scholarly journals Inhibition of Hepatitis B Virus Replication during Adenovirus and Cytomegalovirus Infections in Transgenic Mice

1998 ◽  
Vol 72 (4) ◽  
pp. 2630-2637 ◽  
Author(s):  
Victoria J. Cavanaugh ◽  
Luca G. Guidotti ◽  
Francis V. Chisari
Keyword(s):  
Gene Expression ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Lymphocytic Choriomeningitis ◽  
Murine Cytomegalovirus ◽  
Necrosis Factor Alpha ◽  
Hbv Replication ◽  
B Virus ◽  
Cytomegalovirus Infections

ABSTRACT We have previously demonstrated that hepatitis B virus (HBV) replication and gene expression are abolished in the livers of HBV transgenic mice by cytotoxic T lymphocytes (CTLs) and during lymphocytic choriomeningitis virus (LCMV) infection, stimuli that trigger the production of alpha/beta interferon, gamma interferon, and tumor necrosis factor alpha in the liver. We now report that hepatic HBV replication and gene expression are inhibited by the local induction of these cytokines during adenovirus- and murine cytomegalovirus (MCMV)-induced hepatitis. Further, we show that MCMV also blocks HBV replication and gene expression in the proximal convoluted tubules of the kidney by causing interstitial nephritis and inducing the same cytokines in the renal parenchyma. These results suggest that inflammatory cytokines probably contribute to viral clearance during acute viral hepatitis in humans, and they imply that induction of these cytokines in the liver and other infected tissues of chronically infected patients might have therapeutic value.

scholarly journals Relative Sensitivity of Hepatitis B Virus and Other Hepatotropic Viruses to the Antiviral Effects of Cytokines

2000 ◽  
Vol 74 (5) ◽  
pp. 2255-2264 ◽  
Author(s):  
Heike McClary ◽  
Rick Koch ◽  
Francis V. Chisari ◽  
Luca G. Guidotti
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Viral Infections ◽  
Relative Sensitivity ◽  
Antiviral Effect ◽  
Necrosis Factor Alpha ◽  
Hbv Replication ◽  
Antiviral Effects ◽  
B Virus

ABSTRACT We have previously shown that hepatitis B virus (HBV) replication is inhibited noncytopathically in the livers of transgenic mice following injection of HBV-specific cytotoxic T lymphocytes (CTLs) or infection with unrelated hepatotropic viruses, including lymphocytic choriomeningitis virus (LCMV) and adenovirus. These effects are mediated by gamma interferon (IFNγ), tumor necrosis factor alpha (TNFα), and IFNα/β. In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFNγ (IFNγKO), the TNFα receptor (TNFαRKO), or the IFNα/β receptor (IFNα/βRKO) in order to determine the relative contribution of each cytokine to the antiviral effects observed in each of these systems. Interestingly, we showed that HBV replicates in unmanipulated IFNγKO and IFNα/βRKO mice at levels higher than those observed in control mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. We also showed that IFNγ mediates most of the antiviral effect of the CTLs while IFNα/β is primarily responsible for the early inhibitory effect of LCMV and adenovirus on HBV replication. In addition, we showed that the hepatic induction of IFNα/β observed after injection of poly(I · C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFNα. We also compared the relative sensitivity of LCMV and adenovirus to control by IFNγ, TNFα, or IFNα/β in these animals. Importantly, IFNα/βRKO mice, and to a lesser extent IFNγKO mice, showed higher hepatic levels of LCMV RNA and adenovirus DNA and RNA than control mice, underscoring the importance of both interferons in controlling these other viral infections as well.

scholarly journals Inhibition of Cellular Proteasome Activities Mediates HBX-Independent Hepatitis B Virus Replication In Vivo

2010 ◽  
Vol 84 (18) ◽  
pp. 9326-9331 ◽  
Author(s):  
Zhensheng Zhang ◽  
Eun Sun ◽  
Jing-hsiung James Ou ◽  
T. Jake Liang
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Productive Infection ◽  
Minor Effect ◽  
Hbv Replication ◽  
B Virus ◽  
Culture Models ◽  
A Minor

