{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:56:07Z","timestamp":1787064967214,"version":"build-2736575974"},"reference-count":132,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gothenburg University\/Sahlgrenska Academy","award":["ALF71620"],"award-info":[{"award-number":["ALF71620"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hepatitis B virus infections are the main reason for hepatocellular carcinoma development. Current treatment reduces the viral load but rarely leads to virus elimination. Despite its medical importance, little is known about infection dynamics on the cellular level not at least due to technical obstacles. Regardless of infections leading to extreme viral loads, which may reach 1010 virions per mL serum, hepatitis B viruses are of low abundance and productivity in individual cells. Imaging of the infections in cells is thus a particular challenge especially for cccDNA that exists only in a few copies. The review describes the significance of microscopical approaches on genome and transcript detection for understanding hepatitis B virus infections, implications for understanding treatment outcomes, and recent microscopical approaches, which have not been applied in HBV research.<\/jats:p>","DOI":"10.3390\/v14030557","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T01:50:53Z","timestamp":1646790653000},"page":"557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Imaging of Hepatitis B Virus Nucleic Acids: Current Advances and Challenges"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3144-2656","authenticated-orcid":false,"given":"Luisa F.","family":"Bustamante-Jaramillo","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7305-1026","authenticated-orcid":false,"given":"Joshua","family":"Fingal","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2762-6102","authenticated-orcid":false,"given":"Marie-Lise","family":"Blondot","sequence":"additional","affiliation":[{"name":"Microbiologie Fondamentale et Pathog\u00e9nicit\u00e9 (MFP), CNRS UMR 5234, University of Bordeaux, 33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-2251","authenticated-orcid":false,"given":"Gustaf E.","family":"Rydell","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kann","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden"},{"name":"Region V\u00e4stra G\u00f6taland, Department of Clinical Microbiology, Sahlgrenska University Hospital, 405 30 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1016\/S0140-6736(18)31865-8","article-title":"Chronic hepatitis B virus infection","volume":"392","author":"Seto","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"(2017). EASL, EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol., 67, 370\u2013398.","DOI":"10.1016\/j.jhep.2017.03.021"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.virol.2015.02.031","article-title":"Molecular biology of hepatitis B virus infection","volume":"479\u2013480","author":"Seeger","year":"2015","journal-title":"Virology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1053\/j.gastro.2018.01.034","article-title":"Hepatitis B Virus Does Not Interfere with Innate Immune Responses in the Human Liver","volume":"154","author":"Suslov","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1038\/s12276-021-00579-x","article-title":"Hepatocyte organoids and cell transplantation: What the future holds","volume":"53","author":"Peng","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1073\/pnas.0308478100","article-title":"Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees","volume":"101","author":"Wieland","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9369","DOI":"10.1128\/JVI.79.15.9369-9380.2005","article-title":"Stealth and cunning: Hepatitis B and hepatitis C viruses","volume":"79","author":"Wieland","year":"2005","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1007\/s10620-014-3486-7","article-title":"Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection","volume":"60","author":"Buti","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/1743-422X-8-111","article-title":"Comparison of the efficacy of tenofovir and adefovir in the treatment of chronic hepatitis B: A systematic review","volume":"8","author":"Zhao","year":"2011","journal-title":"Virol. