Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B Virus

Xu, Chunxiao; Guo, Haitao; Pan, Xiao‐Ben; Mao, Richeng; Yu, Wenquan; Xu, Xiaodong; Wei, Lai; Chang, Jinhong; Block, Timothy M.; Guo, Ju‐Tao

doi:10.1128/jvi.00918-10

Cited by 113 publications

(120 citation statements)

References 56 publications

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“…However, we observed a slight increase in cytoplasmic capsid using DAKO (cytosolic Fab3105 stain: day 1 92 %, day 2 88 %, day 5 100 %; cytosolic DAKO stain: day 1 60 %, day 2 75 %, day 5 87 %). Such accumulation was expected for capsids, as their half-life (.24 h) in hepatoma cells is longer than that of monomeric core protein (Deres et al, 2003;Xu et al, 2010).…”

Section: Impact Of Viral Proteins On Core and Capsid Localizationmentioning

confidence: 87%

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Deroubaix

Osseman

Cassany

et al. 2015

Journal of General Virology

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Biopsies from patients show that hepadnaviral core proteins and capsids -collectively called core -are found in the nucleus and cytoplasm of infected hepatocytes. In the majority of studies, cytoplasmic core localization is related to low viraemia while nuclear core localization is associated with high viral loads. In order to better understand the molecular interactions leading to core localization, we analysed transfected hepatoma cells using immune fluorescence microscopy. We observed that expression of core protein in the absence of other viral proteins led to nuclear localization of core protein and capsids, while expression of core in the context of the other viral proteins resulted in a predominantly cytoplasmic localization. Analysis of which viral partner was responsible for cytoplasmic retention indicated that the HBx, surface proteins and HBeAg had no impact but that the viral polymerase was the major determinant. Further analysis revealed that e, an RNA structure to which the viral polymerase binds, was essential for cytoplasmic retention. Furthermore, we showed that core protein phosphorylation at Ser 164 was essential for the cytoplasmic core localization phenotype, which is likely to explain differences observed between individual cells.

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Section: Impact Of Viral Proteins On Core and Capsid Localizationmentioning

confidence: 87%

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Deroubaix

Osseman

Cassany

et al. 2015

Journal of General Virology

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“…In efforts to elucidate the antiviral mechanism of IFNs, it has been demonstrated that IFN-␣-and IFN-␥-induced antiviral responses either prevent the formation of pregenomic RNA (pgRNA)-containing capsids or promote the decay of replication-competent nucleocapsids in murine hepatocytes in culture and in transgenic mice in vivo (3,67,68). Recently, type III IFN (IFN-) has also been shown to inhibit HBV replication in cultured murine hepatocytes through a similar mechanism but with a weaker antiviral activity in transgenic mice (49,54).…”

Section: Interestingly Ido-mediated Tryptophan Deprivation Preferentmentioning

confidence: 99%

“…However, we did not observe any cytotoxic effect in HepG2 cultures transfected with a plasmid expressing IDO (data not shown). In addition, the fact that overexpression of IDO does not affect the steady-state level of HBV pgRNA, for which the half-life is less than 12 h in cell cultures (11,68,69), plus the lack of effect on the steady-state content of cellular proteins, such as TDO and ␤-actin (Fig. 4, bottom, lane 3), strongly suggested that expression of IDO in HepG2 cells did not significantly affect the host cellular transcription and translation machinery but preferentially inhibited HBV protein and DNA biosynthesis.…”

Section: Ifn-␣ and Ifn-␥ Inhibit Hbv Replication In Human Hepatocyte-mentioning

confidence: 99%

“…Interestingly, although it has been shown that HBV can evade host innate immunity surveillance, as evidenced by its failure to induce the expression of interferon-stimulated genes (ISGs) in the liver of chimpanzees during the early phase of infection (66), the virus is sensitive to IFN-␣/␤-induced antiviral response in transgenic mice and in people (30,49). For example, treatment of chronic hepatitis B with pegylated IFN-␣ for 48 weeks can achieve sustained virological response in 30 to 40% of the treated patients (29).In efforts to elucidate the antiviral mechanism of IFNs, it has been demonstrated that IFN-␣-and IFN-␥-induced antiviral responses either prevent the formation of pregenomic RNA (pgRNA)-containing capsids or promote the decay of replication-competent nucleocapsids in murine hepatocytes in culture and in transgenic mice in vivo (3,67,68). Recently, type III IFN (IFN-) has also been shown to inhibit HBV replication in cultured murine hepatocytes through a similar mechanism but with a weaker antiviral activity in transgenic mice (49, 54).…”

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confidence: 99%

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Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

