Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates

Breugel, Pieter C. van; Robert, Eva; Mueller, Henrik; Decorsière, Adrien; Zoulim, Fabien; Hantz, Olivier; Strubin, Michel

doi:10.1002/hep.25928

Cited by 71 publications

(75 citation statements)

References 43 publications

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“…To assess the effect of HBx expression on the transcriptional activity of episomal DNA elements in our model, a vector from which HBx is transcribed (pHSV-HBx) was cotransfected with the luciferase expressing constructs. In line with the literature [9], HBx expression increased luciferase transcription from the different constructs, indicating the HBx transactivated episomal transcription independent of the promoter driving the transcription ( Figure 1C). …”

Section: Statisticssupporting

confidence: 90%

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Inhibition of Histone Deacetylases Stimulates HBV Replication Independent of Protein X

et al. 2015

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aim: HBV expresses an accessory protein called X (HBx), which supports HBV replication by increasing transcription from episomal templates. Here, we investigate whether HBx augments HBV replication by interfering with the deacetylation of HBV DNA associated histones by histone deacetylases (HDACs). materials & methods: To study the effect of HBx on episomal transcription, we transfected HEK 293 cells with luciferaseexpressing constructs together with HBx in the presence and absence of HDAC inhibitors. We confirmed our results in the context of the full HBV replication cycle in HepG2 cells. results & conclusion: Inhibition of HDAC activity and HBx expression stimulated transcription from episomal DNA independently, showing that HBx does not affect the histone deacetylation. HDAC inhibitors also augmented HBV replication in vitro independent of HBx expression. This suggests that treatment with HDAC inhibitors can (re)activate HBV infection in patients with cleared or ongoing HBV infection. KeywordsWorldwide, chronic infections with the HBV affect more than 240,000,000 people, and more than 780,000 people die each year as a consequence of HBV infection. The virus infects hepatocytes in the human liver. After entry, the core particle containing the partially double stranded HBV genome is transported to the nucleus, where the partially double stranded DNA genome is released into the nucleus and repaired by host enzymes to form a fully double stranded episome of covalently closed circular DNA (cccDNA). This episomal cccDNA is wrapped around histones and thus forms a minichromosome that is subject to various epigenetic modifications to both the cccDNA and the associated histones [1]. It has been shown that these epigenetic modifications regulate the transcription of the viral RNAs [2,3].The HBV protein called X (HBx) is essential for HBV replication in vivo [4]. In vitro, HBx acts as a transcriptional transactivator [4][5][6][7][8] that increases transcription from episomal DNA templates independent of promoter sequences [9]. The capacity of HBx to transactivate transcription in vitro is related to its in vivo function and can therefore be used to study HBx functionality [10]. It has been shown that HBx expression critically affects the epigenetic status of the cccDNA [3,11,1,3,2]. In the absence of HBx, the cccDNA-associated histones undergo modifications that effectively abrogate HBV RNA transcription. A hallmark of this transcriptional silencing in the absence of HBx is the deacetylation of the histones around which the cccDNA is wrapped [1,11].The acetylation status of histones is regulated by dynamic processes. Preceding and during transcription, histones are acetylated by histone acetyl transferases. Well-known members are the CREB-binding protein (CBP/p300) and transcription initiation factor TFIID subunit 1 (TAF1).For reprint orders, please contact: reprints@futuremedicine.com

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Section: Statisticssupporting

confidence: 90%

“…In vitro, HBx acts as a transcriptional transactivator [4][5][6][7][8] that increases transcription from episomal DNA templates independent of promoter sequences [9]. The capacity of HBx to transactivate transcription in vitro is related to its in vivo function and can therefore be used to study HBx functionality [10].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone Deacetylases Stimulates HBV Replication Independent of Protein X

et al. 2015

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“…The X protein of HBV activates the transcription of HBV genes, as well as a repertoire of host genes, including TBP (55,56). The X protein has also been shown to bind TBP in vitro and to increase TBP expression in cells (57,58).…”

