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CccDNA dynamics

Ashish Goyal, John M Murray
Cell-free virus is a well-recognized and efficient mechanism for the spread of hepatitis B virus (HBV) infection in the liver. Cell-to-cell transmission (CCT) can be a more efficient means of virus propagation. Despite experimental evidence implying CCT occurs in HBV, its relative impact is uncertain. We develop a 3-D agent-based model where each hepatocyte changes its viral state according to a dynamical process driven by cell-free virus infection, CCT and intracellular replication. We determine the relative importance of CCT in the development and resolution of acute HBV infection in the presence of cytolytic (CTL) and non-CTL mechanisms...
2016: PloS One
Ashish Goyal, John M Murray
UNLABELLED: Hepatitis-D virus (HDV) is a satellite virus of hepatitis-B virus (HBV) whose intracellular products are required for the completion of the HDV life cycle. HDV can replicate in a cell without the presence of HBV but needs hepatitis B surface antigen (HBsAg) to complete virus assembly and packaging. In order to better understand HDV dynamics, we developed a mathematical model and successfully simulated HBV and HDV data under a range of scenarios. Compared to HBV mono-infection, dual HDV infection resulted in lower chronic HBV DNA levels, with more marked suppression for coinfection (1 logs HBV DNA copies/ml lower) compared to superinfection (0...
June 7, 2016: Journal of Theoretical Biology
John M Murray, Ashish Goyal
UNLABELLED: The progression of acute hepatitis B virus (HBV) to chronic infection or clearance is highly dependent on the host immune response composed of cytolytic (CTL) and non-cytolytic (non-CTL) effects. Cytolytic processes induce hepatocyte killing while non-CTL processes inhibit intracellular replication. Both effects are widely recognized and accepted. However, there are uncertainties about the assistance provided by either the loss of covalently circular closed DNA (cccDNA) during cell proliferation or the emergence of refractory cells to immune mediated clearance...
February 7, 2015: Journal of Theoretical Biology
Qiang Liu, Juan Huang, Renyong Jia, Mingshu Wang, Dekang Zhu, Shun Chen, Mafeng Liu, Zhongqiong Yin, Yin Wang, Anchun Cheng
Over the course of duck hepatitis B virus (DHBV) replication, one type of RNA (pregenome/C RNA, 3.5 kb) that corresponds to the whole genome of DHBV is generated from the transcription of viral cccDNA. Previous work has proposed three functions for the pregenome/C RNA: it can serve as the pregenome and be packaged into the core protein during the process of replication, and it encodes the mRNA for both the capsid protein and the viral polymerase. However, little is known about the timing of these functions during the different stages of viral infection...
January 22, 2015: Virus Research
Q Zheng, Y Y Zhu, J Chen, Y R Liu, J You, J Dong, D W Zeng, L Y Gao, L H Chen, J J Jiang
Viral load reduction facilitates recovery of antiviral T-cell responses. Dynamic alterations in intrahepatic viraemia clearance and immune cell reactivity during the early phase of nucleoside analogue (NA) therapy and the impact of these changes on HBeAg seroconversion are unknown. Fifteen HBeAg-positive chronic hepatitis B (CHB) patients were treated with adefovir dipivoxil. T-cell reactivity to HBV core and surface antigens were tested using ELISPOT assay from baseline to week 48 post-treatment (at 4-week intervals)...
December 2014: Journal of Viral Hepatitis
Qiang Li, Furong Lu, Guohong Deng, Kaifa Wang
The contribution of covalently closed circular DNA (cccDNA) and dendritic cells (DCs) to the progression of chronic hepatitis B virus (HBV) infection remains largely unknown. A dynamic model with seven cell types was proposed based on the biological mechanisms of viral replication and the host immune response. The cccDNA self-amplification rate was found to be closely related to both the basic reproduction number of the virus and the immune response. The combination of the cccDNA self-amplification rate and the initial activated DC count induces rich dynamics...
September 21, 2014: Journal of Theoretical Biology
Joshua T Schiffer, Dave A Swan, Daniel Stone, Keith R Jerome
Most chronic viral infections are managed with small molecule therapies that inhibit replication but are not curative because non-replicating viral forms can persist despite decades of suppressive treatment. There are therefore numerous strategies in development to eradicate all non-replicating viruses from the body. We are currently engineering DNA cleavage enzymes that specifically target hepatitis B virus covalently closed circular DNA (HBV cccDNA), the episomal form of the virus that persists despite potent antiviral therapies...
