We have previously identified two antiviral cytokines (interferon [IFN]-γ and IFN-α/β) 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-γ. Conversely, iNOS-deficient mice were not resistant to the antiviral effect of IFN-α/β 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-γ, whereas the antiviral activity of IFN-α/β 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.
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3 April 2000
Brief Definitive Report|
April 03 2000
Nitric Oxide Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice
Luca G. Guidotti,
Luca G. Guidotti
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
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Heike McClary,
Heike McClary
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
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Jacquelyn Moorhead Loudis,
Jacquelyn Moorhead Loudis
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
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Francis V. Chisari
Francis V. Chisari
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
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Luca G. Guidotti
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
Heike McClary
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
Jacquelyn Moorhead Loudis
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
Francis V. Chisari
aDepartment of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037
Received:
October 27 1999
Revision Requested:
December 15 1999
Accepted:
January 19 2000
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Exp Med (2000) 191 (7): 1247–1252.
Article history
Received:
October 27 1999
Revision Requested:
December 15 1999
Accepted:
January 19 2000
Citation
Luca G. Guidotti, Heike McClary, Jacquelyn Moorhead Loudis, Francis V. Chisari; Nitric Oxide Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice. J Exp Med 3 April 2000; 191 (7): 1247–1252. doi: https://doi.org/10.1084/jem.191.7.1247
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