{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:33:49Z","timestamp":1792704829462,"version":"4.5.0"},"reference-count":53,"publisher":"BMJ","issue":"3","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Gut"],"accepted":{"date-parts":[[2017,3,31]]},"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PHH proliferation was triggered by serially transplanting hepatocytes from HBV-infected humanised mice into na\u00efve recipients. Cell proliferation and virological changes were assessed by quantitative PCR, immunofluorescence and RNA in situ hybridisation. Viral integrations were analysed by gel separation and deep sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PHH proliferation strongly reduced all infection markers, including cccDNA (median 2.4\u2005log\/PHH). Remarkably, cell division appeared to cause cccDNA dilution among daughter cells and intrahepatic cccDNA loss. Nevertheless, HBV survived in sporadic non-proliferating human hepatocytes, so that virological markers rebounded as hepatocyte expansion relented. This was due to reinfection of quiescent PHHs since treatment with the entry inhibitor myrcludex-B or nucleoside analogues blocked viral spread and intrahepatic cccDNA accumulation. Viral integrations were detected both in donors and recipient mice but did not appear to contribute to antigen production.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We demonstrate that human hepatocyte division even without involvement of cytolytic mechanisms triggers substantial cccDNA loss. This process may be fundamental to resolve self-limiting acute infection and should be considered in future therapeutic interventions along with entry inhibition strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gutjnl-2016-312162","type":"journal-article","created":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T20:55:25Z","timestamp":1492721725000},"page":"542-552","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":165,"title":["Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo"],"prefix":"10.1136","volume":"67","author":[{"given":"Lena","family":"Allweiss","sequence":"first","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tassilo","family":"Volz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Giersch","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Kah","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Raffa","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Petersen","sequence":"additional","affiliation":[{"name":"IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar W","family":"Lohse","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"},{"name":"German Center for Infection Research (DZIF), Hamburg-L\u00fcbeck-Borstel and Heidelberg Partner Sites, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Beninati","sequence":"additional","affiliation":[{"name":"Department of Human Pathology, University Hospital of Messina, Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Pollicino","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Urban","sequence":"additional","affiliation":[{"name":"German Center for Infection Research (DZIF), Hamburg-L\u00fcbeck-Borstel and Heidelberg Partner Sites, Hamburg, Germany"},{"name":"Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"L\u00fctgehetmann","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"},{"name":"Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Dandri","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"},{"name":"German Center for Infection Research (DZIF), Hamburg-L\u00fcbeck-Borstel and Heidelberg Partner Sites, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2017,4,20]]},"reference":[{"key":"2025120519140654000_67.3.542.1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-309809"},{"key":"2025120519140654000_67.3.542.2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-308943"},{"key":"2025120519140654000_67.3.542.3","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28025"},{"key":"2025120519140654000_67.3.542.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.10.021"},{"key":"2025120519140654000_67.3.542.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1243462"},{"key":"2025120519140654000_67.3.542.6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58847"},{"key":"2025120519140654000_67.3.542.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.05.022"},{"key":"2025120519140654000_67.3.542.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2007.12.024"},{"key":"2025120519140654000_67.3.542.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2012.05.008"},{"key":"2025120519140654000_67.3.542.10","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00833-10"},{"key":"2025120519140654000_67.3.542.11","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.03.018"},{"key":"2025120519140654000_67.3.542.12","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-302056"},{"key":"2025120519140654000_67.3.542.13","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12057"},{"key":"2025120519140654000_67.3.542.14","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21282"},{"key":"2025120519140654000_67.3.542.15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119308"},{"key":"2025120519140654000_67.3.542.