2013: PLoS Computational Biology
Yi Tian, Weibing Yang, Jianxun Song, Yuzhang Wu, Bing Ni
Hepatocellular carcinoma (HCC) remains one of the most prevalent malignant diseases worldwide, and the majority of cases are related to hepatitis B virus (HBV) infection. Interactions between the HBV-encoded X (HBx) protein and host factors are known to play major roles in the onset and progression of HBV-related HCC. These dynamic molecular mechanisms are extremely complex and lead to prominent changes in the host genetic and epigenetic architecture. This review summarizes the current knowledge about HBx-induced epigenetic changes, including aberrations in DNA methylation, histone modifications, and microRNA expression, and their roles in HBV-infected liver cells and HBV-related HCC...
August 2013: Molecular and Cellular Biology
Liping Shi, Shaohua Li, Fang Shen, Haodong Li, Shuiming Qian, Daniel H S Lee, Jim Z Wu, Wengang Yang
Hepadnaviral covalently closed circular DNA (cccDNA) exists as an episomal minichromosome in the nucleus of virus-infected hepatocytes, and serves as the transcriptional template for the synthesis of viral mRNAs. To obtain insight on the structure of hepadnaviral cccDNA minichromosomes, we utilized ducks infected with the duck hepatitis B virus (DHBV) as a model and determined the in vivo nucleosome distribution pattern on viral cccDNA by the micrococcal nuclease (MNase) mapping and genome-wide PCR amplification of isolated mononucleosomal DHBV DNA...
September 2012: Journal of Virology
Chin-Liew Chong, Mong-Liang Chen, Yi-Chieh Wu, Kuen-Nan Tsai, Chien-Chiao Huang, Cheng-Po Hu, King-Song Jeng, Yu-Chi Chou, Chungming Chang
BACKGROUND: The covalently closed-circular DNA (cccDNA) of hepatitis B virus (HBV) is associated with viral persistence in HBV-infected hepatocytes. However, the regulation of cccDNA and its transcription in the host cells at different growth stages is not well understood. METHODS: We took advantages of a stably HBV-producing cell line, 1.3ES2, and examine the dynamic changes of HBV cccDNA, viral transcripts, and viral replication intermediates in different cellular growth stages...
2011: Journal of Biomedical Science
Rahmet Guner, Mustafa Karahocagil, Mehmet Buyukberber, Ozlem Kandemir, Onur Ural, Gaye Usluer, Dilara Inan, Iftihar Koksal, Nurcan Baykam, Kenan Hizel, Tansu Yamazhan, Saban Esen, Mehmet A Tasyaran
OBJECTIVE: The aim of this study was to demonstrate the relation between intrahepatic (IH) hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) levels and the other HBV replicative intermediates and hepatocyte expression of HBV antigens. PATIENTS AND METHODS: Patients with hepatitis B surface antigen (HBsAg) positivity, hepatitis B early antigen negativity, serum HBV DNA levels 10 copies/ml or more, and constantly or intermittently increased alanine aminotransferase levels were included...
November 2011: European Journal of Gastroenterology & Hepatology
Qian Gong, Shu Chen, Jinjun Guo, Hang Sun, Guoxing Zheng, Qi Liu, Hong Ren, Song He
Hepatitis B Virus (HBV) covalently closed circular DNA (cccDNA) is the main replicative intermediate of HBV and is organized into minichromosomes by the interaction with histone and nonhistone proteins. The remodeling of HBV minichromosomes such as post-translational modifications of histone proteins plays an important role in regulating HBV replication. To determine whether other remodeling occurs in addition to acetylation of cccDNA-bound H3 histones in the presence of HBV replication, a cell culture replication model of HBV was used to assess the dynamic status of acetylation, phosphorylation, and methylation of cccDNA-bound H3 histones at various times after transient transfection of linear HBV DNA into human hepatoma, HepG2 cells...
June 2011: DNA and Cell Biology
Ke-kai Zhao, Qing Wang, Xiao-hui Miao, Wen-sheng Xu
OBJECTIVE: To confirm whether DHBV cccDNA could be detected in serum of DHBV-infected ducks after liver injury. METHODS: Twenty four ducks with persistent DHBV infection were divided into 4 groups with the following treatments: A, D-galactosamine (D-GalN, 2.2 g/kg) and lipopolysaccharide (LPS, 100 µg/kg); B, 10 mg/kg of carbon tetrachloride (CCl4) every 12 h twice following D-GalN and LPS; C, 15 mg/kg of CCl4 every 12 h twice following D-GalN and LPS; D, normal saline as normal control (NC)...
