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Yuchen Xia, Arnaud Carpentier, Xiaoming Cheng, Peter Daniel Block, Yao Zhao, Zhensheng Zhang, Ulrike Protzer, T Jake Liang
BACKGROUND AND AIMS: One major obstacle of hepatitis B virus (HBV) research is the lack of efficient cell culture system permissive for viral infection and replication. The aim of our study was to establish a robust HBV infection model by using hepatocyte-like cells (HLCs) derived from human pluripotent stem cells. METHODS: HLCs were differentiated from human embryonic stem cells and induced pluripotent stem cells. Maturation of hepatocyte functions was determined...
October 13, 2016: Journal of Hepatology
Kübra Altinel, Kosuke Hashimoto, Yu Wei, Christine Neuveut, Ishita Gupta, Ana Maria Suzuki, Alexandre Dos Santos, Pierrick Moreau, Tian Xia, Soichi Kojima, Sachi Kato, Yasuhiro Takikawa, Isao Hidaka, Masahito Shimizu, Tomokazu Matsuura, Akihito Tsubota, Hitoshi Ikeda, Sumiko Nagoshi, Harukazu Suzuki, Marie-Louise Michel, Didier Samuel, Marie Annick Buendia, Jamila Faivre, Piero Carninci
: Hepatitis B virus (HBV) is a major cause of liver diseases including hepatocellular carcinoma (HCC), and more than 650,000 people die annually due to HBV-associated liver failure. Extensive studies of individual promoters have revealed that heterogeneous RNA 5' -ends contribute to the complexity of HBV transcriptome and proteome. Here we provide a comprehensive map of HBV transcription start sites (TSSs) in human liver, HCC and blood, as well as several experimental replication systems, at single nucleotide resolution...
September 28, 2016: Journal of Virology
Ching-Lung Lai, Danny Wong, Philip Ip, Malgorzata Kopaniszen, Wai-Kay Seto, James Fung, Fung-Yu Huang, Brian Lee, Giuseppe Cullaro, Chun Kong Chong, Ringo Wu, Charles Cheng, John Yuen, Vincent Ngai, Man-Fung Yuen
BACKGROUND AND AIMS: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), a minichromosome essential for HBV replication, is supposed to be resistant to nucleos(t)ide analogue treatment. We investigated the effect of long-term nucleos(t)ide analogue treatment on cccDNA. METHODS: Among 129 patients who had been enrolled in previous international nucleos(t)ide analogue clinical trials and had liver biopsies at baseline and one year after treatment, we recruited 43 patients on long-term continuous treatment for 72 to 145 months for a third liver biopsy...
September 14, 2016: Journal of Hepatology
Andrew G Cole
The search for a cure for hepatitis B virus infection extends beyond interferon and the existing polymerase inhibitors, and targets different aspects of the virus life cycle to develop agents that operate by alternative mechanisms. Examples of small molecules that disrupt the encapsidation of pgRNA have been known for some time, but recent advances in the understanding of nucleocapsid formation, how compounds interact with core protein, and the development of drug-like molecules have recently progressed the study of capsid assembly modulators to proof of concept in the clinic with respect to reduction of viral load in chronic HBV patients...
September 13, 2016: Current Opinion in Pharmacology
Chean Ring Leong, Kenji Funami, Hiroyuki Oshiumi, Deng Mengao, Hiromi Takaki, Misako Matsumoto, Hussein H Aly, Koichi Watashi, Kazuaki Chayama, Tsukasa Seya
Hepatitis B virus (HBV) barely induces host interferon (IFN)-stimulated genes (ISGs), which allows efficient HBV replication in the immortalized mouse hepatocytes as per human hepatocytes. Here we found that transfection of Isg20 plasmid robustly inhibits the HBV replication in HBV-infected hepatocytes irrespective of IRF3 or IFN promoter activation. Transfection of Isg20 is thus effective to eradicate HBV in the infected hepatocytes. Transfection of HBV genome or ε-stem of HBV pgRNA (active pgRNA moiety) failed to induce Isg20 in the hepatocytes, while control polyI:C (a viral dsRNA analogue mimic) activated MAVS pathway leading to production of type I IFN and then ISGsg20 via the IFN-α/β receptor (IFNAR)...
