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https://www.readbyqxmd.com/read/28725013/baseline-value-of-intrahepatic-hbv-dna-over-cccdna-predicts-patient-s-response-to-interferon-therapy
#1
Di Mu, Fang-Chao Yuan, Yu Chen, Xiao-Yan Jiang, Liang Yan, Ling-Yu Jiang, Jian-Ping Gong, Da-Zhi Zhang, Hong Ren, Yong Liao
Methodology for accurate quantification of intra-hepatic cccDNA has long been a technical challenge, yet it is highly desired in the clinic. Here, we developed a sensitive method for quantification of intrahepatic cccDNA in liver biopsies from patients, which allowed to predict patient's response to interferon therapy at baseline. Twenty-five patients with HBeAg+ CHB were recruited and liver biopsies were obtained at baseline and 1-year after interferon treatment, respectively. Both intrahepatic cccDNA and HBV DNA were absolutely quantified by a droplet digital PCR amplification system...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28709658/ngago-gdna-system-efficiently-suppresses-hepatitis-b-virus-replication-through-accelerating-decay-of-pregenomic-rna
#2
Zhuanchang Wu, Siyu Tan, Leiqi Xu, Lifen Gao, Haizhen Zhu, Chunhong Ma, Xiaohong Liang
Covalently closed circular DNA (cccDNA) in the hepatocytes nucleus is responsible for persistent infection of Hepatitis B virus (HBV). Current antiviral therapy drugs nucleos(t)ide analogs or interferon fail to eradicate HBV cccDNA. Genome editing technique provides an effective approach for HBV treatment through targeting viral cccDNA. Natronobacterium gregoryi Argonaute (NgAgo)-guide DNA (gDNA) system with powerful genome editing prompts us to explore its application in inhibiting HBV replication. Preliminary function verification indicated that NgAgo/EGFP-gDNA obviously inhibited EGFP expression...
July 12, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28709657/detection-of-the-hepatitis-b-virus-hbv-covalently-closed-circular-dna-cccdna-in-mice-transduced-with-a-recombinant-aav-hbv-vector
#3
Julie Lucifora, Anna Salvetti, Xavier Marniquet, Laurent Mailly, Barbara Testoni, Floriane Fusil, Aurore Inchauspé, Maud Michelet, Marie-Louise Michel, Massimo Levrero, Pierre Cortez, Thomas F Baumert, François-Loic Cosset, Cécile Challier, Fabien Zoulim, David Durantel
Hepatitis B Virus (HBV) persists in infected hepatocytes as an episomal covalently-closed-circular DNA mini-chromosome, called cccDNA. As the main nuclear transcription template, HBV cccDNA is a key replication intermediate in the viral life cycle. Little is known about the mechanisms involved in its formation, maintenance and fate under antiviral therapies. This is mainly due to the lack of small immune-competent animal models able to recapitulate the entire HBV replication cycle, including formation of HBV cccDNA...
July 11, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28709006/compartmental-hbv-evolution-and-replication-in-liver-and-extrahepatic-sites-after-nucleos-tide-analogue-therapy-in-chronic-hepatitis-b-carriers
#4
Shan Gao, Zhong-Ping Duan, Yu Chen, Frank van der Meer, Samuel S Lee, Carla Osiowy, Guido van Marle, Carla S Coffin
BACKGROUND: Hepatitis B virus (HBV) variants are associated with nucleos/tide analogue (NA) response and liver disease but it is unknown whether NA influences extrahepatic HBV persistence. OBJECTIVES: To investigate HBV replication and genetic evolution in hepatic and extrahepatic sites of chronic hepatitis B (CHB) before and after NA therapy. STUDY DESIGN: A total of 13 paired plasma, peripheral blood mononuclear cells (PBMC), were collected from chronic HBV carriers at baseline and after a median 53 weeks NA therapy as well as liver biopsy (N=7 baseline, N=5 follow-up)...
July 5, 2017: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
https://www.readbyqxmd.com/read/28696237/persistent-loss-of-hbv-markers-in-serum-without-cellular-immunity-by-combination-of-peg-ifn-plus-etv-therapy-in-humanized-mice
#5
Takuro Uchida, Michio Imamura, C Nelson Hayes, Nobuhiko Hiraga, Hiromi Kan, Masataka Tsuge, Hiromi Abe-Chayama, Yizhou Zhang, Grace Naswa Makokha, Hiroshi Aikata, Daiki Miki, Hidenori Ochi, Yuji Ishida, Chise Tateno, Kazuaki Chayama
Nucleot(s)ide analogues and peg-interferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long term loss of HBsAg in human hepatocyte chimeric mice...
