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Journal of Virology, March 2000, p. 2255-2264, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Relative Sensitivity of Hepatitis B Virus and Other Hepatotropic Viruses to the Antiviral Effects of Cytokinesdagger

Heike McClary, Rick Koch, Francis V. Chisari, and Luca G. Guidotti*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Received 5 October 1999/Accepted 9 December 1999

We have previously shown that hepatitis B virus (HBV) replication is inhibited noncytopathically in the livers of transgenic mice following injection of HBV-specific cytotoxic T lymphocytes (CTLs) or infection with unrelated hepatotropic viruses, including lymphocytic choriomeningitis virus (LCMV) and adenovirus. These effects are mediated by gamma interferon (IFNgamma ), tumor necrosis factor alpha (TNFalpha ), and IFNalpha /beta . In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFNgamma (IFNgamma KO), the TNFalpha receptor (TNFalpha RKO), or the IFNalpha /beta receptor (IFNalpha /beta RKO) in order to determine the relative contribution of each cytokine to the antiviral effects observed in each of these systems. Interestingly, we showed that HBV replicates in unmanipulated IFNgamma KO and IFNalpha /beta RKO mice at levels higher than those observed in control mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. We also showed that IFNgamma mediates most of the antiviral effect of the CTLs while IFNalpha /beta is primarily responsible for the early inhibitory effect of LCMV and adenovirus on HBV replication. In addition, we showed that the hepatic induction of IFNalpha /beta observed after injection of poly(I · C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFNalpha . We also compared the relative sensitivity of LCMV and adenovirus to control by IFNgamma , TNFalpha , or IFNalpha /beta in these animals. Importantly, IFNalpha /beta RKO mice, and to a lesser extent IFNgamma KO mice, showed higher hepatic levels of LCMV RNA and adenovirus DNA and RNA than control mice, underscoring the importance of both interferons in controlling these other viral infections as well.

* 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) 784-2758. Fax: (858) 784-2960. E-mail: guidotti{at}scripps.edu.

dagger Manuscript no. 12745-MEM from the Scripps Research Institute.

Journal of Virology, March 2000, p. 2255-2264, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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