{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:36:08Z","timestamp":1789497368816,"version":"build-2803163510"},"reference-count":165,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Hepatitis B virus (HBV) infection has a multi-dimensional effect on the host, which not only alters the dynamics of immune response but also persists in the hepatocytes to predispose oncogenic factors. The virus exists in multiple forms of which the nuclear localized covalently closed circular DNA (cccDNA) is the most stable and the primary reason for viral persistence even after clearance of surface antigen and viral DNA. The second reason is the existence of pregenomic RNA (pgRNA) containing virion particles. On the other hand, the integration of the viral genome in the host chromosome also leads to persistent production of viral proteins along with the chromosomal instabilities. The interferon treatment or administration of nucleot(s)ide analogs leads to reduction in the viral DNA load, but the pgRNA and surface antigen clearance are a slow process and complete loss of serological HBsAg is rare. The prolonged exposure of immune cells to the viral antigens, particularly HBs antigen, in the blood circulation results in T-cell exhaustion, which disrupts immune clearance of the virus and virus-infected cells. In addition, it predisposes immune-tolerant microenvironment, which facilitates the tumor progression. Thus cccDNA, pgRNA, and HBsAg along with the viral DNA could be the therapeutic targets in the early disease stages that may improve the quality of life of chronic hepatitis B patients by impeding the progression of the disease toward hepatocellular carcinoma.<\/jats:p>","DOI":"10.3389\/fmicb.2021.678537","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T18:29:35Z","timestamp":1630693775000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Persistence of Hepatitis B Virus Infection: A Multi-Faceted Player for Hepatocarcinogenesis"],"prefix":"10.3389","volume":"12","author":[{"given":"Suchandrima","family":"Ghosh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anannya","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soma","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/jmv.1890160209","article-title":"Production of interferon alpha and interferon gamma by peripheral blood leukocytes from patients with chronic hepatitis B virus infection.","volume":"16","author":"Abb","year":"1985","journal-title":"J. Med. Virol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.virol.2008.06.021","article-title":"Characterization of the contribution of spliced RNAs of hepatitis B virus to DNA synthesis in transfected cultures of Huh7 and HepG2 cells.","volume":"379","author":"Abraham","year":"2008","journal-title":"Virology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"10238","DOI":"10.3748\/wjg.v20.i30.10238","article-title":"Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma.","volume":"20","author":"Ali","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"10811","DOI":"10.1128\/jvi.01625-16","article-title":"Single-nucleotide resolution mapping of hepatitis B virus promoters in infected human livers and hepatocellular carcinoma.","volume":"90","author":"Altinel","year":"2016","journal-title":"J. Virol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3389\/fgene.2018.00261","article-title":"Host and viral genetic variation in HBV-related hepatocellular carcinoma.","volume":"9","author":"An","year":"2018","journal-title":"Front. Genet."},{"key":"B6","first-page":"395","article-title":"State of hepatitis B viral genomes in cirrhotic and hepatocellular carcinoma nodules.","volume":"6","author":"Aoki","year":"1989","journal-title":"Mol. Biol. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.meegid.2015.08.024","article-title":"Hepatitis B virus intergenotypic recombinants worldwide: an overview.","volume":"36","author":"Araujo","year":"2015","journal-title":"Infect. Genet. Evol."},{"key":"B8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1365-2613.2001.iep178.x","article-title":"Hepatitis B virus and hepatocellular carcinoma.","volume":"82","author":"Arbuthnot","year":"2001","journal-title":"Int. J. Exp. Pathol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1016\/j.jhep.2013.06.018","article-title":"Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma.","volume":"59","author":"Bayliss","year":"2013","journal-title":"J. Hepatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"4360","DOI":"10.1128\/jvi.02574-12","article-title":"Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription.","volume":"87","author":"Benhenda","year":"2013","journal-title":"J. Virol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"7171","DOI":"10.1128\/jvi.00243-16","article-title":"Single-molecule sequencing reveals complex genome variation of hepatitis B virus during 15 years of chronic infection following liver transplantation.","volume":"90","author":"Betz-Stablein","year":"2016","journal-title":"J. Virol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1186\/s12879-019-4436-y","article-title":"Inhibition of replication of hepatitis B virus using transcriptional repressors that target the viral DNA.","volume":"19","author":"Bloom","year":"2019","journal-title":"BMC Infect. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1002\/hep.510300206","article-title":"The pre-S region determines the intracellular localization and appearance of hepatitis B virus.","volume":"30","author":"Bock","year":"1999","journal-title":"Hepatology"},{"key":"B14","first-page":"71","article-title":"DNA immunization as an efficient strategy for vaccination.","volume":"1","author":"Bolhassani","year":"2009","journal-title":"Avicenna J. Med. Biotechnol."