July 10, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28694331/transcriptional-elongation-control-of-the-hbv-cccdna-transcription-by-super-elongation-complex-sec-and-brd4
#6
Joel Celio Francisco, Qian Dai, Zhuojuan Luo, Yan Wang, Roxanne Hui-Heng Chong, Yee Joo Tan, Wei Xie, Guan-Huei Lee, Chengqi Lin
Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of HBV life cycle. However, factors controlling the HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the Super Elongation Complex (SEC) bind to the HBV genome...
July 10, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28688280/synthesis-of-sulfamoylbenzamide-derivatives-as-hbv-capsid-assembly-effector
#7
Ozkan Sari, Sebastien Boucle, Bryan D Cox, Tugba Ozturk, Olivia Ollinger Russell, Leda Bassit, Franck Amblard, Raymond F Schinazi
The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion...
June 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28635668/the-role-of-cccdna-in-hbv-maintenance
#8
REVIEW
Lena Allweiss, Maura Dandri
Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide; it can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. The molecular mechanisms determining HBV persistence are not fully understood, but these appear to be multifactorial and the unique replication strategy employed by HBV enables its maintenance in infected hepatocytes. Both the stability of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the hepatocyte nucleus, and the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity...
June 21, 2017: Viruses
https://www.readbyqxmd.com/read/28634352/differences-in-sequences-between-hbv-relaxed-circular-dna-and-covalently-closed-circular-dna
#9
Magda Rybicka, Anna Woziwodzka, Tomasz Romanowski, Piotr Stalke, Marcin Dręczewski, Krzysztof Piotr Bielawski
The hepatitis B virus (HBV) genome exists in two forms: circular covalently closed DNA (cccDNA) and relaxed circular DNA (RCDNA). Here, we investigated the presence of differences in the sequences of both forms in paired samples of serum and liver tissue. The serum and liver biopsy samples were collected at the same time from 67 chronically infected patients. The genotyping of the RCDNA and cccDNA was performed using mass spectrometry analysis. The HBV mutations located in the HBV pol (P) and the HBV basal core promoter/pre-core (BCP/PC) regions were included...
June 21, 2017: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/28627393/the-potential-and-challenges-of-crispr-cas-in-eradication-of-hepatitis-b-virus-covalently-closed-circular-dna
#10
REVIEW
Hung-Chih Yang, Pei-Jer Chen
Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection, primarily because of the persistence of covalently closed circular DNA (cccDNA). Although nucleos(t)ide analogues (NAs) can inhibit the reverse transcriptase of HBV and suppress its replication to levels below the detection limit, viremia often rebounds after cessation of therapy. Nuclear cccDNA serves as the HBV replicative template and exhibits extraordinary stability, and is not affected by NAs. Therefore, curing chronic hepatitis B (CHB) requires novel therapy for purging cccDNA from patients...
June 13, 2017: Virus Research
https://www.readbyqxmd.com/read/28611266/retinoid-x-receptor-%C3%AE-dependent-hbv-minichromosome-remodeling-and-viral-replication
#11
Yan Zhang, Song He, Jin-Jun Guo, Hong Peng, Jia-Hao Fan, Qing-Ling Li
BACKGROUND AND AIM: The HBV covalently closed circular DNA (cccDNA) is organized into a minichromosome in the nuclei of infected hepatocytes through interactions with histone and nonhistone proteins. Retinoid X receptor α (RXRα), a liver-enriched nuclear receptor, participates in regulation of HBV replication and transcription through modulation of HBV enhancer 1 and core promoter activity. MATERIAL AND METHODS: This study investigated RXRα involvement in HBV cccDNA epigenetic modifications...
August 1, 2017: Annals of Hepatology
https://www.readbyqxmd.com/read/28608964/hbx-elevated-msl2-modulates-hbv-cccdna-through-inducing-degradation-of-apobec3b-to-enhance-hepatocarcinogenesis
#12
Yuen Gao, Jinyan Feng, Guang Yang, Shuqin Zhang, Yunxia Liu, Yanan Bu, Mingming Sun, Man Zhao, Fuquan Chen, Weiying Zhang, Lihong Ye, Xiaodong Zhang
Chronic hepatitis B virus (HBV) infection is a leading cause in the occurrence of hepatitis B, liver cirrhosis and liver cancer, in which nuclear HBV covalently closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence, plays crucial roles. In the present study, we explored the hypothesis that HBV X protein (HBx)-elevated male-specific lethal 2 (MSL2) activated HBV replication via modulating cccDNA in hepatoma cells, leading to hepatocarcinogenesis. Immunohistochemical analysis revealed that the expression of MSL2 was positively associated with that of HBV and was increased in the liver tissues of HBV-transgenic mice and clinical HCC patients...
