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https://www.readbyqxmd.com/read/28531167/a-role-for-the-host-dna-damage-response-in-hepatitis-b-virus-cccdna-formation-and-beyond
#1
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
#2
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...
May 18, 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
#3
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
https://www.readbyqxmd.com/read/28464339/smaller-reduction-of-hepatitis-b-virus-dna-in-liver-tissue-than-in-serum-in-patients-losing-hbeag
#4
Gianluca Tripodi, Simon B Larsson, Gunnar Norkrans, Magnus Lindh
The prognosis and outcome of treatment for chronic hepatitis B virus (HBV) infection are predicted by levels of HBV DNA in serum. These levels are composed of relaxed circular DNA and double stranded linear DNA in viral particles, whereas HBV DNA in liver tissue also can be covalently closed circular DNA (cccDNA) or integrated into the human genome. The aim of this study was to investigate the quantitative relation between HBV DNA in serum and tissue, its change over time and how these markers relate to serum levels of hepatitis B surface antigen (HBsAg)...
May 2, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/28450868/hepatitis-b-virus-immunopathology-model-systems-and-current-therapies
#5
REVIEW
Praneet Sandhu, Mohammad Haque, Tessa Humphries-Bickley, Swetha Ravi, Jianxun Song
Most people develop acute hepatitis B virus (HBV)-related hepatitis that is controlled by both humoral and cellular immune responses following acute infection. However, a number of individuals in HBV-endemic areas fail to resolve the infection and consequently become chronic carriers. While a vaccine is available and new antiviral drugs are being developed, elimination of persistently infected cells is still a major issue. Standard treatment in HBV infection includes IFN-α, nucleoside, or nucleotide analogs, which has direct antiviral activity and immune modulatory capacities...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28447750/biological-effects-of-bone-marrow-mesenchymal-stem-cells-on-hepatitis-b-virus-in%C3%A2-vitro
#6
Wei-Ping Zheng, Bo-Ya Zhang, Zhong-Yang Shen, Ming-Li Yin, Yi Cao, Hong-Li Song
The aim of the present study was to explore the effects of co‑culturing bone marrow‑derived mesenchymal stem cells (BM-MSCs) cultured with hepatitis B virus (HBV)‑infected lymphocytes in vitro. BM‑MSCs and lymphocytes from Brown Norway rats were obtained from the bone marrow and spleen, respectively. Rats were divided into the following five experimental groups: Group 1, splenic lymphocytes (SLCs); group 2, HepG2.2.15 cells; group 3, BM‑MSCs + HepG2.2.15 cells; group 4, SLCs + HepG2.2.15 cells; and group 5, SLCs + BM‑MSCs + HepG2...
May 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28438570/analysis-of-intrahepatic-total-hbv-dna-cccdna-and-serum-hbsag-level-in-chronic-hepatitis-b-patients-with-undetectable-serum-hbv-dna-during-oral-antiviral-therapy
#7
Jie Li, Xizhen Sun, Jianting Fang, Chuanxi Wang, Guoqing Han, Wanhua Ren
BACKGROUND: This study aimed to investigate the relationship between intrahepatic cccDNA and serum HBsAg in chronic Hepatitis B (CHB) patients with undetectable serum HBV DNA during antiviral therapy. METHODS: We investigated HBsAg serum levels and their relationship to intrahepatic total cccDNA and HBV DNA in CHB patients with undetectable serum HBV DNA during oral antiviral therapy. Intrahepatic cccDNA and HBV DNA quantitation were performed in the same needle biopsy material, while serum HBsAg, HBeAg and HBV DNA levels were measured in samples drawn on the day of the liver biopsy...
