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HBV genomes exist as episomal covalently closed circular DNA (cccDNA) or chromosomal integrants. The relative contribution of these genomes to the viral transcriptome in chronic hepatitis B (CHB) is not well-understood. We developed a qPCR method to estimate the abundance of HBV cccDNA- and integrant-derived viral transcripts and applied this to a cohort of patients diagnosed with CHB in the HBe antigen negative phase of disease. We noted a variable pattern of HBV transcripts from both DNA templates, with preS1\/S2 mRNAs predominating and a significant association between increasing age and the expression of integrant-derived mRNAs, but not with inflammatory status. In contrast, cccDNA-derived transcripts were associated with markers of liver inflammation. Analysis of the inflammatory hepatic transcriptome identified 24 genes significantly associated with cccDNA transcriptional activity. Our study uncovers an immune gene signature that associates with HBV cccDNA transcription and increases our understanding of viral persistence.<\/jats:p>","DOI":"10.3390\/v14051070","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T08:34:29Z","timestamp":1652776469000},"page":"1070","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"Andrea","family":"Magri","sequence":"first","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1880-3496","authenticated-orcid":false,"given":"James M.","family":"Harris","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"D\u2019Arienzo","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7548-9731","authenticated-orcid":false,"given":"Rosalba","family":"Minisini","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"J\u00fchling","sequence":"additional","affiliation":[{"name":"Institut de Recherche sur les Maladies Virales et H\u00e9patiques, University of Strasbourg and Inserm, UMR_S1110, F-67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A. C.","family":"Wing","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK"},{"name":"Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX1 4BH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-2622","authenticated-orcid":false,"given":"Rachele","family":"Rapetti","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Leutner","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Services and Supportive Therapies, ASL Verbano-Cusio-Ossola, 28887 Omegna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Testoni","sequence":"additional","affiliation":[{"name":"Cancer Research Center of Lyon, UMR INSERM 1052, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8864-2168","authenticated-orcid":false,"given":"Thomas F.","family":"Baumert","sequence":"additional","affiliation":[{"name":"Institut de Recherche sur les Maladies Virales et H\u00e9patiques, University of Strasbourg and Inserm, UMR_S1110, F-67000 Strasbourg, France"},{"name":"P\u00f4le H\u00e9pato-Digestif, Institut Hopitalo-Universitaire, H\u00f4pitaux Universitaires de Strasbourg, 67000 Strasbourg, France"},{"name":"Institut Universitaire de France, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2245-0083","authenticated-orcid":false,"given":"Fabien","family":"Zoulim","sequence":"additional","affiliation":[{"name":"Cancer Research Center of Lyon, UMR INSERM 1052, 69008 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6246-0876","authenticated-orcid":false,"given":"Peter","family":"Balfe","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9740-0155","authenticated-orcid":false,"given":"Mario","family":"Pirisi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7229-5886","authenticated-orcid":false,"given":"Jane A.","family":"McKeating","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK"},{"name":"Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX1 4BH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1053\/j.gastro.2018.08.061","article-title":"Insights from Antiviral Therapy into Immune Responses to Hepatitis B and C Virus Infection","volume":"156","author":"Rehermann","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S2468-1253(18)30007-4","article-title":"Defective T-cell immunity in hepatitis B virus infection: Why therapeutic vaccination needs a helping hand","volume":"3","author":"Maini","year":"2018","journal-title":"Lancet Gastroenterol. 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