Interferon-regulated pathways that control hepatitis B virus replication in transgenic mice.
We previously showed that the intrahepatic induction of cytokines such as alpha/beta interferon (IFN-alpha/beta) and gamma interferon (IFN-gamma) inhibits hepatitis B virus (HBV) replication noncytopathically in the livers of transgenic mice. The intracellular pathway(s) responsible for this effect is still poorly understood. To identify interferon (IFN)-inducible intracellular genes that could play a role in our system, we crossed HBV transgenic mice with mice deficient in IFN regulatory factor 1 (IRF-1), the double-stranded RNA-activated protein kinase (PKR), or RNase L (RNase L) (IRF-1(-/-), PKR(-/-), or RNase L(-/-) mice, respectively), three well-characterized IFN-inducible genes that mediate antiviral activity. We showed that unmanipulated IRF-1(-/-) or PKR(-/-) transgenic mice replicate HBV in the liver at slightly higher levels than the respective controls, suggesting that both IRF-1 and PKR individually appear to mediate signals that modulate HBV replication under basal conditions. These same animals were responsive to the antiviral effects of the IFN-alpha/beta inducer poly(I-C) or recombinant murine IFN-gamma, suggesting that under these conditions, either the IRF-1 or the PKR genes can mediate the antiviral activity of the IFNs or other IFN-inducible genes mediate the antiviral effects. Finally, RNase L(-/-) transgenic mice were undistinguishable from controls under basal conditions and after poly(I-C) or IFN-gamma administration, suggesting that RNase L does not modulate HBV replication in this model.
Guidotti
Luca G
LG
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. guidotti@scripps.edu
Morris
Amber
A
Mendez
Heike
H
Koch
Rick
R
Silverman
Robert H
RH
Williams
Bryan R G
BR
Chisari
Francis V
FV
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006509:Hepatitis B / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011994:Recombinant Proteins; D014779:Virus Replication / Q000187:drug effects; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D011070:Poly I-C