Inhibition of Hepatitis B Virus Replication by the Interferon-Inducible MxA Protein

Gordien, Emmanuel; Rosmorduc, Olivier; Peltekian, Cécile; Garreau, Florianne; Bréchot, Christian; Kremsdorf, Dina

doi:10.1128/jvi.75.6.2684-2691.2001

Cited by 170 publications

(143 citation statements)

References 58 publications

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“…Among these ISGs, MxA and OAS1 are antiviral genes, whereas CXCL10 is a chemokine gene responsible for the recruitment of effector CD8 T cells and NK cells to the site of viral infection. MxA likely plays an important role in HBV infection because it has been shown to inhibit HBV replication (39,41,42). Our results show that knockdown of endogenous MxA reversed the inhibition of HBV replication mediated by MDA5 signaling (Fig.…”

Section: Discussionsupporting

confidence: 60%

“…Given that MxA is known to suppress HBV replication (39)(40)(41)(42) and that MxA expression is upregulated in cells cotransfected with the HBV replicative plasmid and the MDA5 expression plasmid (Fig. 5A, top panel), we examined whether MxA contributed to the suppression of HBV replication mediated by the MDA5 signaling pathway.…”

Section: Cotransfection Of Huh7 Cells With the Hbv Replicative Plasmimentioning

confidence: 99%

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Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Lu¹,

Liao

2013

The Journal of Immunology

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Retinoic acid–inducible gene-I (RIG-I) and melanoma differentiation–associated gene 5 (MDA5) belong to the RIG-I–like receptors family of pattern recognition receptors. Both RIG-I and MDA5 have been shown to recognize various viral RNAs, but whether they mediate hepatitis B virus (HBV) infection remains unclear. In this study, we demonstrated that the expression of MDA5, but not RIG-I, was increased in Huh7 cells transfected with the HBV replicative plasmid and in the livers of mice hydrodynamically injected with the HBV replicative plasmid. To further determine the effect of RIG-I–like receptors on HBV replication, we cotransfected the HBV replicative plasmid with RIG-I or MDA5 expression plasmid into Huh7 cells and found that MDA5, but not RIG-I at a similar protein level, significantly inhibited HBV replication. Knockdown of endogenous MDA5, but not RIG-I, in Huh7 cells transfected with the HBV replicative plasmid significantly increased HBV replication. Of particular interest, we found that MDA5, but not RIG-I, was able to associate with HBV-specific nucleic acids, suggesting that MDA5 may sense HBV. Finally, we performed in vivo experiments by hydrodynamic injection of the HBV replicative plasmid into wild-type, MDA5−/−, MDA5+/−, or RIG-I+/− mice, and found that MDA5−/− and MDA5+/− mice, but not RIG-I+/− mice, exhibited an increase of HBV replication as compared with wild-type mice. Collectively, our in vitro and in vivo studies both support a critical role for MDA5 in the innate immune response against HBV infection.

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Section: Discussionsupporting

confidence: 60%

Section: Cotransfection Of Huh7 Cells With the Hbv Replicative Plasmimentioning

confidence: 99%

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Lu¹,

Liao

2013

The Journal of Immunology

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“…Intracellular HBV replicative intermediates were immunoprecipitated using 3 L rabbit polyclonal anti-hepatitis B core antigen (HBcAg) antibodies (Dako, Denmark, or Abcam, UK) as described. 39 Ninety percent of the isolated DNA were separated by electrophoresis on an 0.8% agarose gel, transferred to HybondN ϩ nylon membranes, and hybridized with radiolabeled full-length HBV DNA using ExpressHyb (BD Biosciences, Franklin Lakes, NJ). The HBV DNA was quantified by radiophosphorimaging of the southern blots.…”

Section: Methodsmentioning

confidence: 99%

Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

et al. 2006

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Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-␣) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3B L inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B S and A3C had no effect. A3B L and A3B S were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. T he hepatitis B virus (HBV) infects more than 350 million people worldwide and is a leading cause of end-stage liver disease and of hepatocellular carcinoma. 1 HBV is non-cytopathic for hepatocytes; however, most newly HBV infected adult patients develop acute hepatitis because of a strong immune response that clears HBV from the liver, whereas approximately 5% of newly HBV-infected adult patients generate insufficient immunity and become chronically infected. 1,2 Administration of interferon alpha (IFN-␣) is a mainstay of therapy for chronically HBV-infected patients. 2 Interferons restrict the replication of HBV by inducing the expression of antiviral proteins that inhibit the formation of replication-competent HBV nucleocapsids, and ultimately can result in the resolution of the chronic HBV infection. 2-7 HBV and other hepadnaviruses replicate their partially double-stranded DNA genome within cytoplasmic core particles by reverse transcription of encapsidated pregenomic RNA and thus are related to retroviruses. 8,9 The cytidine deaminase APOBEC3G (A3G), which is encoded within a cluster of seven related editing enzymes (APOBEC3A-G) on chromosome 22, provides broad innate immunity against exogenous and endogenous retroelements. 10-16 Encapsidated into the retroviral particle A3G deaminates dCs of the retroviral minus strand

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“…This could also be demonstrated in vitro by using immortalized hepatocyte cell lines from these animals [7] and involves elimination of pregenomic RNA-containing capsids, inhibition of DNA replication and reduction of steady-state levels of HBV transcripts. The effector mechanisms that have been associated with IFN-induced suppression of HBV-replication include MxA [8] and proteasome mediated activities [9,10] . Additional data suggest a role for GTP-binding proteins, signalling and various other molecules in the control of HBV replication [11] .…”

Section: Introductionmentioning

confidence: 99%

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

Guan

Lu²,

Grunewald³

et al. 2007

WJG

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AIM:To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBVtransfected HepG2.2.15 cells. METHODS:H e p G 2 . 2 . 1 5 a n d H e p G 2 c e l l s w e r e stimulated with various concentrations of IFN-a2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes (ISGs). In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. RESULTS:Two genes (MxA, Cig5) with completely abolished and 4 genes (IFITM1, -2, -3, and 6-16) with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes (IFITM1, 6-16), the response to IFN-a could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Stat1 activation and ISGF3 formation after stimulation with IFN-a in HepG2.2.15 compared to HepG2 cells. CONCLUSION:These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expression by reducing HBV gene expression and replication.

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Inhibition of Hepatitis B Virus Replication by the Interferon-Inducible MxA Protein

Cited by 170 publications

References 58 publications

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Melanoma Differentiation–Associated Gene 5 Senses Hepatitis B Virus and Activates Innate Immune Signaling To Suppress Virus Replication

Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

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