},{"key":"B15","first-page":"1675","article-title":"Circulating IL-2, IL-10 and TNF-alpha in chronic hepatitis B: their relations to HBeAg status and the activity of liver disease.","volume":"47","author":"Bozkaya","year":"2000","journal-title":"Hepatogastroenterology"},{"key":"B16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/ilar.42.2.89","article-title":"The woodchuck model of hepatitis B virus infection.","volume":"42","author":"Bud","year":"2001","journal-title":"ILAR J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"365","DOI":"10.3390\/genes9070365","article-title":"Cellular genomic sites of hepatitis B virus DNA integration.","volume":"9","author":"Budzinska","year":"2018","journal-title":"Genes"},{"key":"B18","doi-asserted-by":"publisher","first-page":"2106","DOI":"10.1002\/hep.30082","article-title":"Hepatitis B virus serum DNA and RNA levels in nucleos(t)ide analog-treated or untreated patients during chronic and acute infection.","volume":"68","author":"Butler","year":"2018","journal-title":"Hepatology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1136\/gutjnl-2011-301281","article-title":"Occult hepatitis B infection in blood donors from South East Asia: molecular characterisation and potential mechanisms of occurrence.","volume":"61","author":"Candotti","year":"2012","journal-title":"Gut"},{"key":"B20","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/0140-6736(90)91874-a","article-title":"Vaccine-induced escape mutant of hepatitis B virus.","volume":"336","author":"Carman","year":"1990","journal-title":"Lancet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1136\/gut.2003.033324","article-title":"Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma.","volume":"53","author":"Chan","year":"2004","journal-title":"Gut"},{"key":"B22","doi-asserted-by":"crossref","first-page":"16459","DOI":"10.1038\/srep16459","article-title":"Hepatitis B virus spliced variants are associated with an impaired response to interferon therapy.","volume":"5","author":"Chen","year":"2015","journal-title":"Sci. Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/mt.2013.212","article-title":"An efficient antiviral strategy for targeting hepatitis B virus genome using transcription activator-like effector nucleases.","volume":"22","author":"Chen","year":"2014","journal-title":"Mol. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"4165","DOI":"10.1128\/jvi.63.10.4165-4171.1989","article-title":"Identification of a doubly spliced viral transcript joining the separated domains for putative protease and reverse transcriptase of hepatitis B virus.","volume":"63","author":"Chen","year":"1989","journal-title":"J. Virol."},{"key":"B25","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/j.1365-2249.2011.04445.x","article-title":"Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus.","volume":"166","author":"Chen","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"13533","DOI":"10.1128\/jvi.02095-12","article-title":"Interaction of the hepatitis B spliced protein with cathepsin B promotes hepatoma cell migration and invasion.","volume":"86","author":"Chen","year":"2012","journal-title":"J. Virol."},{"key":"B27","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.3389\/fimmu.2019.02048","article-title":"HBV-induced immune imbalance in the development of HCC.","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"597","DOI":"10.3390\/ijms20030597","article-title":"Naturally occurring hepatitis B virus mutations leading to endoplasmic reticulum stress and their contribution to the progression of hepatocellular carcinoma.","volume":"20","author":"Choi","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1002\/cld.774","article-title":"Serum hepatitis B Virus RNA as a potential diagnostic biomarker during chronic hepatitis B virus infection.","volume":"13","author":"Cloherty","year":"2019","journal-title":"Clin. Liver Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1038\/mt.2010.20","article-title":"Zinc-finger nucleases as a novel therapeutic strategy for targeting hepatitis B virus DNAs.","volume":"18","author":"Cradick","year":"2010","journal-title":"Mol. Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.1099\/0022-1317-83-11-2773","article-title":"The dominant hepatitis B virus genotype identified in Tibet is a C\/D hybrid.","volume":"83","author":"Cui","year":"2002","journal-title":"J. Gen. Virol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e0128401","DOI":"10.1371\/journal.pone.0128401","article-title":"Does tyrosyl DNA phosphodiesterase-2 play a role in hepatitis B virus genome repair?","volume":"10","author":"Cui","year":"2015","journal-title":"PLoS One"},{"key":"B33","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.2147\/IDR.S240472","article-title":"cccDNA maintenance in chronic hepatits B-Targeting the matrix of viral replication.","volume":"2020","author":"Dandri","year":"2020","journal-title":"Infect. Drug Resist."},{"key":"B34","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1093\/carcin\/bgx145","article-title":"Oncogenic potential of hepatitis B virus subgenotype D1 surpasses D3: significance in the development of hepatocellular carcinoma.","volume":"39","author":"Datta","year":"2018","journal-title":"Carcinogenesis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.canlet.2016.09.028","article-title":"Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma.","volume":"383","author":"Deng","year":"2016","journal-title":"Cancer Lett."},{"key":"B36","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1002\/jmv.20015","article-title":"Clade analysis and surface antigen polymorphism of hepatitis B virus American genotypes.","volume":"72","author":"Devesa","year":"2004","journal-title":"J. Med. Virol."