scholarly journals New Insights on Molecular Mechanism of Hepatitis B Virus Covalently Closed Circular DNA Formation

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2430
Author(s):  
Alexander L. Marchetti ◽  
Haitao Guo
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cellular Functions ◽  
Circular Dna ◽  
Dna Repair Mechanisms ◽  
Covalently Closed Circular Dna ◽  
Hbv Cccdna ◽  
B Virus ◽  
Repair Mechanisms ◽  
Open Circular

The chronic factor of the Hepatitis B Virus (HBV), specifically the covalently closed circular DNA (cccDNA), is a highly stable and active viral episomal genome established in the livers of chronic hepatitis B patients as a constant source of disease. Being able to target and eliminate cccDNA is the end goal for a genuine cure for HBV. Yet how HBV cccDNA is formed from the viral genomic relaxed circular DNA (rcDNA) and by what host factors had been long-standing research questions. It is generally acknowledged that HBV hijacks cellular functions to turn the open circular DNA conformation of rcDNA into cccDNA through DNA repair mechanisms. With great efforts from the HBV research community, there have been several recent leaps in our understanding of cccDNA formation. It is our goal in this review to analyze the recent reports showing evidence of cellular factor’s involvement in the molecular pathway of cccDNA biosynthesis.

scholarly journals Identification of Disubstituted Sulfonamide Compounds as Specific Inhibitors of Hepatitis B Virus Covalently Closed Circular DNA Formation

2012 ◽  
Vol 56 (8) ◽  
pp. 4277-4288 ◽  
Author(s):  
Dawei Cai ◽  
Courtney Mills ◽  
Wenquan Yu ◽  
Ran Yan ◽  
Carol E. Aldrich ◽  
...  
Keyword(s):  
Cell Culture ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Polymerase Activity ◽  
Circular Dna ◽  
Drug Candidates ◽  
Covalently Closed Circular Dna ◽  
Hbv Cccdna ◽  
B Virus

ABSTRACTHepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a central role in viral infection and persistence and is the basis for viral rebound after the cessation of therapy, as well as the elusiveness of a cure even after extended treatment. Therefore, there is an urgent need for the development of novel therapeutic agents that directly target cccDNA formation and maintenance. By employing an innovative cell-based cccDNA assay in which secreted HBV e antigen is a cccDNA-dependent surrogate, we screened an in-house small-molecule library consisting of 85,000 drug-like compounds. Two structurally related disubstituted sulfonamides (DSS), termed CCC-0975 and CCC-0346, emerged and were confirmed as inhibitors of cccDNA production, with low micromolar 50% effective concentrations (EC50s) in cell culture. Further mechanistic studies demonstrated that DSS compound treatment neither directly inhibited HBV DNA replication in cell culture nor reduced viral polymerase activity in thein vitroendogenous polymerase assay but synchronously reduced the levels of HBV cccDNA and its putative precursor, deproteinized relaxed circular DNA (DP-rcDNA). However, DSS compounds did not promote the intracellular decay of HBV DP-rcDNA and cccDNA, suggesting that the compounds interfere primarily with rcDNA conversion into cccDNA. In addition, we demonstrated that CCC-0975 was able to reduce cccDNA biosynthesis in duck HBV-infected primary duck hepatocytes. This is the first attempt, to our knowledge, to identify small molecules that target cccDNA formation, and DSS compounds thus potentially serve as proof-of-concept drug candidates for development into therapeutics to eliminate cccDNA from chronic HBV infection.

scholarly journals Mechanism of Hepatitis B Virus cccDNA Formation

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1463
Author(s):  
Lei Wei ◽  
Alexander Ploss
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Medical Problem ◽  
Circular Dna ◽  
Critical Step ◽  
Hbv Cccdna ◽  
Double Stranded Dna ◽  
Cellular Environment ◽  
B Virus ◽  
Comprehensive Picture

Hepatitis B virus (HBV) remains a major medical problem affecting at least 257 million chronically infected patients who are at risk of developing serious, frequently fatal liver diseases. HBV is a small, partially double-stranded DNA virus that goes through an intricate replication cycle in its native cellular environment: human hepatocytes. A critical step in the viral life-cycle is the conversion of relaxed circular DNA (rcDNA) into covalently closed circular DNA (cccDNA), the latter being the major template for HBV gene transcription. For this conversion, HBV relies on multiple host factors, as enzymes capable of catalyzing the relevant reactions are not encoded in the viral genome. Combinations of genetic and biochemical approaches have produced findings that provide a more holistic picture of the complex mechanism of HBV cccDNA formation. Here, we review some of these studies that have helped to provide a comprehensive picture of rcDNA to cccDNA conversion. Mechanistic insights into this critical step for HBV persistence hold the key for devising new therapies that will lead not only to viral suppression but to a cure.