ABSTRACT The X protein (HBX) of the hepatitis B virus (HBV) is essential for HBV productive infection in vivo. Our previous study (Z. Hu, Z. Zhang, E. Doo, O. Coux, A. L. Goldberg, and T. J. Liang, J. Virol. 73:7231-7240, 1999) shows that interaction of HBX with the proteasome complex may underlie the pleiotropic functions of HBX. Previously, we demonstrated that HBX affects hepadnaviral replication through a proteasome-dependent pathway in cell culture models. In the present study, we studied the effect of the proteasome inhibitor MLN-273 in two HBV mouse models. We demonstrated that administration of MLN-273 to transgenic mice containing the replication-competent HBV genome with the defective HBX gene substantially enhanced HBV replication, while the compound had a minor effect on wild-type HBV transgenic mice. Similar results were obtained by using C57BL/6 mice infected with recombinant adenoviruses expressing the replicating HBV genome. Our data suggest that HBV replication is subjected to regulation by cellular proteasome and HBX functions through the inhibition of proteasome activities to enhance HBV replication in vivo.

scholarly journals Nitric Oxide Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice

2000 ◽  
Vol 191 (7) ◽  
pp. 1247-1252 ◽  
Author(s):  
Luca G. Guidotti ◽  
Heike McClary ◽  
Jacquelyn Moorhead Loudis ◽  
Francis V. Chisari
Keyword(s):  
Nitric Oxide ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Transgenic Mice ◽  
Hbv Replication ◽  
Polycytidylic Acid ◽  
B Virus ◽  
Ifn Γ ◽  
Deficient Mice

We have previously identified two antiviral cytokines (interferon [IFN]-γ and IFN-α/β) that downregulate hepatitis B virus (HBV) replication in the liver of transgenic mice. The cytokine-inducible downstream events that inhibit HBV replication have not been identified. One possible factor is nitric oxide (NO), a pleiotropic free radical with antiviral activity that is produced in the liver by the inducible NO synthase (iNOS). To examine the role of NO in our model, we crossed transgenic mice that replicate HBV with mice that lack a functional iNOS. Importantly, iNOS-deficient mice were almost completely resistant to the noncytopathic inhibitory effect of HBV-specific cytotoxic T lymphocytes on viral replication, an effect that we have shown previously to depend on the intrahepatic induction of IFN-γ. Conversely, iNOS-deficient mice were not resistant to the antiviral effect of IFN-α/β induced by either polyinosinic-polycytidylic acid complex or by lymphocytic choriomeningitis virus (LCMV) infection. These results indicate that NO mediates the antiviral activity of IFN-γ, whereas the antiviral activity of IFN-α/β is NO independent. We also compared the relative sensitivity of LCMV to control by NO in these animals. Interestingly, LCMV replicated to higher levels in the liver of iNOS-deficient mice than control mice, indicating that NO controls LCMV replication in the liver, as well as HBV.

scholarly journals Enhancement of Hepatitis B Virus Replication by Its X Protein in Transgenic Mice

2002 ◽  
Vol 76 (5) ◽  
pp. 2579-2584 ◽  
Author(s):  
Zhenming Xu ◽  
T. S. Benedict Yen ◽  
Lanying Wu ◽  
Charles R. Madden ◽  
Wenjie Tan ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
X Protein ◽  
Multifunctional Protein ◽  
Hbv Replication ◽  
B Virus

ABSTRACT Hepatitis B virus (HBV) X gene encodes a multifunctional protein that can regulate cellular signaling pathways, interact with cellular transcription factors, and induce hepatocellular oncogenesis. In spite of its diverse activities, the precise role of the X protein in the viral life cycle of HBV remains unclear. To investigate this question, we have produced transgenic mice that carry either the wild-type HBV genome or a mutated HBV genome incapable of expressing the 16.5-kDa X protein. Our results indicate that while the X protein is not absolutely essential for HBV replication or its maturation in transgenic mice, it can enhance viral replication, apparently by activating viral gene expression. These results demonstrate a transactivation role of the X protein in HBV replication in transgenic mice.