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31850","article-title":"HBV-pgRNA increases the stemness and promotes the development of HBV-related HCC through reciprocal regulation with IGF2BP3.","volume":"7","author":"Ding","year":"2021","journal-title":"Hepatology"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e1004343","DOI":"10.1371\/journal.ppat.1004343","article-title":"The Tudor domain protein Spindlin1 is involved in intrinsic antiviral defense against incoming hepatitis B Virus and herpes simplex virus type 1.","volume":"10","author":"Ducroux","year":"2014","journal-title":"PLoS pathogens"},{"key":"B39","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.jhep.2017.05.025","article-title":"Alternative splicing of hepatitis B virus: a novel virus\/host interaction altering liver immunity.","volume":"67","author":"Duriez","year":"2017","journal-title":"J. Hepatol."},{"key":"B40","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1002\/jmv.20605","article-title":"Hepatitis B virus genetic diversity.","volume":"78","author":"Echevarr\u00eda","year":"2006","journal-title":"J. Med. Virol."},{"key":"B41","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/286535a0","article-title":"Integration of hepatitis B virus sequences and their expression in a human hepatoma cell.","volume":"286","author":"Edman","year":"1980","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.4254\/wjh.v7.i12.1671","article-title":"Occult hepatitis B virus infection in Egypt.","volume":"7","author":"Elbahrawy","year":"2015","journal-title":"World J. Hepatol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3159","DOI":"10.1128\/jcm.01251-12","article-title":"Hepatitis B virus DNA splicing in Lebanese blood donors and genotype A to E strains: implications for hepatitis B virus DNA quantification and infectivity.","volume":"50","author":"El Chaar","year":"2012","journal-title":"J. Clin. Microbiol."},{"key":"B44","doi-asserted-by":"crossref","first-page":"1264.e","DOI":"10.1053\/j.gastro.2011.12.061","article-title":"Epidemiology of viral hepatitis and hepatocellular carcinoma.","volume":"142","author":"El-Serag","year":"2012","journal-title":"Gastroenterology"},{"key":"B45","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jhepr.2019.07.007","article-title":"Is PD-1 blockade a potential therapy for HBV?","volume":"1","author":"F\u00e9ray","year":"2019","journal-title":"JHEP Rep."},{"key":"B46","doi-asserted-by":"publisher","first-page":"15371","DOI":"10.1007\/s13277-016-5406-2","article-title":"Hepatitis B virus X protein in liver tumor microenvironment.","volume":"37","author":"Fu","year":"2016","journal-title":"Tumour Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2972","DOI":"10.1128\/jcm.00760-17","article-title":"Serum hepatitis B virus DNA, RNA, and HBsAg: which correlated better with intrahepatic covalently closed circular DNA before and after nucleos(t)ide analogue treatment?","volume":"55","author":"Gao","year":"2017","journal-title":"J. Clin. Microbiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"10732","DOI":"10.3748\/wjg.v21.i38.10732","article-title":"Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis.","volume":"21","author":"Geng","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1002\/hep.510270133","article-title":"Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis.","volume":"27","author":"Ghany","year":"1998","journal-title":"Hepatology"},{"key":"B50","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1111\/j.1365-2893.2012.01655.x","article-title":"New HBV subgenotype D9, a novel D\/C recombinant, identified in patients with chronic HBeAg-negative infection in Eastern India.","volume":"20","author":"Ghosh","year":"2013","journal-title":"J. Viral. Hepat."},{"key":"B51","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.jhep.2016.09.028","article-title":"Serum HBV pgRNA as a clinical marker for cccDNA activity.","volume":"66","author":"Giersch","year":"2017","journal-title":"J. Hepatol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/s12864-017-3561-5","article-title":"Genome-wide identification of direct HBx genomic targets.","volume":"18","author":"Guerrieri","year":"2017","journal-title":"BMC Genomics"},{"key":"B53","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1006\/viro.1997.8863","article-title":"Heterogeneity and common features of defective hepatitis B virus genomes derived from spliced pregenomic RNA.","volume":"238","author":"G\u00fcnther","year":"1997","journal-title":"Virology"},{"key":"B54","doi-asserted-by":"publisher","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":"B55","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1002\/hep.29463","article-title":"Hepatitis B virus pregenomic RNA in hepatocellular carcinoma: a nosological and prognostic determinant.","volume":"67","author":"Halgand","year":"2018","journal-title":"Hepatology"},{"key":"B56","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1002\/hep.20748","article-title":"Functional analysis of hepatitis B virus reactivating in hepatitis B surface antigen-negative individuals.","volume":"42","author":"Hass","year":"2005","journal-title":"Hepatology"},{"key":"B57","doi-asserted-by":"publisher","first-page":"e01032","DOI":"10.1128\/JVI.01032-19","article-title":"Revisiting hepatitis B virus: challenges of curative therapies.","volume":"93","author":"Hu","year":"2019","journal-title":"J. Virol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jcv.2017.12.016","article-title":"Serum HBV DNA plus RNA shows superiority in reflecting the activity of intrahepatic cccDNA in treatment-naive HBV-infected individuals.","author":"Huang","year":"2018","journal-title":"J. Clin. Virol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"207","DOI":"10.3389\/fmicb.2019.00207","article-title":"Cell type diversity in hepatitis B virus RNA splicing and its regulation.","volume":"10","author":"Ito","year":"2019","journal-title":"Front. Microbiol."},{"key":"B60","doi-asserted-by":"crossref","first-page":"10478","DOI":"10.1038\/srep10478","article-title":"Comprehensive DNA methylation analysis of hepatitis B virus genome in infected liver tissues.","volume":"5","author":"Jain","year":"2015","journal-title":"Sci. Rep."