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Journal of Virology, April 2003, p. 4033-4042, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4033-4042.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Alpha Inhibition of Hepatitis B Virus Replication Involves Disruption of Capsid Integrity through Activation of NF-{kappa}B

Michael Biermer,{dagger} Robyn Puro, and Robert J. Schneider*

Department of Microbiology, New York University School of Medicine, New York, New York 10016

Received 29 August 2002/ Accepted 20 December 2002

Chronic infection by hepatitis B virus results from an inability to clear the virus, which is associated with liver disease and liver cancer. Tumor necrosis factor alpha (TNF-{alpha}) is associated with noncytopathic clearance of hepatitis B virus in animal models. Here we demonstrate that the nuclear factor {kappa}B (NF-{kappa}B) signaling pathway is a central mediator of inhibition of hepatitis B virus by TNF-{alpha} and we describe the molecular mechanism. TNF-{alpha} is shown to suppress hepatitis B virus DNA replication without cell killing by disrupting the formation or stability of cytoplasmic viral capsids through a pathway requiring the NF-{kappa}B-activating inhibitor of {kappa}B kinase complex IKK-{alpha}/ß and active transcription factor NF-{kappa}B. Hepatitis B virus replication could also be inhibited and viral capsid formation could be disrupted in the absence of TNF-{alpha} solely by overexpression of IKK-{alpha}/ß or strong activation of NF-{kappa}B. In contrast, inhibition of NF-{kappa}B signaling stimulated viral replication, demonstrating that HBV replication is both positively and negatively regulated by the level of activity of the NF-{kappa}B pathway. Studies are presented that exclude the possibility that HBV inhibition by NF-{kappa}B is carried out by secondary production of gamma interferon or alpha/beta interferon. These results identify a novel mechanism for noncytopathic suppression of hepatitis B virus replication that is mediated by the NF-{kappa}B signaling pathway and activated by TNF-{alpha}.

* Corresponding author. Mailing address: Department of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-6006. Fax: (212) 263-8276. E-mail: schner01{at}popmail.med.nyu.edu.

{dagger} Present address: Department of General Virology, Heinrich-Pette-Institut, Hamburg, Germany.

Journal of Virology, April 2003, p. 4033-4042, Vol. 77, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.7.4033-4042.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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