Signal Transduction Pathways That Inhibit Hepatitis B Virus Replication

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 6; pp. 1743 - 1747
• Main Authors: Robek, Michael D., Boyd, Bryan S., Wieland, Stefan F., Chisari, Francis V.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.02.2004; National Acad Sciences
• Subjects: Animals; Antivirals; Biological Sciences; Capsid; Cell Line, Transformed; Cell lines; DNA; Enzyme Inhibitors - pharmacology; Gene expression; Genes; Hepatitis; Hepatitis B; Hepatitis B virus; Hepatitis B virus - physiology; Hepatocytes; Interferons - antagonists & inhibitors; Interferons - pharmacology; JAK protein; Mice; Microbiology; Protein Biosynthesis - drug effects; RNA; Signal Transduction; Transcription, Genetic - drug effects; Virus Replication; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0308340100

The replication of hepatitis B virus (HBV) in hepatocytes is strongly inhibited in response to IFN-α/β and IFNγ. Although it has been previously demonstrated that IFN-α/β eliminates HBV RNA-containing capsids from the cell in a proteasome-dependent manner, the precise cellular pathway that mediates this antiviral effect has not been identified. Because IFN-induced signal transduction involves kinase-mediated activation of gene expression, we used an immortalized hepatocyte cell line that replicates HBV in an IFN-sensitive manner to investigate the role of cellular kinase activity and the cellular transcription and translation machinery in the antiviral effect. Our results indicate that Janus kinase activity is required for the antiviral effect of IFN against HBV, but that phosphatidylinositol 3-kinase, cyclin-dependent kinase, mitogen-activated protein kinase, and NF-κB activity are not. Additionally, we found that inhibitors of cellular transcription and translation completely abolish the antiviral effect, which also appears to require cellular kinase activity downstream of signal transduction and gene expression. Collectively, these results identify IFN-regulated pathways that interrupt the HBV replication cycle by eliminating viral RNA-containing capsids from the cell, and they provide direction for discovery of the terminal effector molecules that ultimately mediate this antiviral effect.