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1086\/656528","article-title":"Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections","volume":"202","author":"Ribeiro","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7177","DOI":"10.1073\/pnas.1606091113","article-title":"Asymmetric partitioning of transfected DNA during mammalian cell division","volume":"113","author":"Wang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1136\/gutjnl-2016-312162","article-title":"Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo","volume":"67","author":"Allweiss","year":"2018","journal-title":"Gut"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Allweiss, L., and Dandri, M. (2017). The Role of cccDNA in HBV Maintenance. Viruses, 9.","DOI":"10.3390\/v9060156"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"veaa063","DOI":"10.1093\/ve\/veaa063","article-title":"Estimating hepatitis B virus cccDNA persistence in chronic infection","volume":"7","author":"Lythgoe","year":"2021","journal-title":"Virus Evol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/hep.31240","article-title":"Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature-Mutation in Treated Chronic Hepatitis B Patients","volume":"73","author":"Huang","year":"2021","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1128\/JVI.01587-08","article-title":"The amount of hepatocyte turnover that occurred during resolution of transient hepadnavirus infections was lower when virus replication was inhibited with entecavir","volume":"83","author":"Mason","year":"2009","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17780","DOI":"10.1073\/pnas.0508913102","article-title":"Dynamics of hepatitis B virus clearance in chimpanzees","volume":"102","author":"Murray","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11652","DOI":"10.1073\/pnas.1635109100","article-title":"Hepatocyte turnover during resolution of a transient hepadnaviral infection","volume":"100","author":"Summers","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41575-020-0342-4","article-title":"Liver regeneration: Biological and pathological mechanisms and implications","volume":"18","author":"Michalopoulos","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e140584","DOI":"10.1172\/jci.insight.140584","article-title":"Single hepatocytes show persistence and transcriptional inactivity of hepatitis B","volume":"5","author":"Balagopal","year":"2020","journal-title":"JCI Insight"},{"key":"ref_21","first-page":"20","article-title":"Earliest hepatitis B virus-hepatocyte genome integration: Sites, mechanism, and significance in carcinogenesis","volume":"7","author":"Chauhan","year":"2021","journal-title":"Hepatoma Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.coviro.2018.01.011","article-title":"Impact of integrated viral DNA on the goal to clear hepatitis B surface antigen with different therapeutic strategies","volume":"30","author":"Lindh","year":"2018","journal-title":"Curr. Opin. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1093\/nar\/gkz1118","article-title":"STRIDE\u2014A fluorescence method for direct, specific in situ detection of individual single- or double-strand DNA breaks in fixed cells","volume":"48","author":"Kordon","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10993","DOI":"10.7150\/thno.43094","article-title":"CRISPR-Sunspot: Imaging of endogenous low-abundance RNA at the single-molecule level in live cells","volume":"10","author":"Sun","year":"2020","journal-title":"Theranostics"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Rydell, G.E., Prakash, K., Larsson, S.B., Skoglund, C., Ringlander, J., Andersson, M., Castedal, M., Norder, H., and Lindh, M. (2021). Quantification of viral RNA in multiple pieces of explant liver tissue shows distinct focal differences of hepatitis B infection. J. Infect. Dis., jiab469.","DOI":"10.1093\/infdis\/jiab469"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10756","DOI":"10.1021\/acs.analchem.1c02227","article-title":"CRISPR Technique Incorporated with Single-Cell RNA Sequencing for Studying Hepatitis B Infection","volume":"93","author":"Le","year":"2021","journal-title":"Anal. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1136\/gutjnl-2021-324554","article-title":"Alternative splicing of viral transcripts: The dark side of HBV","volume":"70","author":"Kremsdorf","year":"2021","journal-title":"Gut"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhao, W., Zhao, S., Li, L., Huang, X., Xing, S., Zhang, Y., Qiu, G., Han, Z., Shang, Y., and Sun, D.E. (2021). Sparse deconvolution improves the resolution of live-cell super-resolution fluorescence microscopy. Nat. Biotechnol.","DOI":"10.1038\/s41587-021-01092-2"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1128\/jvi.69.6.3350-3357.1995","article-title":"The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes","volume":"69","author":"Newbold","year":"1995","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1006\/jmbi.2000.4481","article-title":"Structural organization of the hepatitis B virus minichromosome","volume":"307","author":"Bock","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/jmv.1890080106","article-title":"Detection of hepatitis B virus DNA sequences in infected hepatocytes by in situ cytohybridisation","volume":"8","author":"Gowans","year":"1981","journal-title":"J. Med. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/hep.1840040104","article-title":"Correlation between liver histology and markers of hepatitis B virus replication in infected patients: A study by in situ hybridization","volume":"4","author":"Burrell","year":"1984","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6685","DOI":"10.1073\/pnas.80.21.6685","article-title":"Detection of hepatitis B virus DNA in hepatocytes, bile duct epithelium, and vascular elements by in situ hybridization","volume":"80","author":"Blum","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1099\/0022-1317-64-6-1229","article-title":"Patterns of single- and double-stranded hepatitis B virus DNA and viral antigen accumulation in infected liver cells","volume":"64","author":"Gowans","year":"1983","journal-title":"J. Gen. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0042-6822(84)90332-5","article-title":"Asymmetric replication of hepatitis B virus DNA in human liver: Demonstration of cytoplasmic minus-strand DNA by blot analyses and in situ hybridization","volume":"139","author":"Blum","year":"1984","journal-title":"Virology"},{"key":"ref_36","first-page":"411","article-title":"Hepatitis B virus DNA detected in formalin-fixed liver specimens and its relation to serologic markers and histopathologic features in chronic liver disease","volume":"120","author":"Rijntjes","year":"1985","journal-title":"Am. J. Pathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/jmv.1890150407","article-title":"Detection of HBV-DNA by in situ hybridization using a biotin-labeled probe","volume":"15","author":"Negro","year":"1985","journal-title":"J. Med. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0168-8278(05)80572-0","article-title":"Identification of hepatitis B virus-DNA in the liver by in situ hybridization using a biotinylated probe. Relation to HBcAg expression and histology","volume":"19","author":"Naoumov","year":"1993","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0166-0934(92)90023-7","article-title":"Simultaneous detection of HBV-specific antigens and DNA in paraffin-embedded liver tissue by immunohistochemistry and in situ hybridization using a digoxigenin-labeled probe","volume":"37","author":"Han","year":"1992","journal-title":"J. Virol. Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5465","DOI":"10.1128\/JVI.02303-05","article-title":"Lipid-mediated introduction of hepatitis B virus capsids into nonsusceptible cells allows highly efficient replication and facilitates the study of early infection events","volume":"80","author":"Rabe","year":"2006","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9849","DOI":"10.1073\/pnas.1730940100","article-title":"Nuclear import of hepatitis B virus capsids and release of the viral genome","volume":"100","author":"Rabe","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"109288","DOI":"10.1016\/j.celrep.2021.109288","article-title":"Transcriptionally inactive hepatitis B virus episome DNA preferentially resides in the vicinity of chromosome 19 in 3D host genome upon infection","volume":"35","author":"Tang","year":"2021","journal-title":"Cell Rep."},{"key":"ref_43","doi-asserted-by":"crossref","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":"2017","journal-title":"J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.jhep.2016.10.009","article-title":"Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions","volume":"66","author":"Xia","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.omtm.2020.11.014","article-title":"CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice","volume":"20","author":"Stone","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1172\/JCI83339","article-title":"In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection","volume":"126","author":"Zhang","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1136\/jclinpath-2020-206440","article-title":"Clinical relevance of the in situ assay for HBV DNA: A cross-sectional study in patients with chronic hepatitis B","volume":"73","author":"Liu","year":"2020","journal-title":"J. Clin. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e27220","DOI":"10.1097\/MD.0000000000027220","article-title":"Evaluation of the in situ assay for HBV DNA: An observational real-world study in chronic hepatitis B","volume":"100","author":"Li","year":"2021","journal-title":"Medicine"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e98","DOI":"10.1038\/emi.2017.84","article-title":"Establishment of a fluorescent in situ hybridization assay for imaging hepatitis B virus nucleic acids in cell culture models","volume":"6","author":"Zhang","year":"2017","journal-title":"Emerg. Microbes Infect."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Yue, L., Li, C., Xu, M., Wu, M., Ding, J., Liu, J., Zhang, X., and Yuan, Z. (2021). Probing the spatiotemporal patterns of HBV multiplication reveals novel features of its subcellular processes. