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https://www.readbyqxmd.com/read/29159681/advanced-strategies-for-eliminating-the-cccdna-of-hbv
#1
REVIEW
Jingwu Dong, Jie Ying, Xiaoyan Qiu, Yu Lu, Miaomiao Zhang
Persistent hepatitis B virus (HBV) infection of hepatocytes is associated with a covalently closed circular DNA (cccDNA) episome. Although serologic hepatitis B surface antigen tests are negative, the presence of cccDNA is obviously increased in HBeAg-positive patients compared with that in HBeAg-negative patients, inactive carriers and patients. Moreover, trace cccDNA levels can also be found in the liver cells of patients with resolved hepatitis B infections. Therefore, clearance of cccDNA in hepatocytes could be an effective cure for HBV...
November 20, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29156567/the-role-of-infected-cell-proliferation-in-the-clearance-of-acute-hbv-infection-in-humans
#2
Ashish Goyal, Ruy M Ribeiro, Alan S Perelson
Around 90-95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans...
November 18, 2017: Viruses
https://www.readbyqxmd.com/read/29129707/apobec3b-edits-hbv-dna-and-inhibits-hbv-replication-during-reverse-transcription
#3
Yanmeng Chen, Jie Hu, Xuefei Cai, Yao Huang, Xing Zhou, Zeng Tu, Jieli Hu, John E Tavis, Ni Tang, Ailong Huang, Yuan Hu
Hepatitis B virus is a partially double-stranded DNA virus that replicates by reverse transcription, which occurs within viral core particles in the cytoplasm. The cytidine deaminase APOBEC3B is a cellular restriction factor for HBV. Recently, it was reported that APOBEC3B can edit HBV cccDNA in the nucleus, causing its degradation. However, whether and how it can edit HBV core-associated DNAs during reverse transcription is unclear. Our studies to address this question revealed the following: First, silencing endogenous APOBEC3B in an HBV infection system lead to upregulation of HBV replication...
November 10, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29079518/efficacy-of-nvr-3-778-alone-and-in-combination-with-pegylated-interferon-vs-entecavir-in-upa-scid-mice-with-humanized-livers-and-hbv-infection
#4
Klaus Klumpp, Takashi Shimada, Lena Allweiss, Tassilo Volz, Marc Lütgehetmann, G Hartman, Osvaldo A Flores, Angela M Lam, Maura Dandri
BACKGROUND & AIMS: NVR3-778 is a capsid assembly modulator in clinical development. We determined the in vivo anti-viral efficacy and effects on innate and endoplasmic reticulum (ER) stress responses of NVR3-778 alone or in combination with pegylated interferon alpha (peg-IFN) and compared with entecavir. METHODS: We performed 2 studies, with a total of 61 uPA/SCID mice with humanized livers. Mice were infected with a HBV genotype C preparation; we waited 8 weeks for persistent infection of the human hepatocytes in livers of mice...
October 24, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29065733/hepatitis-b-core-protein-as-a-therapeutic-target
#5
Lung-Yi Mak, Danny Ka-Ho Wong, Wai-Kay Seto, Ching-Lung Lai, Man Fung Yuen
Chronic hepatitis B virus (HBV) infection is difficult to cure, due to the presence of covalently-closed-circular DNA and virus-mediated blunting of host immune response. Existing therapies with nucleos(t)ide analogue or pegylated-interferon are not sufficient to achieve a high rate of HBV surface antigen seroclearance, a more desirable treatment outcome. Novel therapeutic agents targeting alternative viral replication steps are being developed. In this review, we will discuss the hepatitis B core antigen (HBcAg) as a therapeutic target...
December 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29062901/new-directions-in-hepatitis-b-therapy-research
#6
REVIEW
Marta Lewandowska, Anna Piekarska
Chronic hepatitis B treatment is available for a long period, allowing disease control and infection suppression, but it is rarely responsible for HBsAg clearance. None of the drugs available aim at cccDNA, the obstacle in HBV infection eradication. Complications related to CHB, such as liver insufficiency, cirrhosis, and hepatocellular carcinoma are reduced in conditions of good viremia suppression, but still exist even after HBsAg seroclearance, what makes a need for urgent forthcoming of new therapeutics...