scholarly journals Cytokine-Sensitive Replication of Hepatitis B Virus in Immortalized Mouse Hepatocyte Cultures

2002 ◽  
Vol 76 (11) ◽  
pp. 5646-5653 ◽  
Author(s):  
Valérie Pasquetto ◽  
Stefan F. Wieland ◽  
Susan L. Uprichard ◽  
Marco Tripodi ◽  
Francis V. Chisari
Keyword(s):  
Gene Expression ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
B Virus ◽  
Ifn Γ

ABSTRACT 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.

scholarly journals Interferon-Regulated Pathways That Control Hepatitis B Virus Replication in Transgenic Mice

2002 ◽  
Vol 76 (6) ◽  
pp. 2617-2621 ◽  
Author(s):  
Luca G. Guidotti ◽  
Amber Morris ◽  
Heike Mendez ◽  
Rick Koch ◽  
Robert H. Silverman ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Transgenic Mice ◽  
Rnase L ◽  
Hbv Replication ◽  
Antiviral Effects ◽  
B Virus ◽  
Ifn Γ ◽  
Inducible Genes

ABSTRACT We previously showed that the intrahepatic induction of cytokines such as alpha/beta interferon (IFN-α/β) and gamma interferon (IFN-γ) 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-α/β inducer poly(I-C) or recombinant murine IFN-γ, 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-γ administration, suggesting that RNase L does not modulate HBV replication in this model.

Inhibition of hepatitis b virus surface antigen gene expression in carcinogen-induced liver tumors from transgenic mice

1994 ◽  
Vol 9 (4) ◽  
pp. 185-192 ◽  
Author(s):  
Hend Farza ◽  
Tommaso A. Dragani ◽  
Thomas Metzler ◽  
Giacomo Manenti ◽  
Pierre Tiollais ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Surface Antigen ◽  
Liver Tumors ◽  
Virus Surface ◽  
Virus Surface Antigen ◽  
Antigen Gene ◽  
B Virus

scholarly journals Alkoxyalkyl Esters of 9-(S)-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo

2009 ◽  
Vol 53 (7) ◽  
pp. 2865-2870 ◽  
Author(s):  
John D. Morrey ◽  
Brent E. Korba ◽  
James R. Beadle ◽  
David L. Wyles ◽  
Karl Y. Hostetler
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Transgenic Mice ◽  
Adefovir Dipivoxil ◽  
Murine Cytomegalovirus ◽  
Cross Resistance ◽  
B Virus

ABSTRACT Alkoxyalkyl esters of acyclic nucleoside phosphonates have previously been shown to have increased antiviral activity when they are administered orally in animal models of viral diseases, including lethal infections with vaccinia virus, cowpox virus, ectromelia virus, murine cytomegalovirus, and adenovirus. 9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was previously shown to have activity against hepatitis B virus (HBV) in vitro. To assess the effect of alkoxyalkyl esterification of (S)-HPMPA, we prepared the hexadecyloxypropyl (HDP), 15-methyl-hexadecyloxypropyl (15M-HDP), and octadecyloxyethyl (ODE) esters and compared their activities with the activity of adefovir dipivoxil in vitro and in vivo. Alkoxyalkyl esters of (S)-HPMPA were 6 to 20 times more active than unmodified (S)-HPMPA on the basis of their 50% effective concentrations in 2.2.15 cells. The increased antiviral activity appeared to be due in part to the increased uptake and conversion of HDP-(S)-HPMPA to HPMPA diphosphate observed in HepG2 cells in vitro. HDP-(S)-HPMPA retained full activity against HBV mutants resistant to lamivudine (L180M, M204V), but cross-resistance to a mutant resistant to adefovir (N236T) was detected. HDP-(S)-HPMPA is orally bioavailable and provides excellent liver exposure to the drug. Oral treatment of HBV transgenic mice with HDP-(S)-HPMPA, 15M-HDP-(S)-HPMPA, and ODE-(S)-HPMPA for 14 days reduced liver HBV DNA levels by roughly 1.5 log units, a response equivalent to that of adefovir dipivoxil.

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