},{"key":"B61","doi-asserted-by":"publisher","first-page":"5502","DOI":"10.1128\/jvi.74.12.5502-5508.2000","article-title":"Evidence that the 5\u2019-end cap structure is essential for encapsidation of hepatitis B virus pregenomic RNA.","volume":"74","author":"Jeong","year":"2000","journal-title":"J. Virol."},{"key":"B62","doi-asserted-by":"crossref","first-page":"8055","DOI":"10.1038\/s41598-018-26414-4","article-title":"Distinctiveness in virological features and pathogenic potentials of subgenotypes D1, D2, D3 and D5 of Hepatitis B virus.","volume":"8","author":"Khatun","year":"2018","journal-title":"Sci. Rep."},{"key":"B63","doi-asserted-by":"publisher","first-page":"7657","DOI":"10.3748\/wjg.v23.i43.7657","article-title":"Functional interaction of endoplasmic reticulum stress and hepatitis B virus in the pathogenesis of liver diseases.","volume":"23","author":"Kim","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"e1007124","DOI":"10.1371\/journal.ppat.1007124","article-title":"Flap endonuclease 1 is involved in cccDNA formation in the hepatitis B virus.","volume":"14","author":"Kitamura","year":"2018","journal-title":"PLoS Pathog"},{"key":"B65","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.3390\/ijms16023307","article-title":"Significant roles of regulatory T cells and myeloid derived suppressor cells in hepatitis B virus persistent infection and hepatitis B virus-related HCCs.","volume":"16","author":"Kondo","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"B66","doi-asserted-by":"crossref","first-page":"E4244","DOI":"10.1073\/pnas.1409986111","article-title":"Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses.","volume":"111","author":"Koniger","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B67","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1159\/000360947","article-title":"Genotypes and genetic variability of hepatitis B virus.","volume":"57","author":"Kramvis","year":"2014","journal-title":"Intervirology"},{"key":"B68","doi-asserted-by":"crossref","first-page":"e680","DOI":"10.1128\/AAC.00680-17","article-title":"Hepatitis B virus capsid assembly modulators, but not nucleoside analogs, inhibit the production of extracellular pregenomic RNA and spliced RNA variants.","volume":"61","author":"Lam","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"B69","doi-asserted-by":"crossref","first-page":"271","DOI":"10.14218\/JCTH.2015.00024","article-title":"IL-6 plays a crucial role in HBV infection.","volume":"3","author":"Lan","year":"2015","journal-title":"J. Clin. Transl. Hepatol."},{"key":"B70","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1056\/NEJMoa043470","article-title":"Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.","volume":"352","author":"Lau","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"B71","doi-asserted-by":"publisher","first-page":"433","DOI":"10.3389\/fmicb.2014.00433","article-title":"Modulation of the unfolded protein response by the human hepatitis B virus.","volume":"5","author":"Lazar","year":"2014","journal-title":"Front. Microbiol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"778","DOI":"10.3390\/v11090778","article-title":"Immune-escape hepatitis B virus mutations associated with viral reactivation upon immunosuppression.","volume":"11","author":"Lazarevic","year":"2019","journal-title":"Viruses"},{"key":"B73","doi-asserted-by":"publisher","first-page":"5573","DOI":"10.1128\/jvi.72.7.5573-5578.1998","article-title":"Role of the pre-S2 domain of the large envelope protein in hepatitis B virus assembly and infectivity.","volume":"72","author":"Le Seyec","year":"1998","journal-title":"J. Virol."},{"key":"B74","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.1128\/jvi.73.3.2052-2057.1999","article-title":"Infection process of the hepatitis B virus depends on the presence of a defined sequence in the pre-S1 domain.","volume":"73","author":"Le Seyec","year":"1999","journal-title":"J. Virol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"289","DOI":"10.3748\/wjg.v5.i4.289","article-title":"Establishment and characterization of four human hepatocellular carcinoma cell lines containing hepatitis B virus DNA.","volume":"5","author":"Lee","year":"1999","journal-title":"World J. Gastroenterol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"15460","DOI":"10.1074\/jbc.m309280200","article-title":"Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells.","volume":"279","author":"Lee","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B77","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.3389\/fimmu.2020.01037","article-title":"Anti-PD-1\/PD-L1 blockade immunotherapy employed in treating hepatitis B virus infection-related advanced hepatocellular carcinoma: a literature review.","volume":"11","author":"Li","year":"2020","journal-title":"Front. Immunol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1128\/jvi.02831-12","article-title":"Hepatitis B virus mRNA-mediated miR-122 inhibition upregulates PTTG1-binding protein, which promotes hepatocellular carcinoma tumor growth and cell invasion.","volume":"87","author":"Li","year":"2013","journal-title":"J. Virol."},{"key":"B79","first-page":"67","article-title":"Regulatory T-cells promote hepatitis B virus infection and hepatocellular carcinoma progression.","volume":"2","author":"Li","year":"2016","journal-title":"Chronic Dis. Transl. Med."},{"key":"B80","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1002\/hep.22881","article-title":"Hepatitis B: the virus and disease.","volume":"49","author":"Liang","year":"2009","journal-title":"Hepatology"},{"key":"B81","doi-asserted-by":"crossref","first-page":"a021436","DOI":"10.1101\/cshperspect.a021436","article-title":"Hepatitis B virus genotypes and variants.","volume":"5","author":"Lin","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B82","doi-asserted-by":"crossref","first-page":"e1275","DOI":"10.1128\/JCM.01275-19","article-title":"Diagnostic value of detection of pregenomic RNA in sera of hepatitis B virus-infected patients with different clinical outcomes.","volume":"58","author":"Lin","year":"2020","journal-title":"J. Clin. Microbiol."