Section: Discussionmentioning

confidence: 99%

Doubly Spliced RNA of Hepatitis B Virus Suppresses Viral Transcription via TATA-Binding Protein and Induces Stress Granule Assembly

Tsai

Chong

Chou

et al. 2015

J Virol

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The risk of liver cancer in patients infected with the hepatitis B virus (HBV) and their clinical response to interferon alpha therapy vary based on the HBV genotype. The mechanisms underlying these differences in HBV pathogenesis remain unclear. In HepG2 cells transfected with a mutant HBV G2335A expression plasmid that does not transcribe the 2.2-kb doubly spliced RNA (2.2DS-RNA) expressed by wild-type HBV genotype A, the level of HBV pregenomic RNA (pgRNA) was higher than that in cells transfected with an HBV genotype A expression plasmid. By using cotransfection with HBV genotype D and 2.2DS-RNA expression plasmids, we found that a reduction of pgRNA was observed in the cells even in the presence of small amounts of the 2. T he hepatitis B virus (HBV) causes acute and chronic liver diseases in humans. Millions of people worldwide suffer from HBV-induced liver disorders, and HBV infection increases the risk of hepatic cirrhosis and hepatocellular carcinoma (1, 2). Type I interferons (IFNs), including IFN-␣ and IFN-␤, exert antiviral activity and important immunomodulatory effects in the innate immune response against HBV infection (3-5). However, the mechanism through which HBV evades the host immune response in chronically infected patients has not been fully elucidated.In addition to the factors such as viral load and naturally occurring mutants, the HBV genotype, classified as A through J based on genomic sequence, has been shown to be associated with disease progression and responses to IFN-based therapy (6). Previous studies have shown that chronic hepatitis B patients infected with genotype A or B exhibit higher rates of seroclearance of HBV e antigen (HBeAg) and viral DNA in response to IFN-␣ therapy than patients with genotype C or D infection (7-9) and that chronically infected children with HBV genotype A infection have lower viral DNA loads and exhibit less severe symptoms than patients with genotype D infection (10, 11). Clinical studies have also shown that differences between HBV genotypes correlate with deoxycytidine analog resistance (12) and hepatic pathogenesis (13).

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“…Because HBx does not bind DNA directly, its interaction with cccDNA must be mediated by another HBV or cellular protein. Interestingly, the cccDNA remains transcriptionally silent in cells that express a mutant HBx protein that is unable to bind cellular DDB1 (Lucifora et al 2011;van Breugel et al 2012), suggesting a role for the HBx-DDB1 interaction in the regulation of HBV transcription from the cccDNA template. This is an attractive idea, because DDB1 is a known DNA-binding protein.…”

Section: Hbx and Cccdnamentioning

confidence: 99%

Hepatitis B Virus X and Regulation of Viral Gene Expression

Slagle

Bouchard

2016

Cold Spring Harb Perspect Med

118

117

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The efficient replication of hepatitis B virus (HBV) requires the HBV regulatory hepatitis B virus X (HBx) protein. The exact contributions of HBx are not fully understood, in part because of the limitations of the assays used for its study. When HBV replication is driven from a plasmid DNA, the contribution of HBx is modest. However, there is an absolute requirement for HBx in assays that recapitulate the infectious virus life cycle. There is much evidence that HBx can contribute directly to HBV replication by acting on viral promoters embedded within protein coding sequences. In addition, HBx may also contribute indirectly by modulating cellular pathways to benefit virus replication. Understanding the mechanism(s) of HBx action during virus replication may provide insight into novel ways to disrupt chronic HBV replication.

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Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates

Cited by 71 publications

References 43 publications

Inhibition of Histone Deacetylases Stimulates HBV Replication Independent of Protein X

Inhibition of Histone Deacetylases Stimulates HBV Replication Independent of Protein X

Doubly Spliced RNA of Hepatitis B Virus Suppresses Viral Transcription via TATA-Binding Protein and Induces Stress Granule Assembly

Hepatitis B Virus X and Regulation of Viral Gene Expression

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