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009838"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5184","DOI":"10.1128\/JVI.03553-13","article-title":"Limited hepatitis B virus replication space in the chronically hepatitis C virus-infected liver","volume":"88","author":"Wieland","year":"2014","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1101\/gr.260018.119","article-title":"Background-suppressed live visualization of genomic loci with an improved CRISPR system based on a split fluorophore","volume":"30","author":"Chaudhary","year":"2020","journal-title":"Genome Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.cell.2014.09.039","article-title":"A protein-tagging system for signal amplification in gene expression and fluorescence imaging","volume":"159","author":"Tanenbaum","year":"2014","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.4161\/rna.35506","article-title":"RNA imaging in living cells\u2014Methods and applications","volume":"11","author":"Urbanek","year":"2014","journal-title":"RNA biology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fchem.2016.00029","article-title":"RNA Fluorescence with Light-Up Aptamers","volume":"4","author":"Ouellet","year":"2016","journal-title":"Front. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1038\/s41467-020-14932-7","article-title":"Live cell imaging of single RNA molecules with fluorogenic Mango II arrays","volume":"11","author":"Cawte","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"101801","DOI":"10.1016\/j.isci.2020.101801","article-title":"Recent Advances in the Molecular Beacon Technology for Live-Cell Single-Molecule Imaging","volume":"23","author":"Mao","year":"2020","journal-title":"iScience"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"963","DOI":"10.3390\/v4060963","article-title":"Application of live-cell RNA imaging techniques to the study of retroviral RNA trafficking","volume":"4","author":"Bann","year":"2012","journal-title":"Viruses"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1021\/acs.accounts.1c00276","article-title":"Quantum Dots: A Promising Fluorescent Label for Probing Virus Trafficking","volume":"54","author":"Wang","year":"2021","journal-title":"Acc. Chem. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1369\/0022155411398487","article-title":"Quantum dots in cell biology","volume":"59","author":"Barroso","year":"2011","journal-title":"J. Histochem. Cytochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/sj.ejhg.5201226","article-title":"The peptide nucleic acids (PNAs), powerful tools for molecular genetics and cytogenetics","volume":"12","author":"Pellestor","year":"2004","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3762\/bjoc.14.17","article-title":"Fluorogenic PNA probes","volume":"14","author":"Vilaivan","year":"2018","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1089\/108729001317022269","article-title":"PNA beacons for duplex DNA","volume":"11","author":"Kuhn","year":"2001","journal-title":"Antisense Nucleic Acid Drug Dev."},{"key":"ref_64","first-page":"119","article-title":"PNA openers and their applications","volume":"208","author":"Demidov","year":"2002","journal-title":"Methods Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.chom.2013.09.004","article-title":"Tracking viral genomes in host cells at single-molecule resolution","volume":"14","author":"Wang","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1128\/JVI.02639-14","article-title":"Nuclear import of adenovirus DNA involves direct interaction of hexon with an N-terminal domain of the nucleoporin Nup214","volume":"89","author":"Cassany","year":"2015","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1159\/000149646","article-title":"Cytoplasmic (but not nuclear) hepatitis B virus (HBV) core antigen reflects HBV DNA synthesis at the level of the infected hepatocyte","volume":"24","author":"Gowans","year":"1985","journal-title":"Intervirology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/S0140-6736(84)90703-7","article-title":"Molecular pathogenesis of hepatitis B virus infection: Simultaneous detection of viral DNA and antigens in paraffin-embedded liver sections","volume":"2","author":"Blum","year":"1984","journal-title":"Lancet"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.1600-0676.1992.tb01052.x","article-title":"In situ hybridization in viral hepatitis","volume":"12","author":"Negro","year":"1992","journal-title":"Liver"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/0092-8674(82)90157-X","article-title":"Replication of the genome of a hepatitis B\u2014Like virus by reverse transcription of an RNA intermediate","volume":"29","author":"Summers","year":"1982","journal-title":"Cell"},{"key":"ref_71","first-page":"633","article-title":"Detection of viral genomes in the liver by in situ hybridization using 35S-, bromodeoxyuridine-, and biotin-labeled probes","volume":"134","author":"Niedobitek","year":"1989","journal-title":"Am. J. Pathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1172\/JCI86650","article-title":"New perspectives on the hepatitis B virus life cycle in the human liver","volume":"126","author":"Revill","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_73","first-page":"330","article-title":"Das Fluoreszenzmikroskop","volume":"28","author":"Heimstadt","year":"1911","journal-title":"Z. Wiss Mikrosk."