},{"key":"B83","first-page":"11","article-title":"Structural and functional analysis of 2.2 kb spliced variant of hepatitis B virus genomes isolated from liver tissues from hepatocellular carcinoma patients.","volume":"16","author":"Lin","year":"2002","journal-title":"Zhonghua Shi YanHe Lin Chuang Bing Du Xue Za Zhi"},{"key":"B84","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/hep.30607","article-title":"Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and Up-regulate programmed death ligand 1 expression in macrophages.","volume":"70","author":"Liu","year":"2019","journal-title":"Hepatology"},{"key":"B85","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s12876-019-0966-4","article-title":"Serum HBV RNA quantification: useful for monitoring natural history of chronic hepatitis B infection.","volume":"19","author":"Liu","year":"2019","journal-title":"BMC Gastroenterol"},{"key":"B86","doi-asserted-by":"publisher","first-page":"e1006784","DOI":"10.1371\/journal.ppat.1006784","article-title":"The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation.","volume":"13","author":"Long","year":"2017","journal-title":"PLoS Pathog."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1126\/science.1243462","article-title":"Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.","volume":"343","author":"Lucifora","year":"2014","journal-title":"Science"},{"key":"B88","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1073\/pnas.0409332102","article-title":"Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection.","volume":"102","author":"Mason","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B89","doi-asserted-by":"publisher","first-page":"8308","DOI":"10.1128\/jvi.00833-10","article-title":"Clonal expansion of normal-appearing human hepatocytes during chronic hepatitis B virus infection.","volume":"84","author":"Mason","year":"2010","journal-title":"J. Virol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"8396","DOI":"10.1128\/jvi.00700-09","article-title":"Detection of clonally expanded hepatocytes in chimpanzees with chronic hepatitis B virus infection.","volume":"83","author":"Mason","year":"2009","journal-title":"J. Virol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1007\/s12072-008-9112-z","article-title":"The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B.","volume":"3","author":"McMahon","year":"2009","journal-title":"Hepatol. Int."},{"key":"B92","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1146\/annurev.physiol.64.082201.100300","article-title":"Bile salt transporters.","volume":"64","author":"Meier","year":"2002","journal-title":"Annu. Rev. Physiol."},{"key":"B93","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3748\/wjg.v16.i2.225","article-title":"Prevalence of occult hepatitis B virus infection in haemodialysis patients from central Greece.","volume":"16","author":"Mina","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"B94","doi-asserted-by":"crossref","first-page":"9653","DOI":"10.1038\/s41598-017-09965-w","article-title":"Synergistic impact of mutations in hepatitis B virus genome contribute to its occult phenotype in chronic hepatitis C virus carriers.","volume":"7","author":"Mondal","year":"2017","journal-title":"Sci. Rep."},{"key":"B95","doi-asserted-by":"publisher","first-page":"4107","DOI":"10.1128\/jvi.66.7.4107-4116.1992","article-title":"The arginine-rich domain of the hepatitis B virus core protein is required for pregenome encapsidation and productive viral positive-strand DNA synthesis but not for virus assembly.","volume":"66","author":"Nassal","year":"1992","journal-title":"J. Virol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.virusres.2007.12.024","article-title":"Hepatitis B viruses: reverse transcription a different way.","volume":"134","author":"Nassal","year":"2008","journal-title":"Virus Res."},{"key":"B97","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1056\/nejm199605303342202","article-title":"Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.","volume":"334","author":"Niederau","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"B98","doi-asserted-by":"publisher","first-page":"10307","DOI":"10.1128\/jvi.00996-06","article-title":"Molecular evolution of hepatitis B virus over 25 years.","volume":"80","author":"Osiowy","year":"2006","journal-title":"J. Virol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1128\/jvi.61.3.782-786.1987","article-title":"Regulation of secretion of the hepatitis B virus major surface antigen by the preS-1 protein.","volume":"61","author":"Ou","year":"1987","journal-title":"J. Virol."},{"key":"B100","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/apt.15226","article-title":"Myeloid-derived suppressor cells induce regulatory T cells in chronically HBV infected patients with high levels of hepatitis B surface antigen and persist after antiviral therapy.","volume":"49","author":"Pal","year":"2019","journal-title":"Aliment Pharmacol. Ther."},{"key":"B101","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.ijid.2021.02.116","article-title":"Factors and virological significance of hepatitis B virus pregenomic RNA status after 5 years of antiviral therapy.","volume":"105","author":"Pan","year":"2021","journal-title":"Int. J. Infect. Dis."},{"key":"B102","doi-asserted-by":"publisher","first-page":"101","DOI":"10.5009\/gnl.2007.1.2.101","article-title":"Molecular pathogenesis of hepatitis-B-virus-associated hepatocellular carcinoma.","volume":"1","author":"Park","year":"2007","journal-title":"Gut Liver"},{"key":"B103","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1111\/j.1462-5822.2009.01363.x","article-title":"Morphogenesis of hepatitis B virus and its subviral envelope particles.","volume":"11","author":"Patient","year":"2009","journal-title":"Cell Microbiol."