September 8, 2016: Oncotarget
Chunlan Liu, Dawei Cai, Lin Zhang, Wei Tang, Ran Yan, Haitao Guo, Xulin Chen
The development of new agents to target HBV cccDNA is urgently needed because of the limitations of current available drugs for treatment of hepatitis B. By using a cell-based assay in which the production of HBeAg is in a cccDNA-dependent manner, we screened a compound library derived from Chinese herbal remedies for inhibitors against HBV cccDNA. Three hydrolyzable tannins, specifically punicalagin, punicalin and geraniin, emerged as novel anti-HBV agents. These compounds significantly reduced the production of secreted HBeAg and cccDNA in a dose-dependent manner in our assay, without dramatic alteration of viral DNA replication...
October 2016: Antiviral Research
Nuruddin Unchwaniwala, Nathan M Sherer, Daniel D Loeb
UNLABELLED: To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria...
October 1, 2016: Journal of Virology
Mohsin Khan, Gulam Hussain Syed, Seong-Jun Kim, Aleem Siddiqui
Hepatitis B virus (HBV) suppresses innate immune signaling to establish persistent infection. Although HBV is a DNA virus, its pre-genomic RNA (pgRNA) can be sensed by RIG-I and activates MAVS to mediate interferon (IFN) λ synthesis. Despite of the activation of RIG-I-MAVS axis by pgRNA, the underlying mechanism explaining how HBV infection fails to induce interferon-αβ (IFN) synthesis remained uncharacterized. We demonstrate that HBV induced parkin is able to recruit the linear ubiquitin assembly complex (LUBAC) to mitochondria and abrogates IFN β synthesis...
June 2016: PLoS Pathogens
Jie Wang, Tao Shen, Xiangbo Huang, G Renuka Kumar, Xiangmei Chen, Zhenzhen Zeng, Ruiyang Zhang, Ran Chen, Tong Li, Tianying Zhang, Quan Yuan, Pao-Chen Li, Qi Huang, Richard Colonno, Jidong Jia, Jinlin Hou, Malcolm A McCrae, Zhiliang Gao, Hong Ren, Ningshao Xia, Hui Zhuang, Fengmin Lu
BACKGROUND & AIMS: Hepatitis B virus (HBV) RNA in serum has recently been linked to efficacy and prognosis of chronic hepatitis B (CHB) treatment. This study explored the nature, origin, underlying mechanisms, and potential clinical significance of serum HBV RNA. METHODS: The levels of HBV DNA and RNA were determined in the supernatant of induced HepAD38, HBV-expressing HepG2.2.15 cells and primary human hepatocytes (PHH), and in the serum of transgenic mice and CHB patients...
October 2016: Journal of Hepatology
Jianxiong Zhao, Jing Tu, Ningning Fan, Xiangmei Chen, Fengmin Lu, Yu Zhang, Liang Zhang, Chao Tian, Zhili Zhang, Junyi Liu, Xiaowei Wang
BACKGROUND: Novel nonnucleoside hepatitis B virus inhibitors have been recently developed for the reason of drug-resistant mutations and adverse effects of nucleoside analogs. In this study, two series of 2-arylthio-5-iodo pyrimidine analogs were firstly reported as potential anti-HBV agents. METHODOLOGY: Target compounds were prepared according to two high-yielded synthetic routes, and their anti-HBV activities were evaluated on Hep2.2.15 and HepAD38 cell lines, respectively...
