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      Baseline value of intrahepatic HBV DNA over cccDNA predicts patient’s response to interferon therapy

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          Abstract

          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. Patients were categorized as either responder or non-responder group based on their HBeAg status 1-year after interferon therapy. Levels of both intrahepatic HBV DNA and HBV cccDNA were significantly reduced after interferon treatment among the responders, but not the non-responders, in comparison with their levels at baseline. Baseline values of intrahepatic HBV DNA over cccDNA significantly correlated with patient’s response to PEG-IFN therapy (P = 0.000). In addition, HBeAg seroconversion also correlates with a significant reduction in intrahepatic pgRNA production among the responders after interferon therapy (P = 0.030). In conclusion, our results suggest that baseline value of intrahepatic HBV DNA over cccDNA may be a preferable indicator for selecting appropriate patients for IFN-based therapy in the clinic.

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          Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function.

          HBV cccDNA, the template for transcription of all viral mRNAs, accumulates in the nucleus of infected cells as a stable episome organized into minichromosomes by histones and non-histone viral and cellular proteins. Using a cccDNA-specific chromatin immunoprecipitation (ChIP)-based quantitative assay, we have previously shown that transcription of the HBV minichromosome is regulated by epigenetic changes of cccDNA-bound histones and that modulation of the acetylation status of cccDNA-bound H3/H4 histones impacts on HBV replication. We now show that the cellular histone acetyltransferases CBP, p300, and PCAF/GCN5, and the histone deacetylases HDAC1 and hSirt1 are all recruited in vivo onto the cccDNA. We also found that the HBx regulatory protein produced in HBV replicating cells is recruited onto the cccDNA minichromosome, and the kinetics of HBx recruitment on the cccDNA parallels the HBV replication. As expected, an HBV mutant that does not express HBx is impaired in its replication, and exogenously expressed HBx transcomplements the replication defects. p300 recruitment is severely impaired, and cccDNA-bound histones are rapidly hypoacetylated in cells replicating the HBx mutant, whereas the recruitment of the histone deacetylases hSirt1 and HDAC1 is increased and occurs at earlier times. Finally, HBx mutant cccDNA transcribes significantly less pgRNA. Altogether our results further support the existence of a complex network of epigenetic events that influence cccDNA function and HBV replication and identify an epigenetic mechanism (i.e., to prevent cccDNA deacetylation) by which HBx controls HBV replication.
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            Attacking hepatitis B virus cccDNA--The holy grail to hepatitis B cure.

            HBV deposits a covalently closed circular DNA form, called cccDNA, in the nucleus of infected cells. As the central transcription template, the cccDNA minichromosome is a key intermediate in the HBV life cycle. Its location in the nucleus makes cccDNA a difficult target for antivirals and immune response, and therefore it is responsible for chronicity of HBV infection. While little is known about the mechanisms involved in cccDNA formation, current research is accumulating data on the mechanisms regulating transcription from cccDNA, and the first potential targeting approaches have been reported. This review will summarize our knowledge about cccDNA biology and the latest advances in cccDNA targeting strategies in order to finally achieve an HBV cure.
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              Chronic hepatitis B: update of recommendations.

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                Author and article information

                Contributors
                renhong0531@vip.sina.com
                yongliao@hospital.cqmu.edu.cn
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                19 July 2017
                19 July 2017
                2017
                : 7
                : 5937
                Affiliations
                [1 ]Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Chongqing, P.R. China
                [2 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, Institute for Viral Hepatitis, , Chongqing Medical University, ; Chongqing, P.R. China
                [3 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, Department of Infectious Diseases, The Second Affiliated Hospital, , Chongqing Medical University, ; Chongqing, P.R. China
                [4 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, Department of Hepatobiliary Surgery, The Second Affliated Hospital, , Chongqing Medical University, ; Chongqing, P.R. China
                Article
                5242
                10.1038/s41598-017-05242-y
                5517439
                82b056e1-e808-493f-8a0c-f63f2b5baa7e
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 November 2016
                : 25 May 2017
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