},{"key":"ref_74","first-page":"1010","article-title":"Das Fluoreszenzmikroskop","volume":"12","author":"Reichert","year":"1911","journal-title":"Phys. Z"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/0014-4827(80)90087-7","article-title":"A new method for fluorescence microscopical localisation of specific DNA sequences by in situ hybridization of fluorochromelabelled RNA","volume":"128","author":"Bauman","year":"1980","journal-title":"Exp. Cell Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4381","DOI":"10.1073\/pnas.79.14.4381","article-title":"Immunological method for mapping genes on Drosophila polytene chromosomes","volume":"79","author":"Levine","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e00722-18","DOI":"10.1128\/JVI.00722-18","article-title":"Hepatitis B Virus Deregulates the Cell Cycle to Promote Viral Replication and a Premalignant Phenotype","volume":"92","author":"Xia","year":"2018","journal-title":"J. Virol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1136\/gutjnl-2020-322571","article-title":"Therapeutic shutdown of HBV transcripts promotes reappearance of the SMC5\/6 complex and silencing of the viral genome in vivo","volume":"71","author":"Allweiss","year":"2021","journal-title":"Gut"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13072-018-0204-2","article-title":"Episomal HBV persistence within transcribed host nuclear chromatin compartments involves HBx","volume":"11","author":"Hensel","year":"2018","journal-title":"Epigenet. Chromatin"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e01391-17","DOI":"10.1128\/JVI.01391-17","article-title":"Distribution of Hepatitis B Virus Nuclear DNA","volume":"92","author":"Li","year":"2018","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2819","DOI":"10.1128\/jvi.64.6.2819-2824.1990","article-title":"Hepadnavirus envelope proteins regulate covalently closed circular DNA amplification","volume":"64","author":"Summers","year":"1990","journal-title":"J. Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"12372","DOI":"10.1073\/pnas.2033898100","article-title":"Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver","volume":"100","author":"Zhang","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jhep.2020.01.028","article-title":"Full-length 5\u2032RACE identifies all major HBV transcripts in HBV-infected hepatocytes and patient serum","volume":"73","author":"Stadelmayer","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_84","doi-asserted-by":"crossref","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":"ref_85","doi-asserted-by":"crossref","first-page":"22593","DOI":"10.1016\/S0021-9258(17)31687-3","article-title":"Novel short transcripts of hepatitis B virus X gene derived from intragenic promoter","volume":"269","author":"Zheng","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1002\/hep4.1507","article-title":"Hepatitis B Virus RNA Profiles in Liver Biopsies by Digital Polymerase Chain Reaction","volume":"4","author":"Prakash","year":"2020","journal-title":"Hepatol. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1126\/science.1138140","article-title":"CRISPR provides acquired resistance against viruses in prokaryotes","volume":"315","author":"Barrangou","year":"2007","journal-title":"Science"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-biochem-060815-014607","article-title":"CRISPR\/Cas9 in Genome Editing and Beyond","volume":"85","author":"Wang","year":"2016","journal-title":"Annu. Rev. Biochem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"bpy002","DOI":"10.1093\/biomethods\/bpy002","article-title":"Applications of the CRISPR\/Cas system beyond gene editing","volume":"3","author":"Anton","year":"2018","journal-title":"Biol. Methods Protocols"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"26077","DOI":"10.3390\/ijms161125950","article-title":"Application of CRISPR\/Cas9 Technology to HBV","volume":"16","author":"Lin","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.gpb.2018.10.001","article-title":"Progress and Challenges for Live-cell Imaging of Genomic Loci Using CRISPR-based Platforms","volume":"17","author":"Wu","year":"2019","journal-title":"Genom. Proteom. Bioinf."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5807","DOI":"10.1111\/jcmm.13925","article-title":"The applications of CRISPR\/Cas system in molecular detection","volume":"22","author":"Zhou","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1016\/j.cell.2013.12.001","article-title":"Dynamic imaging of genomic loci in living human cells by an optimized CRISPR\/Cas system","volume":"155","author":"Chen","year":"2013","journal-title":"Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"11870","DOI":"10.1073\/pnas.1515692112","article-title":"CASFISH: CRISPR\/Cas9-mediated in situ labeling of genomic loci in fixed cells","volume":"112","author":"Deng","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"14725","DOI":"10.1038\/ncomms14725","article-title":"Live