The Journal of Experimental Medicine
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Published online 3 April 2000.
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*NITRIC OXIDE
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© The Rockefeller University Press, 0022-1007/2000/4/1247/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 7, April 3, 2000 1247-1252

Brief Definitive Report

Nitric Oxide Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice

Luca G. Guidottia, Heike McClarya, Jacquelyn Moorhead Loudisa, and Francis V. Chisaria
a Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Correspondence to: Luca G. Guidotti, The Scripps Research Institute, Department of Molecular and Experimental Medicine, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel:858-784-2758 Fax:858-784-2960 E-mail:guidotti{at}scripps.edu.

We have previously identified two antiviral cytokines (interferon [IFN]-{gamma} and IFN-{alpha}/ß) that downregulate hepatitis B virus (HBV) replication in the liver of transgenic mice. The cytokine-inducible downstream events that inhibit HBV replication have not been identified. One possible factor is nitric oxide (NO), a pleiotropic free radical with antiviral activity that is produced in the liver by the inducible NO synthase (iNOS). To examine the role of NO in our model, we crossed transgenic mice that replicate HBV with mice that lack a functional iNOS. Importantly, iNOS-deficient mice were almost completely resistant to the noncytopathic inhibitory effect of HBV-specific cytotoxic T lymphocytes on viral replication, an effect that we have shown previously to depend on the intrahepatic induction of IFN-{gamma}. Conversely, iNOS-deficient mice were not resistant to the antiviral effect of IFN-{alpha}/ß induced by either polyinosinic-polycytidylic acid complex or by lymphocytic choriomeningitis virus (LCMV) infection. These results indicate that NO mediates the antiviral activity of IFN-{gamma}, whereas the antiviral activity of IFN-{alpha}/ß is NO independent. We also compared the relative sensitivity of LCMV to control by NO in these animals. Interestingly, LCMV replicated to higher levels in the liver of iNOS-deficient mice than control mice, indicating that NO controls LCMV replication in the liver, as well as HBV.

Key Words: nitric oxide, cytokine, liver, hepatitis B virus, lymphocytic choriomeningitis virus


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