scholarly journals Hepatitis B Core-Related Antigen as Surrogate Biomarker of Intrahepatic Hepatitis B Virus Covalently-Closed-Circular DNA in Patients with Chronic Hepatitis B: A Meta-Analysis

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 187
Author(s):  
Gian Paolo Caviglia ◽  
Angelo Armandi ◽  
Chiara Rosso ◽  
Davide Giuseppe Ribaldone ◽  
Rinaldo Pellicano ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis B Surface Antigen ◽  
Meta Analysis ◽  
Circular Dna ◽  
Non Invasive ◽  
Hbv Cccdna ◽  
B Virus ◽  
Chronic Hbv ◽  
Intrahepatic Hbv

Hepatitis B virus (HBV) covalently-closed-circular (ccc)DNA is the key molecule responsible for viral persistence within infected hepatocytes. The evaluation of HBV cccDNA is crucial for the management of patients with chronic HBV infection and for the personalization of treatment. However, the need for liver biopsy is the principal obstacle for the assessment of intrahepatic HBV cccDNA. In the last decade, several studies have investigated the performance of hepatitis B core-related antigen (HBcrAg) as a surrogate of HBV cccDNA amount in the liver. In this meta-analysis, we collected 14 studies (1271 patients) investigating the correlation between serum HBcrAg and intrahepatic HBV cccDNA. Serum HBcrAg showed a high correlation with intrahepatic HBV cccDNA (r = 0.641, 95% confidence interval (CI) 0.510–0.743, p < 0.001). In a head-to-head comparison, we observed that the performance of HBcrAg was significantly superior to that of hepatitis B surface antigen (r = 0.665 vs. r = 0.475, respectively, p < 0.001). Subgroup analysis showed that the correlation between HBcrAg and intrahepatic HBV cccDNA was high, both in hepatitis B e antigen-positive and -negative patients (r = 0.678, 95% CI 0.403–0.840, p < 0.001, and r = 0.578, 95% CI 0.344–0.744, p < 0.001, respectively). In conclusion, the measurement of serum HBcrAg qualifies as a reliable non-invasive surrogate for the assessment of an intrahepatic HBV cccDNA reservoir.

scholarly journals How to Clear HBV cccDNA: CRISPR/Cas9 Might Be Promising

2017 ◽  
Author(s):  
Yan Qiu ◽  
Ying Liu ◽  
Wen Ren ◽  
Jing Ren
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Health Concern ◽  
Liver Carcinoma ◽  
Major Health ◽  
Circular Dna ◽  
Hbv Cccdna ◽  
B Virus

BACKGROUND: Chronic hepatitis B infected with Hepatitis B virus remains a major health concern worldwide. Despite standard interferon-&alpha; and nucleotide analogues have been shown to reduce the deterioration of liver disease among chronic hepatitis B patients, covalently closed circular DNA was still difficult to eradicate. METHODS: A literature search of Pubmed and Web of science was performed with the following key words: &lsquo;CRISPR&rsquo;, &lsquo;CRISPR/Cas9&rsquo;, &lsquo;hepatitis B&rsquo;, &lsquo;HBV&rsquo;, &lsquo;chronic hepatitis B&rsquo; and &lsquo;HBV cccDNA&rsquo;. The information about CRISPR/Cas9 for the treatment of HBV cccDNA or hepatitis B was reviewed. RESULTS: CRISPR/Cas9 could treat hepatitis B through suppressing or clearing HBV cccDNA with different gRNAs. CONCLUSION: With the emergence of CRISPR/Cas9 (the RNA-guided clustered regulatory interspaced short palindromic repeats, CRISPR) editing technology, clearance of hepatitis B virus and better prevention of liver carcinoma seemed to be possible.

scholarly journals Duck hepatitis B virus covalently closed circular DNA appears to survive hepatocyte mitosis in the growing liver

Virology ◽  
2013 ◽  
Vol 446 (1-2) ◽  
pp. 357-364 ◽  
Author(s):  
Georget Y. Reaiche-Miller ◽  
Michael Thorpe ◽  
Huey Chi Low ◽  
Qiao Qiao ◽  
Catherine A. Scougall ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Duck Hepatitis B Virus ◽  
Circular Dna ◽  
Covalently Closed Circular Dna ◽  
Duck Hepatitis ◽  
B Virus
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