September 2017: Clin Exp Hepatol
https://www.readbyqxmd.com/read/29059468/hepatitis-b-virus-sensitivity-to-interferon-%C3%AE-in-hepatocytes-is-more-associated-with-cellular-interferon-response-than-with-viral-genotype
#7
Fang Shen, Yaming Li, Yang Wang, Vitina Sozzi, Peter A Revill, Jiangxia Liu, Lu Gao, Guang Yang, Mengji Lu, Kathrin Sutter, Ulf Dittmer, Jieliang Chen, Zhenghong Yuan
Interferon-α (IFN-α) is used to treat chronic HBV infection but only 20-40% of patients respond well. Clinical observations have suggested that HBV genotype is associated with the response to IFN therapy, however, its role in viral responsiveness to IFN in HBV-infected hepatocytes remain unclear. Here, we produced infectious virions of HBV genotypes A to D to infect three well-recognized cell culture-based HBV infection systems including primary human hepatocytes (PHH), differentiated HepaRG (dHepaRG) and HepG2-NTCP cells to quantitatively compare the antiviral effect of IFN-α on HBV across genotypes and cell models...
October 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29048354/hepatitis-b-virus-and-dna-damage-response-interactions-and-consequences-for-the-infection
#8
REVIEW
Andoni Gómez-Moreno, Urtzi Garaigorta
Hepatitis B virus (HBV) is a major etiologic agent of acute and chronic hepatitis, and end-stage liver disease. Establishment of HBV infection, progression to persistency and pathogenesis are determined by viral and cellular factors, some of which remain still undefined. Key steps of HBV life cycle e.g., transformation of genomic viral DNA into transcriptionally active episomal DNA (cccDNA) or transcription of viral mRNAs from cccDNA, take place in the nucleus of infected cells and strongly depend on enzymatic activities provided by cellular proteins...
October 19, 2017: Viruses
https://www.readbyqxmd.com/read/29046450/distribution-of-hepatitis-b-virus-nuclear-dna
#9
Mingming Li, Ji A Sohn, Christoph Seeger
Chronic hepatitis B affects over 300 million people who are at risk of developing liver cancer. The basis for the persistence of hepatitis B virus (HBV) in hepatocytes, even in the presence of available antiviral therapies, lies in the accumulation of covalently closed circular (ccc) DNA in nuclei of infected cells. While methods for cccDNA quantification from liver biopsies and cell lines expressing the virus are known, information about cccDNA formation, stability and turnover are lacking. In particular, little is known about the fate of cccDNA during cell division...
October 18, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29035003/hepatitis-b-core-related-antigen-hbcrag-an-emerging-marker-for-chronic-hepatitis-b-virus-infection
#10
REVIEW
L-Y Mak, D K-H Wong, K-S Cheung, W-K Seto, C-L Lai, M-F Yuen
BACKGROUND: Chronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non-invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core-related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB...
October 16, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29018874/flavocoxid-exerts-a-potent-antiviral-effect-against-hepatitis-b-virus
#11
Teresa Pollicino, Cristina Musolino, Natasha Irrera, Alessandra Bitto, Daniele Lombardo, Martina Timmoneri, Letteria Minutoli, Giovanni Raimondo, Giovanni Squadrito, Francesco Squadrito, Domenica Altavilla
INTRODUCTION: Flavocoxid is a proprietary blend of two flavonoids, baicalin and catechin, and recent evidence has shown that bioflavonoids may exert antiviral activities. The potential antiviral activity of Flavocoxid against hepatitis B virus (HBV) was evaluated. Additionally, it was investigated if Flavocoxid used in combination with Entecavir could potentiate its anti-HBV activity. MATERIALS AND METHODS: Hepatoma cells replicating HBV were treated with Flavocoxid, or Entecavir alone or in combination for up to 5 days...