},{"key":"B104","doi-asserted-by":"crossref","first-page":"S125","DOI":"10.1016\/S1386-6532(05)80021-6","article-title":"The concept of hepatitis B virus mutant escape.","volume":"34","author":"Pawlotsky","year":"2005","journal-title":"J. Clin. Virol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"e0220376","DOI":"10.1371\/journal.pone.0220376","article-title":"Genomic modeling of hepatitis B virus integration frequency in the human genome.","volume":"14","author":"Podlaha","year":"2019","journal-title":"PLoS One"},{"key":"B106","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1096\/fj.14-258715","article-title":"Alternative splicing-regulated protein of hepatitis B virus hacks the TNF-alpha-stimulated signaling pathways and limits the extent of liver inflammation.","volume":"29","author":"Pol","year":"2015","journal-title":"FASEB J."},{"key":"B107","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.jhep.2014.04.041","article-title":"Hepatitis B virus PreS\/S gene variants: pathobiology and clinical implications.","volume":"61","author":"Pollicino","year":"2014","journal-title":"J. Hepatol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"e1005893","DOI":"10.1371\/journal.ppat.1005893","article-title":"DNA polymerase kappa is a key cellular factor for the formation of covalently closed circular DNA of hepatitis B virus.","volume":"12","author":"Qi","year":"2016","journal-title":"PLoS Pathog"},{"key":"B109","doi-asserted-by":"publisher","first-page":"425","DOI":"10.3748\/wjg.v20.i2.425","article-title":"Core promoter: a critical region where the hepatitis B virus makes decisions.","volume":"20","author":"Quarleri","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"B110","doi-asserted-by":"crossref","first-page":"10833","DOI":"10.1038\/srep10833","article-title":"CRISPR\/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus.","volume":"5","author":"Ramanan","year":"2015","journal-title":"Sci. Rep."},{"key":"B111","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.jhep.2015.06.023","article-title":"HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase.","volume":"63","author":"Riviere","year":"2015","journal-title":"J. Hepatol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/0270-9139(95)90346-1","article-title":"In vivo and in vitro expression of defective hepatitis B virus particles generated by spliced hepatitis B virus RNA.","volume":"22","author":"Rosmorduc","year":"1995","journal-title":"Hepatology"},{"key":"B113","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1136\/gutjnl-2019-319637","article-title":"Hepatitis B protein HBx binds the DLEU2 lncRNA to sustain cccDNA and host cancer-related gene transcription.","volume":"69","author":"Salerno","year":"2020","journal-title":"Gut"},{"key":"B114","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1053\/gast.2002.37041","article-title":"Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients.","volume":"123","author":"Sanchez-Tapias","year":"2002","journal-title":"Gastroenterology"},{"key":"B115","doi-asserted-by":"publisher","first-page":"a021394","DOI":"10.1101\/cshperspect.a021394","article-title":"Assembly and Release of Hepatitis B Virus.","volume":"5","author":"Selzer","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B116","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1002\/hep.30548","article-title":"Exosomal interferon-induced transmembrane protein 2 transmitted to dendritic cells inhibits interferon alpha pathway activation and blocks anti-hepatitis B virus efficacy of exogenous interferon alpha.","volume":"69","author":"Shi","year":"2019","journal-title":"Hepatology"},{"key":"B117","doi-asserted-by":"publisher","first-page":"15467","DOI":"10.1128\/jvi.79.24.15467-15476.2005","article-title":"Recombination in the genesis and evolution of hepatitis B virus genotypes.","volume":"79","author":"Simmonds","year":"2005","journal-title":"J. Virol."},{"key":"B118","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.virol.2016.06.024","article-title":"Cellular uptake of hepatitis B virus envelope L particles is independent of sodium taurocholate cotransporting polypeptide, but dependent on heparan sulfate proteoglycan.","volume":"497","author":"Somiya","year":"2016","journal-title":"Virology"},{"key":"B119","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1006\/viro.2000.0331","article-title":"Genotype-specific synthesis and secretion of spliced hepatitis B virus genomes in hepatoma cells.","volume":"271","author":"Sommer","year":"2000","journal-title":"Virology"},{"key":"B120","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/s0168-8278(02)00422-1","article-title":"The expression of hepatitis B spliced protein (HBSP) encoded by a spliced hepatitis B virus RNA is associated with viral replication and liver fibrosis.","volume":"38","author":"Soussan","year":"2003","journal-title":"J. Hepatol."},{"key":"B121","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1111\/j.1440-1746.2008.05348.x","article-title":"Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection.","volume":"23","author":"Su","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B122","doi-asserted-by":"publisher","first-page":"4011","DOI":"10.1128\/jvi.63.9.4011-4018.1989","article-title":"Hepatitis B virus transcript produced by RNA splicing.","volume":"63","author":"Su","year":"1989","journal-title":"J. Virol."},{"key":"B123","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1128\/jvi.65.3.1310-1317.1991","article-title":"Morphogenetic and regulatory effects of mutations in the envelope proteins of an avian hepadnavirus.","volume":"65","author":"Summers","year":"1991","journal-title":"J. Virol."