May 2016: Future Medicinal Chemistry
Lemonica Koumbi, Teresa Pollicino, Giovanni Raimondo, Dimitrios Stampoulis, Salim Khakoo, Peter Karayiannis
In chronic hepatitis B virus (HBV) infection, variants with mutations in the basal core promoter (BCP) and precore region predominate and associate with more severe disease forms. Studies on their effect on viral replication remain controversial. Increasing evidence shows that epigenetic modifications of cccDNA regulate HBV replication and disease outcome. Here we determined the transcription and viral replication efficiency of well-defined BCP and precore mutations and their effect on cccDNA epigenetic control...
July 15, 2016: Virus Research
Pinghu Zhang, Fei Liu, Fang Guo, Qiong Zhao, Jinhong Chang, Ju-Tao Guo
Inhibitors of hepadnaviral DNA polymerases are predicted to inhibit both minus and plus strand of viral DNA synthesis and arrest viral DNA replication at the stage of pregenomic (pg) RNA-containing nucleocapsids. However, analyses of the RNA species of human and duck hepatitis B viruses (HBV and DHBV, respectively) in hepatoma cells treated with viral DNA polymerase inhibitors revealed the genesis of novel RNA species migrating slightly faster than the full-length pgRNA. The DNA polymerase inhibitor-induced accumulation of these RNA species were abolished in the presence of alpha-interferon or HBV nucleocapsid assembly inhibitors...
July 2016: Antiviral Research
Laurie Ludgate, Kuancheng Liu, Laurie Luckenbaugh, Nicholas Streck, Stacey Eng, Christian Voitenleitner, William E Delaney, Jianming Hu
UNLABELLED: Multiple subunits of the hepatitis B virus (HBV) core protein (HBc) assemble into an icosahedral capsid that packages the viral pregenomic RNA (pgRNA). The N-terminal domain (NTD) of HBc is sufficient for capsid assembly, in the absence of pgRNA or any other viral or host factors, under conditions of high HBc and/or salt concentrations. The C-terminal domain (CTD) is deemed dispensable for capsid assembly although it is essential for pgRNA packaging. We report here that HBc expressed in a mammalian cell lysate, rabbit reticulocyte lysate (RRL), was able to assemble into capsids when (low-nanomolar) HBc concentrations mimicked those achieved under conditions of viral replication in vivo and were far below those used previously for capsid assembly in vitro Furthermore, at physiologically low HBc concentrations in RRL, the NTD was insufficient for capsid assembly and the CTD was also required...
June 15, 2016: Journal of Virology
Patrizia Caligiuri, Rita Cerruti, Giancarlo Icardi, Bianca Bruzzone
Hepatitis B virus (HBV) affects approximately two billion people worldwide and more than 240 million people in the world are currently chronic carrier that could develop serious complications in the future, like liver cirrhosis and hepatocellular carcinoma. Although an extended HBV immunization program is being carried out since the early '80s, representing effective preventive measure, leading to a dramatic reduction of HBV hepatitis incidence, globally HBV infection still represents a major public health problem...
January 7, 2016: World Journal of Gastroenterology: WJG
Simon B Larsson, Sebastian Malmström, Charles Hannoun, Gunnar Norkrans, Magnus Lindh
BACKGROUND: Hepatitis B virus (HBV) DNA in serum of chronically infected patients declines by 3-4 log10 units at loss of HBe antigen (HBeAg) from serum. The mechanisms behind this decline, and the much smaller decline of surface antigen (HBsAg) levels, are still not well known. The aim of this study was to get a better understanding of this process by analysing both serum and intrahepatic markers of HBV replication. METHODS: Levels of HBV DNA and HBsAg in serum, and covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) and S-RNA and total intrahepatic HBV DNA (ihDNA) in liver biopsies from 84 chronically infected patients (16 positive and 68 negative for HBeAg) were analysed...