June 13, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28592528/hdm2-promotes-neddylation-of-hbv-hbx-to-enhance-its-stability-and-function
#13
Ningning Liu, Jinfang Zhang, Xiaohai Yang, Tong Jiao, Xin Zhao, Wenxia Li, Jianhua Zhu, Pu Yang, Jianping Jin, Jirun Peng, Zhiwei Li, Xin Ye
Hepatitis B virus-encoded X protein (HBx) plays a critical role in HBV-related hepatocarcinoma development. In this study, we demonstrated that HBx is specifically modified by NEDD8. We found that E3 ligase HDM2 promotes NEDDylation of HBx to enhance HBx stability by preventing its ubiquitination-mediated degradation. Consistently, analysis of 160 HCC patient specimens indicated that the amount of HDM2 protein correlates with HBx protein level. We identified that HBx K91 and K95 as the key HBx NEDDylation sites and observed that the NEDDylation-deficient HBx has shorter half-life...
June 7, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28587292/detection-of-hbv-covalently-closed-circular-dna
#14
REVIEW
Xiaoling Li, Jinghua Zhao, Quan Yuan, Ningshao Xia
Chronic hepatitis B virus (HBV) infection affects approximately 240 million people worldwide and remains a serious public health concern because its complete cure is impossible with current treatments. Covalently closed circular DNA (cccDNA) in the nucleus of infected cells cannot be eliminated by present therapeutics and may result in persistence and relapse. Drug development targeting cccDNA formation and maintenance is hindered by the lack of efficient cccDNA models and reliable cccDNA detection methods...
June 6, 2017: Viruses
https://www.readbyqxmd.com/read/28584155/capsid-assembly-modulators-have-a-dual-mechanism-of-action-in-primary-human-hepatocytes-infected-with-hepatitis-b-virus
#15
Jan Martin Berke, Pascale Dehertogh, Karen Vergauwen, Ellen van Damme, Wendy Mostmans, Koen Vandyck, Frederik Pauwels
Hepatitis B Virus (HBV) capsid assembly is a critical step in the propagation of the virus mediated by the core protein. Due to its multiple functions in the viral life cycle, core became an attractive target for new antiviral therapies. Capsid assembly modulators (CAMs) accelerate the kinetics of capsid assembly and prevent encapsidation of the polymerase-pregenomic RNA (pol-pgRNA) complex thereby blocking viral replication. CAM JNJ-632 is a novel and potent inhibitor of HBV replication in vitro across genotypes A-D...
June 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28566379/discovery-and-mechanistic-study-of-benzamide-derivatives-that-modulate-hepatitis-b-virus-capsid-assembly
#16
Shuo Wu, Qiong Zhao, Pinghu Zhang, John Kulp, Lydia Hu, Nicky Hwang, Jiming Zhang, Timothy M Block, Xiaodong Xu, Yanming Du, Jinhong Chang, Ju-Tao Guo
Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies...
May 31, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28559272/an-effective-anti-viral-approach-targeting-hepatitis-b-virus-using-njk14047-a-novel-and-selective-biphenyl-amide-p38-mapk-inhibitor
#17
So-Young Kim, Hong Kim, Sang-Won Kim, Na-Rae Lee, Chae-Min Yi, Jinyuk Heo, Bum-Joon Kim, Nam-Jung Kim, Kyung-Soo Inn
Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B still remains as a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28531167/a-role-for-the-host-dna-damage-response-in-hepatitis-b-virus-cccdna-formation-and-beyond
#18
REVIEW
Sabrina Schreiner, Michael Nassal
Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions...
May 22, 2017: Viruses
https://www.readbyqxmd.com/read/28521532/new-antivirals-for-the-treatment-of-chronic-hepatitis-b
#19
REVIEW
Vincent Soriano, Pablo Barreiro, Laura Benitez, Jose M Peña, Carmen de Mendoza
Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription...
July 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28499864/role-of-hepatitis-b-core-protein-in-hbv-transcription-and-recruitment-of-histone-acetyltransferases-to-cccdna-minichromosome
#20
Chun Kong Chong, Ching Yan Serene Cheng, Sin Yi Jasmine Tsoi, Fung-Yu Huang, Fen Liu, Wai-Kay Seto, Ching-Lung Lai, Man-Fung Yuen, Danny Ka-Ho Wong
The hepatitis B core protein (HBc) has been suggested to interact with covalently closed circular DNA (cccDNA) and regulate hepatitis B virus (HBV) transcription. However, direct evidence is lacking. We aimed to identify the specific HBc region(s) responsible for transcription regulation and its interaction with cccDNA. Seventeen mutants with mutations at the four arginine-rich clusters of the HBc carboxyl-terminal domain (CTD) were created. The effect of HBc mutations on the levels of HBV DNA, RNA, and hepatitis B surface antigen (HBsAg) were measured...
May 10, 2017: Antiviral Research
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