L-/- mice, respectively), three well-characterized IFN-inducible genes that mediate antiviral activity. We showed that unmanipulated IRF-1-/- or PKR-/- transgenic mice replicate HBV in the liver at slightly higher levels than the respective controls, suggesting that both IRF-1 and PKR individually appear to mediate signals that modulate HBV replication under basal conditions. These same animals were responsive to the antiviral effects of the IFN-{alpha}/ß inducer poly(I-C) or recombinant murine IFN-{gamma}, suggesting that under these conditions, either the IRF-1 or the PKR genes can mediate the antiviral activity of the IFNs or other IFN-inducible genes mediate the antiviral effects. Finally, RNase L-/- transgenic mice were undistinguishable from controls under basal conditions and after poly(I-C) or IFN-{gamma} administration, suggesting that RNase L does not modulate HBV replication in this model.

* Corresponding author. Mailing address: The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-2758. Fax: (858) 784-2960. E-mail: guidotti{at}scripps.edu.

{dagger} Manuscript 14438-MEM from The Scripps Research Institute.

Journal of Virology, March 2002, p. 2617-2621, Vol. 76, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.6.2617-2621.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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