October 10, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/29018834/in-situ-liver-expression-of-hbsag-cd3-bispecific-antibodies-for-hbv-immunotherapy
#12
Robert L Kruse, Thomas Shum, Xavier Legras, Mercedes Barzi, Frank P Pankowicz, Stephen Gottschalk, Karl-Dimiter Bissig
Current therapies against hepatitis B virus (HBV) do not reliably cure chronic infection, necessitating new therapeutic approaches. The T cell response can clear HBV during acute infection, and the adoptive transfer of antiviral T cells during bone marrow transplantation can cure patients of chronic HBV infection. To redirect T cells to HBV-infected hepatocytes, we delivered plasmids encoding bispecific antibodies directed against the viral surface antigen (HBsAg) and CD3, expressed on almost all T cells, directly into the liver using hydrodynamic tail vein injection...
December 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28974891/curcumin-inhibits-hepatitis-b-virus-infection-by-down-regulating-cccdna-bound-histone-acetylation
#13
Zhi-Qiang Wei, Yong-Hong Zhang, Chang-Zheng Ke, Hong-Xia Chen, Pan Ren, Yu-Lin He, Pei Hu, De-Qiang Ma, Jie Luo, Zhong-Ji Meng
AIM: To investigate the potential effect of curcumin on hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and the underlying mechanism. METHODS: A HepG2.2.15 cell line stably transfected with HBV was treated with curcumin, and HBV surface antigen (HBsAg) and e antigen (HBeAg) expression levels were assessed by ELISA. Intracellular HBV DNA replication intermediates and cccDNA were detected by Southern blot and real-time PCR, respectively. The acetylation levels of histones H3 and H4 were measured by Western blot...
September 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28954926/rnai-based-treatment-of-chronically-infected-patients-and-chimpanzees-reveals-that-integrated-hepatitis-b-virus-dna-is-a-source-of-hbsag
#14
Christine I Wooddell, Man-Fung Yuen, Henry Lik-Yuen Chan, Robert G Gish, Stephen A Locarnini, Deborah Chavez, Carlo Ferrari, Bruce D Given, James Hamilton, Steven B Kanner, Ching-Lung Lai, Johnson Y N Lau, Thomas Schluep, Zhao Xu, Robert E Lanford, David L Lewis
Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. Evidence suggests that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with an RNA interference (RNAi)-based therapeutic targeting HBV transcripts, ARC-520, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors (NUCs)...
September 27, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28945802/hbv-core-protein-allosteric-modulators-differentially-alter-cccdna-biosynthesis-from-de-novo-infection-and-intracellular-amplification-pathways
#15
Fang Guo, Qiong Zhao, Muhammad Sheraz, Junjun Cheng, Yonghe Qi, Qing Su, Andrea Cuconati, Lai Wei, Yanming Du, Wenhui Li, Jinhong Chang, Ju-Tao Guo
Hepatitis B virus (HBV) core protein assembles viral pre-genomic (pg) RNA and DNA polymerase into nucleocapsids for reverse transcriptional DNA replication to take place. Several chemotypes of small molecules, including heteroaryldihydropyrimidines (HAPs) and sulfamoylbenzamides (SBAs), have been discovered to allosterically modulate core protein structure and consequentially alter the kinetics and pathway of core protein assembly, resulting in formation of irregularly-shaped core protein aggregates or "empty" capsids devoid of pre-genomic RNA and viral DNA polymerase...
