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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-B

Michael Biermer, 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-) is associated with noncytopathic clearance of hepatitis B virus in animal models. Here we demonstrate that the nuclear factor B (NF-B) signaling pathway is a central mediator of inhibition of hepatitis B virus by TNF- and we describe the molecular mechanism. TNF- 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-B-activating inhibitor of B kinase complex IKK-/ß and active transcription factor NF-B. Hepatitis B virus replication could also be inhibited and viral capsid formation could be disrupted in the absence of TNF- solely by overexpression of IKK-/ß or strong activation of NF-B. In contrast, inhibition of NF-B signaling stimulated viral replication, demonstrating that HBV replication is both positively and negatively regulated by the level of activity of the NF-B pathway. Studies are presented that exclude the possibility that HBV inhibition by NF-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-B signaling pathway and activated by TNF-.

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

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