Tumor Necrosis Factor Alpha Inhibition of Hepatitis B Virus Replication Involves Disruption of Capsid Integrity through Activation of NF-κB
Open Access
- 1 April 2003
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 77 (7), 4033-4042
- https://doi.org/10.1128/jvi.77.7.4033-4042.2003
Abstract
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-α) is associated with noncytopathic clearance of hepatitis B virus in animal models. Here we demonstrate that the nuclear factor κB (NF-κB) signaling pathway is a central mediator of inhibition of hepatitis B virus by TNF-α and we describe the molecular mechanism. TNF-α 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-κB-activating inhibitor of κB kinase complex IKK-α/β and active transcription factor NF-κB. Hepatitis B virus replication could also be inhibited and viral capsid formation could be disrupted in the absence of TNF-α solely by overexpression of IKK-α/β or strong activation of NF-κB. In contrast, inhibition of NF-κB signaling stimulated viral replication, demonstrating that HBV replication is both positively and negatively regulated by the level of activity of the NF-κB pathway. Studies are presented that exclude the possibility that HBV inhibition by NF-κB 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-κB signaling pathway and activated by TNF-α.Keywords
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