September 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28944845/efficient-inhibition-of-duck-hepatitis-b-virus-dna-by-the-crispr-cas9-system
#16
Qingfen Zheng, Li Bai, Sujun Zheng, Mei Liu, Jinyan Zhang, Ting Wang, Zhongwei Xu, Yu Chen, Jiansheng Li, Zhongping Duan
Current therapeutic strategies cannot eradicate hepatitis B virus covalently closed circular DNA (HBV cccDNA), which accounts for the persistence of HBV infection. Very recently, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‑associated protein 9 (Cas9) system has been used as an efficient and powerful tool for viral genome editing. Given that the primary duck hepatocyte (PDH) infected with duck hepatitis B virus (DHBV) has been widely used to study human HBV infection in vitro, the present study aimed to demonstrate the targeted inhibition of DHBV DNA, especially cccDNA, by the CRISPR/Cas9 system using this model...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28915572/down-regulation-of-ntcp-expression-by-cyclin-d1-in-hepatitis-b-virus-related-hepatocellular-carcinoma-has-clinical-significance
#17
Jingting Kang, Jie Wang, Jin Cheng, Zhiliang Cao, Ran Chen, Huiyu Li, Shuang Liu, Xiangmei Chen, Jianhua Sui, Fengmin Lu
The sodium-dependent taurocholate cotransporter polypeptide (NTCP) has been identified as a liver specific functional receptor for the hepatitis B virus (HBV). Previous studies indicated that the expression of NTCP may be associated with the proliferation status of hepatocytes. However, the involvement of NTCP in hepatocellular carcinoma (HCC) cells proliferation remains unclear. In this study, we confirmed that NTCP was down-regulated in HCC tumor tissues compared with that in the adjacent non-tumor tissues (P < 0...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28887167/identification-of-slug-and-sox7-as-transcriptional-repressors-binding-to-the-hepatitis-b-virus-core-promoter
#18
Hui Ling Ko, Tze Hau Lam, Huijin Ng, Jiaying Toh, Liang Wei Wang, Ee Chee Ren
BACKGROUND & AIMS: The Hepatitis B Virus (HBV) may gain entry into non-liver cells but does not actively replicate in them. We investigated the possibility that these cells possess mechanisms that block HBV core promoter (HBVCP) transcription, specifically absent in liver cells, which together with other liver-specific mechanisms, such as sodium-taurocholate cotransporting polypeptide-mediated entry, enable liver cells to effectively produce HBV. METHODS: Liver and non-liver cell lines were screened for their capacity to activate the HBVCP and synthesize pre-genomic RNA (pgRNA)...
September 5, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28870671/relationship-between-serum-hbv-rna-levels-and-intrahepatic-viral-as-well-as-histologic-activity-markers-in-entecavir-treated-patients
#19
Jing Wang, Yiqi Yu, Guojun Li, Chuan Shen, Zhefeng Meng, Jianming Zheng, Yanhong Jia, Shaolong Chen, Xiao Zhang, Mengqi Zhu, Jiangjiang Zheng, Zhangzhang Song, Jing Wu, Lingyun Shao, Peiyu Qian, Xiaona Mao, Xuanyi Wang, Yuxian Huang, Caiyan Zhao, Jiming Zhang, Chao Qiu, Wenhong Zhang
BACKGROUND & AIMS: In diagnostics, serum hepatitis B virus (HBV)-RNA levels are valuable when the HBV-DNA load in circulation is effectively suppressed by nucleos(t)ide analogue (NUC) therapy. This study aimed to determine the intrahepatic viral replication activity reflected in serum HBV-RNA and whether HBV-RNA contributes to liver histological changes in patients treated with NUC. METHODS: A cross-sectional set of serum and liver biopsy samples was obtained from patients treated with entecavir, who had undetectable levels of serum HBV-DNA...
September 21, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28839466/the-grna-mirna-grna-ternary-cassette-combining-crispr-cas9-with-rnai-approach-strongly-inhibits-hepatitis-b-virus-replication
#20
Jie Wang, Ran Chen, Ruiyang Zhang, Shanlong Ding, Tianying Zhang, Quan Yuan, Guiwen Guan, Xiangmei Chen, Ting Zhang, Hui Zhuang, Frederick Nunes, Timothy Block, Shuang Liu, Zhongping Duan, Ningshao Xia, Zhongwei Xu, Fengmin Lu
The CRISPR/Cas9 system is a novel genome editing technology which has been successfully used to inhibit HBV replication. Here, we described a novel gRNA-microRNA (miRNA)-gRNA ternary cassette driven by a single U6 promoter. With an anti-HBV pri-miR31 mimic integrated between two HBV-specific gRNAs, both gRNAs could be separated from the long transcript of gRNA-miR-HBV-gRNA ternary cassette through Drosha/DGCR8 processing. The results showed that the gRNA-miR-HBV-gRNA ternary cassette could efficiently express two gRNAs and miR-HBV...
2017: Theranostics
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