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5415.825"},{"key":"2025120519140654000_67.3.542.17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2893.2007.00911.x"},{"key":"2025120519140654000_67.3.542.18","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2011-301073"},{"key":"2025120519140654000_67.3.542.19","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.12.6356-6363.2002"},{"key":"2025120519140654000_67.3.542.20","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23611"},{"key":"2025120519140654000_67.3.542.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001082"},{"key":"2025120519140654000_67.3.542.22","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.004861-0"},{"key":"2025120519140654000_67.3.542.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.12.008"},{"key":"2025120519140654000_67.3.542.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.03.011"},{"key":"2025120519140654000_67.3.542.25","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.36592"},{"key":"2025120519140654000_67.3.542.26","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.23314"},{"key":"2025120519140654000_67.3.542.27","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2015.09.026"},{"key":"2025120519140654000_67.3.542.28","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.1.68-76.2003"},{"key":"2025120519140654000_67.3.542.29","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23226"},{"key":"2025120519140654000_67.3.542.30","doi-asserted-by":"crossref","first-page":"e0142599","DOI":"10.1371\/journal.pone.0142599","article-title":"IL6 Inhibits HBV transcription by targeting the epigenetic control of the nuclear cccDNA minichromosome","volume":"10","author":"Palumbo","year":"2015","journal-title":"PLoS ONE"},{"key":"2025120519140654000_67.3.542.31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004780"},{"key":"2025120519140654000_67.3.542.32","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1389"},{"key":"2025120519140654000_67.3.542.33","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01902-09"},{"key":"2025120519140654000_67.3.542.34","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12807"},{"key":"2025120519140654000_67.3.542.35","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1995.9004"},{"key":"2025120519140654000_67.3.542.36","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2004.054452"},{"key":"2025120519140654000_67.3.542.37","doi-asserted-by":"crossref","first-page":"9392","DOI":"10.1128\/jvi.71.12.9392-9399.1997","article-title":"Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus","volume":"71","author":"Moraleda","year":"1997","journal-title":"J Virol"},{"key":"2025120519140654000_67.3.542.38","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3300867"},{"key":"2025120519140654000_67.3.542.39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606091113"},{"key":"2025120519140654000_67.3.542.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2013.08.014"},{"issue":"1","key":"2025120519140654000_67.3.542.41","doi-asserted-by":"crossref","first-page":"S41","DOI":"10.1016\/j.jhep.2016.02.009","article-title":"Attacking hepatitis B virus cccDNA\u2014the holy grail to hepatitis B cure","volume":"64","author":"Lucifora","year":"2016","journal-title":"J Hepatol"},{"key":"2025120519140654000_67.3.542.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.12.089"},{"key":"2025120519140654000_67.3.542.43","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00430-014-0377-7","article-title":"Circumventing failed antiviral immunity in chronic hepatitis B virus infection: triggering virus-specific or innate-like T cell response?","volume":"204","author":"Koh","year":"2015","journal-title":"Med Microbiol Immunol"},{"key":"2025120519140654000_67.3.542.44","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.3748\/wjg.v20.i20.6236","article-title":"Role of hepatitis B virus DNA integration in human hepatocarcinogenesis","volume":"20","author":"Hai","year":"2014","journal-title":"World J Gastroenterol"},{"key":"2025120519140654000_67.3.542.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1635109100"},{"key":"2025120519140654000_67.3.542.46","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.30203"},{"key":"2025120519140654000_67.3.542.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.10.001"},{"key":"2025120519140654000_67.3.542.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409332102"},{"key":"2025120519140654000_67.3.542.49","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00700-09"},{"key":"2025120519140654000_67.3.542.50","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.3.1495-1505.2000"},{"key":"2025120519140654000_67.3.542.51","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.05.039"},{"key":"2025120519140654000_67.3.542.52","doi-asserted-by":"publisher","DOI":"10.1111\/apt.13272"},{"key":"2025120519140654000_67.3.542.53","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiw412"}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gutjnl-2016-312162","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T03:14:12Z","timestamp":1764990852000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gutjnl-2016-312162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,20]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,2,8]]},"published-print":{"date-parts":[[2018,3]]}},"alternative-id":["10.1136\/gutjnl-2016-312162"],"URL":"https:\/\/doi.org\/10.1136\/gutjnl-2016-312162","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,20]]}}}