April 21, 2017: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/28428345/proliferation-of-primary-human-hepatocytes-and-prevention-of-hepatitis-b-virus-reinfection-efficiently-deplete-nuclear-cccdna-in-vivo
#8
Lena Allweiss, Tassilo Volz, Katja Giersch, Janine Kah, Giuseppina Raffa, Joerg Petersen, Ansgar W Lohse, Concetta Beninati, Teresa Pollicino, Stephan Urban, Marc Lütgehetmann, Maura Dandri
OBJECTIVE: The stability of the covalently closed circular DNA (cccDNA) in nuclei of non-dividing hepatocytes represents a key determinant of HBV persistence. Contrarily, studies with animal hepadnaviruses indicated that hepatocyte turnover can reduce cccDNA loads but knowledge on the proliferative capacity of HBV-infected primary human hepatocytes (PHHs) in vivo and the fate of cccDNA in dividing PHHs is still lacking. This study aimed to determine the impact of human hepatocyte division on cccDNA stability in vivo...
April 20, 2017: Gut
https://www.readbyqxmd.com/read/28426720/a-new-model-mimicking-persistent-hbv-e-antigen-negative-infection-using-covalently-closed-circular-dna-in-immunocompetent-mice
#9
Lei Wang, Min Cao, Qing Lu Wei, Zhong Hua Zhao, Qin Xiang, Hui Juan Wang, Hua Tang Zhang, Guo Qi Lai
Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem. HBV e antigen (HBeAg)-negative strains have become prevalent. Previously, no animal model mimicked the clinical course of HBeAg-negative HBV infection. To establish an HBeAg-negative HBV infection model, the 3.2-kb full-length genome of HBeAg-negative HBV was cloned from a clinical sample and then circularized to form covalently closed circular (cccDNA). The resulting cccDNA was introduced into the liver of C57BL/6J mice through hydrodynamic injection...
2017: PloS One
https://www.readbyqxmd.com/read/28401569/influences-on-viral-replication-and-sensitivity-to-gls4-a-hap-compound-of-naturally-occurring-t109-v124-mutations-in-hepatitis-b-virus-core-protein
#10
Jianghua Wang, Haiying Zhang, Yingjun Zhang, Dong Jiang, Jing Li, Siegfried Goldmann, Qingyun Ren, Ran Fei, Xueyan Wang, Lai Wei
Heteroaryldihydropyrimidine (HAP) compounds inhibit HBV replication by binding to a hydrophobic pocket at the interface between hepatitis B virus core protein (HBcAg) dimer, which interrupts capsid assembly by changing the kinetics and thermodynamics during this process. Structure biological studies have identified several amino acids in HBcAg crucial for compound binding. Here we investigated the polymorphisms of T109 and V124 amino acids in HBV sequences submitted to GenBank database. Naturally occurring T109 and V124 and/or possible compensatory mutations in neighbored amino acids were introduced into HBV-expressing plasmids...
April 12, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/28387980/immune-balance-in-hepatitis-b-infection-present-and-future-therapies
#11
REVIEW
Ashish Kumar Vyas, Ankur Jindal, Syed Hissar, Gayatri Ramakrishna, Nirupama Trehanpati
Chronic hepatitis B virus (HBV) infection affects millions of people worldwide and about half a million people die every year. India represents the second largest pool of chronic HBV infections with an estimated 40 million chronically infected patients. Persistence or clearance of HBV infection mainly depends upon host immune responses. Chronically infected individuals remain in immune tolerant phase unless HBV flares and leads to development of chronic active hepatitis or acute on chronic liver failure. Strategies based on inhibition of viral replication (nucleoside analogues) or immune modulation (Interferons) as monotherapy, or in combination in sequential therapies, are currently being used globally for reducing HBV viral load and mediating HBsAg clearance...