},{"key":"B124","doi-asserted-by":"crossref","first-page":"23237","DOI":"10.1038\/srep23237","article-title":"Mutual antagonism between hepatitis B viral mRNA and host microRNA let-7.","volume":"6","author":"Takata","year":"2016","journal-title":"Sci. Rep."},{"key":"B125","doi-asserted-by":"crossref","first-page":"a021428","DOI":"10.1101\/cshperspect.a021428","article-title":"Immune response in hepatitis B virus infection.","volume":"5","author":"Tan","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B126","doi-asserted-by":"publisher","first-page":"e1007742","DOI":"10.1371\/journal.ppat.1007742","article-title":"DNA polymerase alpha is essential for intracellular amplification of hepatitis B virus covalently closed circular DNA.","volume":"15","author":"Tang","year":"2019","journal-title":"PLoS Pathog"},{"key":"B127","doi-asserted-by":"publisher","first-page":"5539","DOI":"10.1128\/jvi.65.10.5539-5543.1991","article-title":"Defective hepatitis B virus particles are generated by packaging and reverse transcription of spliced viral RNAs in vivo.","volume":"65","author":"Terr\u00e9","year":"1991","journal-title":"J. Virol."},{"key":"B128","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1046\/j.1440-1746.2002.02605.x","article-title":"Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent.","volume":"17","author":"Thukar","year":"2002","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B129","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1006\/viro.2002.1448","article-title":"Restoration of replication phenotype of lamivudine resistant hepatitis B virus mutants by compensatory changes in the \u201cfingers\u201d subdomain of the viral polymerase selected as a consequence of mutations in the overlapping S gene.","volume":"299","author":"Torresi","year":"2002","journal-title":"Virology"},{"key":"B130","first-page":"700","article-title":"Immunological mechanisms of hepatitis B virus persistence in newborns.","volume":"138","author":"Trehanpati","year":"2013","journal-title":"Indian J. Med. Res."},{"key":"B131","doi-asserted-by":"crossref","first-page":"35056","DOI":"10.1038\/srep35056","article-title":"Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival.","volume":"6","author":"Tu","year":"2016","journal-title":"Sci. Rep."},{"key":"B132","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1158\/2326-6066.CIR-18-0277","article-title":"T cell-inflamed versus Non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection.","volume":"6","author":"Trujillo","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"B133","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1128\/jvi.37.1.239-243.1981","article-title":"Integration pattern of hepatitis B virus DNA sequences in human hepatoma cell lines.","volume":"37","author":"Twist","year":"1981","journal-title":"J. Virol."},{"key":"B134","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1038\/280815a0","article-title":"Nucleotide sequence of the gene coding for the major protein of hepatitis B virus surface antigen.","volume":"280","author":"Valenzuela","year":"1979","journal-title":"Nature"},{"key":"B135","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1111\/jvh.12498","article-title":"Characterization of hepatitis B virus surface antigen variability and impact on HBs antigen clearance under nucleos(t)ide analogue therapy.","volume":"23","author":"Velay","year":"2016","journal-title":"J. Viral. Hepat."},{"key":"B136","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/j.1365-2893.2005.00581.x","article-title":"Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States.","volume":"12","author":"Wai","year":"2005","journal-title":"J. Viral. Hepat."},{"key":"B137","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1016\/s0002-9440(10)63599-7","article-title":"Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress.","volume":"163","author":"Wang","year":"2003","journal-title":"Am. J. Pathol."},{"key":"B138","doi-asserted-by":"publisher","first-page":"3454","DOI":"10.1128\/jvi.02164-09","article-title":"Distinct hepatitis B virus dynamics in the immunotolerant and early immunoclearance phases.","volume":"84","author":"Wang","year":"2010","journal-title":"J. Virol."},{"key":"B139","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jhep.2017.08.021","article-title":"Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients.","volume":"68","author":"Wang","year":"","journal-title":"J Hepatol"},{"key":"B140","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1111\/jvh.12908","article-title":"Natural history of serum HBV-RNA in chronic HBV infection.","volume":"25","author":"Wang","year":"","journal-title":"J Viral Hepat"},{"key":"B141","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ijid.2019.12.026","article-title":"Occurrence of occult hepatitis B virus infection associated with envelope protein mutations according to anti-HBs carriage in blood donors.","volume":"92","author":"Wang","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"B142","doi-asserted-by":"publisher","first-page":"18484","DOI":"10.1074\/jbc.m113.458158","article-title":"Hepatitis B viral RNA directly mediates down-regulation of the tumor suppressor microRNA miR-15a\/miR-16-1 in hepatocytes.","volume":"288","author":"Wang","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B143","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.jcv.2004.10.008","article-title":"Genetic variability of the S gene of hepatitis B virus: clinical and diagnostic impact.","volume":"32","author":"Weber","year":"2005","journal-title":"J. Clin. Virol."},{"key":"B144","doi-asserted-by":"publisher","first-page":"2994","DOI":"10.1128\/jvi.68.5.2994-2999.1994","article-title":"Hepadnavirus P protein utilizes a tyrosine residue in the TP domain to prime reverse transcription.","volume":"68","author":"Weber","year":"1994","journal-title":"J. Virol."},{"key":"B145","volume-title":"World\u2019s Hepatitis Day.","year":"2020"},{"key":"B146","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1128\/jvi.61.3.904-911.1987","article-title":"Replication strategy of human hepatitis B virus.","volume":"61","author":"Will","year":"1987","journal-title":"J. Virol."