cell imaging of low- and non-repetitive chromosome loci using CRISPR-Cas9","volume":"8","author":"Qin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"11707","DOI":"10.1038\/ncomms11707","article-title":"CRISPR-dCas9 and sgRNA scaffolds enable dual-colour live imaging of satellite sequences and repeat-enriched individual loci","volume":"7","author":"Fu","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nbt.3526","article-title":"Multiplexed labeling of genomic loci with dCas9 and engineered sgRNAs using CRISPRainbow","volume":"34","author":"Ma","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/s41592-018-0174-0","article-title":"CRISPR-Sirius: RNA Scaffolds for Signal Amplification in Genome Imaging","volume":"15","author":"Ma","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nature13769","article-title":"Programmable RNA recognition and cleavage by CRISPR\/Cas9","volume":"516","author":"Oakes","year":"2014","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.molcel.2019.10.024","article-title":"Dynamic Imaging of RNA in Living Cells by CRISPR-Cas13 Systems","volume":"76","author":"Yang","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1126\/science.1207339","article-title":"RNA mimics of green fluorescent protein","volume":"333","author":"Paige","year":"2011","journal-title":"Science"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1099\/jgv.0.000755","article-title":"Development and characterization of Sindbis virus with encoded fluorescent RNA aptamer Spinach2 for imaging of replication and immune-mediated changes in intracellular viral RNA","volume":"98","author":"Nilaratanakul","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.virusres.2016.11.031","article-title":"Detection of human immunodeficiency virus RNAs in living cells using Spinach RNA aptamers","volume":"228","author":"Burch","year":"2017","journal-title":"Virus Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1128\/JVI.80.2.682-688.2006","article-title":"Live-cell characterization and analysis of a clinical isolate of bovine respiratory syncytial virus, using molecular beacons","volume":"80","author":"Santangelo","year":"2006","journal-title":"J. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"101271","DOI":"10.1016\/j.nantod.2021.101271","article-title":"In-situ quantitation of genome release of Japanese encephalitis viruses by quantum dot-based single-virus tracking","volume":"40","author":"Liu","year":"2021","journal-title":"Nano Today"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"9789","DOI":"10.1021\/ja102585v","article-title":"Hairpin DNA-Functionalized Gold Colloids for the Imaging of mRNA in Live Cells","volume":"132","author":"Jayagopal","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"8397","DOI":"10.1128\/AEM.71.12.8397-8401.2005","article-title":"Visualization and detection of infectious coxsackievirus replication using a combined cell culture-molecular beacon assay","volume":"71","author":"Wang","year":"2005","journal-title":"Appl Environ. Microbiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"17522","DOI":"10.1073\/pnas.0807066105","article-title":"Visualizing the dynamics of viral replication in living cells via Tat peptide delivery of nuclease-resistant molecular beacons","volume":"105","author":"Yeh","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3245","DOI":"10.1093\/nar\/gki629","article-title":"Visualizing the dynamic behavior of poliovirus plus-strand RNA in living host cells","volume":"33","author":"Cui","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.1093\/nar\/gkn475","article-title":"Imaging and characterizing influenza A virus mRNA transport in living cells","volume":"36","author":"Wang","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e00135-20","DOI":"10.1128\/JVI.00135-20","article-title":"Remodeling of the Core Leads HIV-1 Preintegration Complex into the Nucleus of Human Lymphocytes","volume":"94","author":"Gazi","year":"2020","journal-title":"J. Virol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e00571-18","DOI":"10.1128\/JVI.00571-18","article-title":"Real-Time Visualization and Quantification of Human Cytomegalovirus Replication in Living Cells Using the ANCHOR DNA Labeling Technology","volume":"92","author":"Kappler","year":"2018","journal-title":"J. Virol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e00795-18","DOI":"10.1128\/JVI.00795-18","article-title":"In Vivo Labelling of Adenovirus DNA Identifies Chromatin Anchoring and Biphasic Genome Replication","volume":"92","author":"Komatsu","year":"2018","journal-title":"J. Virol."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Gallardo, F., Schmitt, D., Brandely, R., Brua, C., Silvestre, N., Findeli, A., Foloppe, J., Top, S., Kappler-Gratias, S., and Quentin-Froignant, C. (2020). Fluorescent Tagged Vaccinia Virus Genome Allows Rapid and Efficient Measurement of Oncolytic Potential and Discovery of Oncolytic Modulators. Biomedicines, 8.","DOI":"10.3390\/biomedicines8120543"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1002\/j.1460-2075.1992.tb05420.x","article-title":"Hepadnaviral assembly is initiated by polymerase binding to the encapsidation signal in the viral RNA genome","volume":"11","author":"Bartenschlager","year":"1992","journal-title":"EMBO J."