September 21, 2010: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Ke-kai Zhao, Qing Wang, Xiao-hui Miao, Wen-sheng Xu
OBJECTIVE: To confirm whether it is feasible to detect HBV cccDNA based on an analysis of its stability and clearance dynamics in the blood of ducks. METHODS: Twelve 1-week-old ducklings were randomized into group A and group B, and each duckling was intravenously injected with 1 milliliter of serum containing 1.2 x 10(9) copies of HBV virion (group A) or plasmid pBS HBV 3.6 II (group B). At 0.25, 2, 4, 6, 8, 12, 24 and 32 h post-injection, serum HBV DNA level in each duckling was quantified by Real-time fluorescent PCR...
May 5, 2009: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Fei-Fei Li, Wan-Hua Ren, Gui-Hang Ding, Jun Shi, Guo-Qing Han
OBJECTIVE: To explore the dynamics of hepatitis B virus covalently closed circular DNA (cccDNA) and optimal duration of treatment after serum virology response. METHODS: HBV cccDNA in liver biopsies and the serum HBV DNA were quantified by real time PCR, the serum makers were detected by enzyme-linked immunosorbent assay. RESULTS: (1) The cccDNA in biopsy samples continued to decrease after serum virology responded. (2) The longer the treatment after serum virology response, the lower the cccDNA level in liver tissue...
March 2009: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
Wei-fang Liang, Zhi-hua Liu, Jie Yang, Kang-xian Luo
OBJECTIVE: o study the replication of hepatitis B virus (HBV) in HepG2 cells infected with Ad-1.2 HBV. METHODS: HepG2 cells were transfected with adenovirus containing 1.2 copies of HBV DNA. The expression of HBV antigens were detected in the culture medium by means of enzyme-linked immunosorbent assay (ELISA), and the covalently closed circular DNA (cccDNA) in the cells was extracted with plasmid extraction kit and detected by real-time PCR with selective primer after treatment with mung bean nuclease...
September 2007: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Mao-chang Liu, Gui-qiang Wang, Wen-hua Piao, Hong-li Xi, Hai-ying Lu, Yan Wang, Qin-huan Wang
BACKGROUND: To determine the presence of covalently closed circular DNA (cccDNA), and to investigate the expression kinetics of HBV DNA, HBsAg and HBeAg in 2.2.15 cell. METHODS: HBV cccDNA was assessed by polymerase chain reaction, HBV DNA was measured by Taqman quantitative PCR and HBsAg and HBeAg was measured by EIA. RESULTS: HBV cccDNA was found in both intracellular and extracellular space. There was a good correlation between HBsAg, HBeAg and HBV DNA in the supernatant of 2...
December 2005: Chinese Journal of Experimental and Clinical Virology
M-C Liu, M Yu, N-L Zhang, W-B Gong, Y Wang, W-H Piao, Q-H Wang, G-Q Wang
The 2.2.15 cells-derived from HepG2 cells transfected with a plasmid containing hepatitis B virus (HBV) DNA secrete surface antigen (HBsAg) particles, nucleocapsids and virions (Proc Natl Acad Sci U S A 1987; 84: 1005-1009). The latter elicit acute hepatitis in chimpanzees (Proc Natl Acad Sci U S A 1987; 84: 4641-4644). We studied the presence of intracellular and extracellular HBV covalently closed circular (ccc) DNA in this culture system by polymerase chain reaction (PCR), kinetically analysed HBsAg and hepatitis B e antigen (HBeAg) released in the culture media by quantitative enzyme-linked immunosorbent assay and quantitated by real-time PCR but HBV DNA from intracellular and extracellular HBV-DNA...
March 2004: Journal of Viral Hepatitis
Sharon Lewin, Tomos Walters, Stephen Locarnini
Hepatitis B virus (HBV) causes a generally non-cytopathic infection in the liver. Even though HBV is a DNA virus, it replicates via reverse transcription which is coordinated within the viral nucleocapsid by the virus-specific polymerase. The major transcriptional template is the viral mimichromosome from which the viral DNA exists as a covalently closed circular (ccc) molcule. The virus infects hepatocytes but can also be found in non-hepatocyte reservoirs such as bile-duct epithelium, mesangial cells of the kidney, pancreatic islet cells and lymphoid cells...
September 2002: Antiviral Research
Leonieke M M Wolters, Bettina E Hansen, Hubert G M Niesters, Deborah DeHertogh, Robert A de Man
BACKGROUND/AIMS: Nucleoside analogues inhibit hepatitis B virus (HBV) replication. Entecavir, a new guanine nucleoside, has also been shown to reduce covalently closed circular DNA (cccDNA) to undetectable levels in woodchucks chronically infected with hepatitis virus. Mathematical description of changes in viral load during and after therapy may help to understand the several events that take place during nucleoside analogue treatment. METHODS: Ten chronic hepatitis B patients were evaluated with a mathematical model during and after withdrawal of four doses of entecavir...
July 2002: Journal of Hepatology
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