},{"key":"B147","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1099\/vir.0.012740-0","article-title":"Biological significance of amino acid substitutions in hepatitis B surface antigen (HBsAg) for glycosylation, secretion, antigenicity and immunogenicity of HBsAg and hepatitis B virus replication.","volume":"91","author":"Wu","year":"2010","journal-title":"J. Gen. Virol."},{"key":"B148","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1128\/jvi.65.4.1680-1686.1991","article-title":"Characterization and genetic analysis of alternatively spliced transcripts of hepatitis B virus in infected human liver tissues and transfected HepG2cells.","volume":"65","author":"Wu","year":"1991","journal-title":"J. Virol."},{"key":"B149","doi-asserted-by":"crossref","first-page":"e1273","DOI":"10.1128\/JVI.01273-18","article-title":"Hepatitis B spliced protein (HBSP) suppresses fas-mediated hepatocyte Apoptosis via activation of PI3K\/Akt signaling.","volume":"92","author":"Wu","year":"2018","journal-title":"J. Virol."},{"key":"B150","doi-asserted-by":"publisher","first-page":"104824","DOI":"10.1016\/j.antiviral.2020.104824","article-title":"Hepatitis B virus cccDNA: formation, regulation and therapeutic potential.","volume":"180","author":"Xia","year":"2020","journal-title":"Antiviral. Res."},{"key":"B151","doi-asserted-by":"publisher","first-page":"7387","DOI":"10.1128\/jvi.71.10.7387-7392.1997","article-title":"Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum.","volume":"71","author":"Xu","year":"1997","journal-title":"J. Virol."},{"key":"B152","doi-asserted-by":"publisher","first-page":"2559","DOI":"10.1128\/jvi.67.5.2559-2565.1993","article-title":"A transcription initiation site for the hepatitis B virus X gene is directed by the promoter binding protein.","volume":"67","author":"Yaginuma","year":"1993","journal-title":"J. Virol."},{"key":"B153","first-page":"e00049","article-title":"Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.","volume":"13","author":"Yan","year":"2012"},{"key":"B154","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.omtn.2020.03.005","article-title":"Permanent inactivation of HBV genomes by CRISPR\/Cas9-mediated non-cleavage base editing.","volume":"20","author":"Yang","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"B155","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1093\/nsr\/nwu038","article-title":"The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma.","volume":"1","author":"Yang","year":"2014","journal-title":"Nat. Sci. Rev."},{"key":"B156","doi-asserted-by":"publisher","first-page":"23346","DOI":"10.18632\/oncotarget.8109","article-title":"Hepatitis B virus PreS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability.","volume":"7","author":"Yen","year":"2016","journal-title":"Oncotarget"},{"key":"B157","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.lab.2005.10.003","article-title":"Effects of hepatitis B virus X protein on the development of liver cancer.","volume":"147","author":"Zhang","year":"2006","journal-title":"J. Lab Clin. Med."},{"key":"B158","doi-asserted-by":"publisher","first-page":"e56711","DOI":"10.1371\/journal.pone.0056711","article-title":"Comparative analysis of CpG islands among HBV genotypes.","volume":"8","author":"Zhang","year":"2013","journal-title":"PLoS One"},{"key":"B159","doi-asserted-by":"publisher","first-page":"e110442","DOI":"10.1371\/journal.pone.0110442","article-title":"Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection.","volume":"9","author":"Zhang","year":"2014","journal-title":"PLoS One"},{"key":"B160","doi-asserted-by":"publisher","first-page":"100034","DOI":"10.1016\/j.xinn.2020.100034","article-title":"Insights into hepatitis B virus DNA integration-55 years after virus discovery.","volume":"1","author":"Zhao","year":"2020","journal-title":"Innovation"},{"key":"B161","doi-asserted-by":"crossref","first-page":"12992","DOI":"10.1038\/ncomms12992","article-title":"Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma [published correction appears in Nat Commun. 2016 Nov 08;7:13591. Lee, TP [corrected to Lee, TL]].","volume":"7","author":"Zhao","year":"2016","journal-title":"Nat. Commun."},{"key":"B162","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/j.virol.2004.08.033","article-title":"Mutant hepatitis B virus surface antigens (HBsAg) are immunogenic but may have a changed specificity.","volume":"329","author":"Zheng","year":"2004","journal-title":"Virology"},{"key":"B163","doi-asserted-by":"crossref","first-page":"e36068","DOI":"10.5812\/hepatmon.36068","article-title":"Interleukin-7 in patients with chronic hepatitis B may have effect on T follicular helper cells and specific cellular immunity.","volume":"16","author":"Zhong","year":"2016","journal-title":"Hepat Mon."},{"key":"B164","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s00239-007-0054-1","article-title":"Bayesian estimates of the evolutionary rate and age of hepatitis B virus.","volume":"65","author":"Zhou","year":"2007","journal-title":"J. Mol. Evol."},{"key":"B165","doi-asserted-by":"crossref","first-page":"258","DOI":"10.14218\/JCTH.2018.00054","article-title":"HBV cccDNA and its potential as a therapeutic target.","volume":"7","author":"Zhu","year":"2019","journal-title":"J. Clin. Transl. Hepatol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.678537\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T08:32:22Z","timestamp":1699432342000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.678537\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,30]]},"references-count":165,"alternative-id":["10.3389\/fmicb.2021.678537"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.678537","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,30]]},"article-number":"678537"}}