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"6631","DOI":"10.1093\/emboj\/cdg633","article-title":"Visualizing telomere dynamics in living mammalian cells using PNA probes","volume":"22","author":"Molenaar","year":"2003","journal-title":"EMBO J."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1021\/bc300249f","article-title":"PNA FIT-Probes for the Dual Color Imaging of Two Viral mRNA Targets in Influenza H1N1 Infected Live Cells","volume":"23","author":"Kummer","year":"2012","journal-title":"Bioconjug. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.ymthe.2006.03.010","article-title":"Labeling and intracellular tracking of functionally active plasmid DNA with semiconductor quantum dots","volume":"14","author":"Srinivasan","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.chembiol.2013.02.012","article-title":"Fluorescence imaging of single-copy DNA sequences within the human genome using PNA-directed padlock probe assembly","volume":"20","author":"Yaroslavsky","year":"2013","journal-title":"Chem. Biol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"100589","DOI":"10.1016\/j.jbc.2021.100589","article-title":"Identification and characterization of a G-quadruplex structure in the pre-core promoter region of hepatitis B virus covalently closed circular DNA","volume":"296","author":"Badmalia","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Ruggiero, E., Zanin, I., Terreri, M., and Richter, S.N. (2021). G-Quadruplex Targeting in the Fight against Viruses: An Update. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222010984"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4939-9666-7_1","article-title":"G-Quadruplex DNA and RNA","volume":"2035","author":"Yang","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"5182","DOI":"10.1021\/jacs.8b10265","article-title":"Lighting up the Native Viral RNA Genome with a Fluorogenic Probe for the Live-Cell Visualization of Virus Infection","volume":"141","author":"Luo","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4627","DOI":"10.1093\/nar\/gkaa186","article-title":"Selective targeting of mutually exclusive DNA G-quadruplexes: HIV-1 LTR as paradigmatic model","volume":"48","author":"Tassinari","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"410","DOI":"10.3389\/fchem.2021.705458","article-title":"The Application of Nucleic Acid Probe\u2013Based Fluorescent Sensing and Imaging in Cancer Diagnosis and Therapy","volume":"9","author":"Huang","year":"2021","journal-title":"Front. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/bs.mcb.2014.10.002","article-title":"Chapter 2\u2014Single-molecule imaging in live cell using gold nanoparticles","volume":"Volume 125","author":"Paluch","year":"2015","journal-title":"Methods in Cell Biology"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"13454","DOI":"10.1021\/jacs.9b04659","article-title":"Quantum Dot Nanobeacons for Single RNA Labeling and Imaging","volume":"141","author":"Ma","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"3896","DOI":"10.1021\/nn305189n","article-title":"Encapsulating Quantum Dots into Enveloped Virus in Living Cells for Tracking Virus Infection","volume":"7","author":"Zhang","year":"2013","journal-title":"ACS Nano"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1038\/sj.gt.3300544","article-title":"Development of replicative and nonreplicative hepatitis B virus vectors","volume":"4","author":"Chaisomchit","year":"1997","journal-title":"Gene Ther."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1128\/JVI.03328-12","article-title":"Novel recombinant hepatitis B virus vectors efficiently deliver protein and RNA encoding genes into primary hepatocytes","volume":"87","author":"Hong","year":"2013","journal-title":"J. Virol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.jhep.2011.02.015","article-title":"Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection","volume":"55","author":"Lucifora","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1099\/vir.0.019224-0","article-title":"HBx protein is indispensable for development of viraemia in human hepatocyte chimeric mice","volume":"91","author":"Tsuge","year":"2010","journal-title":"J. Gen. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/3\/557\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:34:16Z","timestamp":1760135656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/3\/557"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,8]]},"references-count":132,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["v14030557"],"URL":"https:\/\/doi.org\/10.3390\/v14030557","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,8]]}}}