TY - JOUR
T1 - Cytokine-sensitive replication of hepatitis B virus in immortalized mouse hepatocyte culturest
AU - Pasquetto, Valérie
AU - Wieland, Stefan F.
AU - Uprichard, Susan L.
AU - Tripodi, Marco
AU - Chisari, Francis V.
PY - 2002
Y1 - 2002
N2 - We have previously shown that alpha/beta interferon (IFN-α/β) and gamma interferon (IFN-γ) inhibit hepatitis B virus (HBV) replication by eliminating pregenomic RNA containing viral capsids from the hepatocyte. We have also shown that HBV-specific cytotoxic T lymphocytes that induce IFN-γ and tumor necrosis factor alpha (TNF-α) in the liver can inhibit HBV gene expression by destabilizing preformed viral mRNA. In order to further study the antiviral activity of IFN-α/β, IFN-γ, and TNF-α at the molecular level, we sought to reproduce these observations in an in vitro system. Accordingly, hepatocytes were derived from the livers of HBV-transgenic mice that also expressed the constitutively active cytoplasmic domain of the human hepatocyte growth factor receptor (c-Met). Here, we show that the resultant well-differentiated, continuous hepatocyte cell lines (HBV-Met) replicate HBV and that viral replication in these cells is efficiently controlled by IFN-α/β or IFN-γ, which eliminate pregenomic RNA-containing capsids from the cells as they do in the liver. Furthermore, we demonstrate that IFN-γ, but not IFN-α/β, is capable of inhibiting HBV gene expression in this system, especially when it acts synergistically with TNF-α. These cells should facilitate the analysis of the intracellular signaling pathways and effector mechanisms responsible for these antiviral effects.
AB - We have previously shown that alpha/beta interferon (IFN-α/β) and gamma interferon (IFN-γ) inhibit hepatitis B virus (HBV) replication by eliminating pregenomic RNA containing viral capsids from the hepatocyte. We have also shown that HBV-specific cytotoxic T lymphocytes that induce IFN-γ and tumor necrosis factor alpha (TNF-α) in the liver can inhibit HBV gene expression by destabilizing preformed viral mRNA. In order to further study the antiviral activity of IFN-α/β, IFN-γ, and TNF-α at the molecular level, we sought to reproduce these observations in an in vitro system. Accordingly, hepatocytes were derived from the livers of HBV-transgenic mice that also expressed the constitutively active cytoplasmic domain of the human hepatocyte growth factor receptor (c-Met). Here, we show that the resultant well-differentiated, continuous hepatocyte cell lines (HBV-Met) replicate HBV and that viral replication in these cells is efficiently controlled by IFN-α/β or IFN-γ, which eliminate pregenomic RNA-containing capsids from the cells as they do in the liver. Furthermore, we demonstrate that IFN-γ, but not IFN-α/β, is capable of inhibiting HBV gene expression in this system, especially when it acts synergistically with TNF-α. These cells should facilitate the analysis of the intracellular signaling pathways and effector mechanisms responsible for these antiviral effects.
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U2 - 10.1128/JVI.76.11.5646-5653.2002
DO - 10.1128/JVI.76.11.5646-5653.2002
M3 - Article
C2 - 11991993
AN - SCOPUS:0036097046
VL - 76
SP - 5646
EP - 5653
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 11
ER -