December 9, 2015: Virology Journal
Hui Wang, KeHui Liu, Bernard A M Fang, HaiQing Wu, FengDi Li, XiaoGang Xiang, WeiLiang Tang, GangDe Zhao, LanYi Lin, Shisan Bao, Qing Xie
BACKGROUND: The initiation of hepatitis B virus (HBV) replication involves the formation of covalently closed circular DNA (cccDNA) and its transcription into pregenomic RNA (pgRNA) in hepatocyte nuclei. The regulatory mechanism of HBV replication by acetyltransferase is thus far not well understood, but human acetyltransferase has been reported as being involved in the regulation of HBV replication. RESULTS: Depletion of KAT8 or HAT1 via RNA interference (RNAi) markedly down-regulated HBV-DNA and pgRNA levels in HepG2...
2015: Cell & Bioscience
Li Yang, Ya-Juan Wang, Hai-Jun Chen, Li-Ping Shi, Xian-Kun Tong, Yang-Ming Zhang, Gui-Feng Wang, Wen-Long Wang, Chun-Lan Feng, Pei-Lan He, Yi-Bin Xu, Meng-Ji Lu, Wei Tang, Fa-Jun Nan, Jian-Ping Zuo
During the hepatitis B virus (HBV) life cycle, nucleocapsid assembly is essential for HBV replication. Both RNA reverse transcription and DNA replication occur within the HBV nucleocapsid. HBV nucleocapsid is consisted of core protein (HBcAg), whose carboxy-terminal domain (CTD) contains an Arg-rich domain (ARD). The ARD of HBcAg does contribute to the encapsidation of pregenomic RNA (pgRNA). Previously, we reported a small-molecule, NZ-4, which dramatically reduced the HBV DNA level in an in vitro cell setting...
January 2016: Antiviral Research
D K-H Wong, J Fung, C-K Lee, W-K Seto, J Leung, F-Y Huang, C-K Lin, C-L Lai, M-F Yuen
We studied the intrahepatic hepatitis B virus (HBV) replicative status in 40 people with occult hepatitis B infection (OBI) and 40 patients with chronic hepatitis B (CHB). Intrahepatic HBV DNA, covalently closed circular DNA (cccDNA), and pre-genomic RNA (pgRNA) were quantified. Patients with OBI had median necroinflammation and fibrosis scores of 1 and 0, respectively. Intrahepatic total HBV DNA, cccDNA and pgRNA were detectable in 30 (77%), one (3%) and five (13%) of the participants with OBI, respectively...
March 2016: Clinical Microbiology and Infection
Gianna Aurora Palumbo, Cecilia Scisciani, Natalia Pediconi, Leonardo Lupacchini, Dulce Alfalate, Francesca Guerrieri, Ludovica Calvo, Debora Salerno, Silvia Di Cocco, Massimo Levrero, Laura Belloni
The HBV covalently closed circular DNA (cccDNA) is organized as a mini-chromosome in the nuclei of infected hepatocytes by histone and non-histone proteins. Transcription from the cccDNA of the RNA replicative intermediate termed pre-genome (pgRNA), is the critical step for genome amplification and ultimately determines the rate of HBV replication. Multiple evidences suggest that cccDNA epigenetic modifications, such as histone modifications and DNA methylation, participate in regulating the transcriptional activity of the HBV cccDNA...
2015: PloS One
Dong-Kyun Ryu, Yeji Ahn, Wang-Shick Ryu, Marc P Windisch
After encapsidation, where pregenomic RNA (pgRNA) is packaged into viral nucleocapsids, hepatitis B virus (HBV) uses the pgRNA as a template to replicate its DNA genome by reverse transcription. To date, there are only two encapsidation detection methods for evaluating the amount of pgRNA packaged into nucleocapsids: (i) the RNase protection assay and (ii) the native agarose gel electrophoresis assay. However, these methods are complex and laborious because they require multiple pgRNA purification steps followed by detection via an isotope-labeled probe...
November 2015: BioTechniques
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