April 7, 2017: Scandinavian Journal of Immunology
https://www.readbyqxmd.com/read/28382278/removal-of-integrated-hepatitis-b-virus-dna-using-crispr-cas9
#12
Hao Li, Chunyu Sheng, Shan Wang, Lang Yang, Yuan Liang, Yong Huang, Hongbo Liu, Peng Li, Chaojie Yang, Xiaoxia Yang, Leili Jia, Jing Xie, Ligui Wang, Rongzhang Hao, Xinying Du, Dongping Xu, Jianjun Zhou, Mingzhen Li, Yansong Sun, Yigang Tong, Qiao Li, Shaofu Qiu, Hongbin Song
The presence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and the permanent integration of HBV DNA into the host genome confers the risk of viral reactivation and hepatocellular carcinoma. Nucleoside/nucleotide analogs alone have little or no capacity to eliminate replicative HBV templates consisting of cccDNA or integrated HBV DNA. Recently, CRISPR/Cas9 technology has been widely applied as a promising genome-editing tool, and HBV-specific CRISPR-Cas9 systems were shown to effectively mediate HBV cccDNA disruption...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28373196/development-of-a-novel-site-specific-pegylated-interferon-beta-for-antiviral-therapy-for-chronic-hepatitis-b
#13
Masataka Tsuge, Takuro Uchida, Nobuhiko Hiraga, Hiromi Kan, Grace Naswa Makokha, Hiromi Abe-Chayama, Daiki Miki, Michio Imamura, Hidenori Ochi, C Nelson Hayes, Rieko Shimozono, Tomokatsu Iwamura, Hideki Narumi, Tomohiko Suzuki, Mie Kainoh, Tadatsugu Taniguchi, Kazuaki Chayama
Although nucleot(s)ide analogues and pegylated-interferon-α2a (PEG-IFNα2a) can suppress hepatitis B virus (HBV) replication, it is difficult to achieve complete HBV elimination from hepatocytes. A novel site-specific pegylated recombinant human IFNβ (TRK-560) was recently developed. In the present study, we evaluated the antiviral effects of TRK-560 on HBV replication in vitro and in vivoIn vitro and in vivo HBV replication models were treated with antivirals including TRK-560, and changes in HBV markers were evaluated...
April 3, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28368357/identifying-and-characterizing-interplay-between-hepatitis-b-virus-x-protein-and-smc5-6
#14
REVIEW
Christine M Livingston, Dhivya Ramakrishnan, Michel Strubin, Simon P Fletcher, Rudolf K Beran
Hepatitis B X protein (HBx) plays an essential role in the hepatitis B virus (HBV) replication cycle, but the function of HBx has been elusive until recently. It was recently shown that transcription from the HBV genome (covalently-closed circular DNA, cccDNA) is inhibited by the structural maintenance of chromosome 5/6 complex (Smc5/6), and that a key function of HBx is to redirect the DNA-damage binding protein 1 (DDB1) E3 ubiquitin ligase to target this complex for degradation. By doing so, HBx alleviates transcriptional repression by Smc5/6 and stimulates HBV gene expression...
April 3, 2017: Viruses
https://www.readbyqxmd.com/read/28297795/-the-potential-use-of-serum-hbv-rna-to-guide-the-functional-cure-of-chronic-hepatitis-b
#15
F M Lu, J Wang, X M Chen, J N Jiang, W H Zhang, J M Zhao, H Ren, J L Hou, N S Xia
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in infected hepatocytes is the main cause of off-therapy viral rebound. The half-life of cccDNA is only 33-50 days, so the conversion of newly synthesized rcDNA to cccDNA in the nucleus is essential for the maintenance of cccDNA pool in infected hepatocytes. Though not directly targeting the existing cccDNA, current nucleos(t)ide analogues (NAs) may exhaust the cccDNA reservoir by blocking the rcDNA formation. Indeed, a prolonged consolidation therapy post loss of serum HBV DNA can achieve sustained remission and thus safe drug discontinuation in a small proportion of chronic hepatitis B (CHB) patients...
February 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/28286056/detection-of-hbv-dna-and-antigens-in-hbsag-positive-patients-with-primary-hepatocellular-carcinoma
#16
Sha Fu, Ning Li, Peng-Cheng Zhou, Yan Huang, Rong-Rong Zhou, Xue-Gong Fan
BACKGROUND: Hepatitis B virus (HBV) markers include HBV deoxyribonucleic acid (DNA) and HBV antigens. The former involves HBV covalently closed circular DNA (cccDNA) as well as total HBV DNA, whereas the latter involves HBsAg, HBcAg, and HBx. METHODS: Samples of tumor and adjacent non-tumor liver tissue were collected from 28 HBV-associated HCC patients. Intrahepatic total HBV DNA and cccDNA were measured using the real-time PCR Taqman assay. HBV antigens in hepatocytes were detected using immunohistochemical staining...