Mao

Zhang

Jiang

et al. 2011

J Virol

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112

101

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Alpha interferon (IFN-␣) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-␥) is a key mediator of host innate and adaptive antiviral immunity against hepatitis B virus (HBV) infection in vivo.In an effort to elucidate the antiviral mechanism of these cytokines, 37 IFN-stimulated genes (ISGs), which are highly inducible in hepatocytes, were tested for their ability to inhibit HBV replication upon overexpression in human hepatoma cells. One ISG candidate, indoleamine 2,3-dioxygenase (IDO), an IFN-␥-induced enzyme catalyzing tryptophan degradation, efficiently reduced the level of intracellular HBV DNA without altering the steady-state level of viral RNA. Furthermore, expression of an enzymatically inactive IDO mutant did not inhibit HBV replication, and tryptophan supplementation in culture completely restored HBV replication in IDO-expressing cells, indicating that the antiviral effect elicited by IDO is mediated by tryptophan deprivation. Interestingly, IDO-mediated tryptophan deprivation preferentially inhibited viral protein translation and genome replication but did not significantly alter global cellular protein synthesis. Finally, tryptophan supplementation was able to completely restore HBV replication in IFN-␥-but not IFN-␣-treated cells, which strongly argues that IDO is the primary mediator of IFN-␥-elicited antiviral response against HBV in human hepatocyte-derived cells.Hepatitis B virus (HBV) is a hepatotropic virus in the family of Hepadnaviridae (18, 56) which has infected two billion people worldwide. Although most infected adults can resolve the infection, approximately 5 to 10% of adulthood infections and more than 90% of neonatal infections become lifelong persistent, which causes a significant public health burden currently affecting more than 350 million individuals worldwide (36,41). Patients with chronic hepatitis B carry a high risk of cirrhosis and primary hepatocellular carcinoma (5, 36).It is generally believed that the outcomes of HBV infection and disease pathogenesis are primarily determined by the host adaptive antiviral immune response (9). The resolution of HBV infection is associated with a robust, polyclonal viral antigen-specific cytotoxic T lymphocyte (CTL) response that kills and/or noncytopathically cures virally infected hepatocytes. The latter effect is primarily mediated by inflammatory cytokines, including gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) (17,18,20,21). Interestingly, although it has been shown that HBV can evade host innate immunity surveillance, as evidenced by its failure to induce the expression of interferon-stimulated genes (ISGs) in the liver of chimpanzees during the early phase of infection (66), the virus is sensitive to IFN-␣/␤-induced antiviral response in transgenic mice and in people (30,49). For example, treatment of chronic hepatitis B with pegylated IFN-␣ for 48 weeks can achieve sustained virological response in 30 to 40% of the treated patients (29).In efforts to elucidate the antiviral mechanism ...

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“…ISG modulation results in an antiviral response in target cells aimed at limiting both viral replication and spreading. IFN-α has been reported to inhibit HBV replication through a variety of mechanisms, including a block of RNA-containing core particle formation, an accelerated decay of replication-competent core particles, and degradation of the pgRNA (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome

Belloni¹,

Allweiss²,

Guerrieri³

et al. 2012

J. Clin. Invest.

514

422

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HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and IntroductionHepatitis B Virus (HBV) infection remains a major health problem worldwide despite the availability of a highly effective preventive vaccine. HBV is a noncytopathic hepatotropic DNA virus that belongs to the family Hepadnaviridae, whose members share a distinctive strategy for replication. HBV replication occurs in the cytoplasm within viral capsids (core particles), where a genomesized RNA replicative intermediate, termed the pregenome (pgRNA), is converted by the virally encoded RNA-dependent and DNA-dependent reverse transcriptase/polymerase into a specific open circular (OC) duplex DNA (1). Transcription in the nucleus of the pgRNA from the covalently closed circular DNA (cccDNA) is the critical step for genome amplification and ultimately determines the rate of HBV replication (2). The cccDNA, which also serves as the template for the transcription of all viral messenger RNAs, is organized into a minichromosome in the nuclei of infected hepatocytes by histone and nonhistone proteins, and its function is regulated, similarly to cellular chromatin, by the activity of nuclear transcription factors, transcriptional coactivators and corepressors, and chromatin-modifying enzymes (2-4).Current antiviral therapies involve the use of nucleoside analogs and pegylated IFN-α (5). IFN-α, a type I IFN, engages the IFN-α/β receptor complex to activate the intracellular Jak/Stat signaling pathway, which modulates the transcription of a diverse set of target genes, referred to as IFN-stimulated genes (ISGs) (6). ISG

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Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B Virus

Cited by 113 publications

References 56 publications

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells

IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome

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