March 9, 2017: Clinics and Research in Hepatology and Gastroenterology
https://www.readbyqxmd.com/read/28282964/serum-hepatitis-b-core-related-antigen-is-a-satisfactory-surrogate-marker-of-intrahepatic-covalently-closed-circular-dna-in-chronic-hepatitis-b
#17
En-Qiang Chen, Shu Feng, Meng-Lan Wang, Ling-Bo Liang, Ling-Yun Zhou, Ling-Yao Du, Li-Bo Yan, Chuan-Min Tao, Hong Tang
Recently, hepatitis B core-related antigen (HBcrAg) has been suggested as an additional marker of hepatitis B virus (HBV) infection. This study aimed to investigate whether serum quantitative HBcrAg (qHBcrAg) was a satisfactory surrogate marker of intrahepatic covalently closed circular DNA (cccDNA). A total of 139 patients with liver biopsy were enrolled, consisting of 59 patients in immune tolerance (IT) phase, 52 patients in immune clearance (IC) phase, 18 patients in low-replication (LR) phase, and 10 patients in reactivation phase...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275452/advancing-the-regulatory-path-on-hepatitis-b-virus-treatment-and-curative-research-a-stakeholders-consultation
#18
EDITORIAL
Jonathan Liu, Pedro Goicochea, Timothy Block, Carol L Brosgart, Eric F Donaldson, Oliver Lenz, Seng Gee Lim, Ed G Marins, Poonam Mishra, Marion G Peters, Veronica Miller
Hepatitis B infection remains a significant disease burden around the world, with an estimated two billion individuals infected and 350 million living with chronic hepatitis B. Current antivirals are efficacious, but require lifelong treatment for the majority of infected individuals. The field is galvanised to improve diagnostics and treatment with the goal to develop shorter, finite treatments leading to viral control after treatment discontinuation. Achievement of complete and functional cure is challenged by the complexity of the virus life cycle, the lack of adequate preclinical models, the cccDNA-mediated persistence of HBV in liver cells, the lack of validated biomarkers to predict viral control and cure, and the probable need for combination treatment involving antiviral- and immune-based strategies...
January 1, 2017: Journal of Virus Eradication
https://www.readbyqxmd.com/read/28242208/interplay-between-sirt1-and-hepatitis-b-virus-x-protein-in-the-activation-of-viral-transcription
#19
Jian-Jun Deng, Ka-Yiu Edwin Kong, Wei-Wei Gao, Hei-Man Vincent Tang, Vidyanath Chaudhary, Yun Cheng, Jie Zhou, Chi-Ping Chan, Danny Ka-Ho Wong, Man-Fung Yuen, Dong-Yan Jin
Hepatitis B virus (HBV) genome is organized into a minichromosome known as covalently closed circular DNA (cccDNA), which serves as the template for all viral transcripts. SIRT1 is an NAD(+)-dependent protein deacetylase which activates HBV transcription by promoting the activity of cellular transcription factors and coactivators. How SIRT1 and viral transactivator X protein (HBx) might affect each other remains to be clarified. In this study we show synergy and mutual dependence between SIRT1 and HBx in the activation of HBV transcription...
February 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28236308/prmt5-restricts-hepatitis-b-virus-replication-via-epigenetic-repression-of-cccdna-transcription-and-interference-with-pgrna-encapsidation
#20
Wen Zhang, Jieliang Chen, Min Wu, Xiaonan Zhang, Min Zhang, Lei Yue, Yaming Li, Jiangxia Liu, Baocun Li, Fang Shen, Yang Wang, Lu Bai, Ulrike Protzer, Massimo Levrero, Zhenghong Yuan
Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The covalently closed circular DNA (cccDNA) minichromosome, which serves as the template for the transcription of viral RNAs, plays a key role in viral persistence. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation of cccDNA-bound histone 3 (H3) and H4, the potential contributions of histone methylation and related host factors remain obscured. Here, by screening a series of methyltransferases and demethylases, we identified protein arginine methyltransferase 5 (PRMT5) as an effective restrictor of HBV transcription and replication...
February 25, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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