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Episomal and integrated hepatitis B transcriptome mapping uncovers heterogeneity with the potential for drug-resistance

  • World Health Organisation. Global hepatitis report 2024: action for access in low- and middle-income countries. (2024).

  • Revill, P. A. et al. The evolution and clinical impact of hepatitis B virus genome diversity. Nat. Rev. Gastroenterol. Hepatol. 17, 618–634 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • McNaughton, A. L. et al. Insights from deep sequencing of the HBV genome-unique, tiny, and misunderstood. Gastroenterology 156, 384–399 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, M. et al. Infection courses, virological features and IFN-alpha responses of HBV genotypes in cell culture and animal models. J. Hepatol. 75, 1335–1345 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • European Association for the Study of the Liver. Electronic address, e.e.e. & European Association for the Study of the, L EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 83, 502–583 (2025).

    Article 

    Google Scholar
     

  • Yan, H. et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 1, e00049 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ni, Y. et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146, 1070–1083 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Turton, K. L., Meier-Stephenson, V., Badmalia, M. D., Coffin, C. S. & Patel, T. R. Host transcription factors in hepatitis B virus RNA synthesis. Viruses 12, 160 (2020).

  • Hong, X., Kim, E. S. & Guo, H. Epigenetic regulation of hepatitis B virus covalently closed circular DNA: implications for epigenetic therapy against chronic hepatitis B. Hepatology 66, 2066–2077 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Junker-Niepmann, M., Bartenschlager, R. & Schaller, H. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J. 9, 3389–3396 (1990).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, Y. et al. An RNA-based system to study hepatitis B virus replication and evaluate antivirals. Sci. Adv. 9, eadg6265 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seeger, C. & Mason, W. S. Hepatitis B virus biology. Microbiol. Mol. Biol. Rev. 64, 51–68 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tu, T., Zhang, H. & Urban, S. Hepatitis B virus DNA integration: in vitro models for investigating viral pathogenesis and persistence. Viruses 13, 180 (2021).

  • Zoulim, F., Chen, P. J., Dandri, M., Kennedy, P. & Seeger, C. Hepatitis B virus DNA integration: implications for diagnostics, therapy, and outcome. J. Hepatol. 81, 1087–1099 (2024).

  • Tu, T., Budzinska, M. A., Shackel, N. A. & Urban, S. HBV DNA Integration: molecular Mechanisms and Clinical Implications. Viruses 9, 75 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Decorsiere, A. et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature 531, 386–389 (2016).

    Article 
    ADS 
    PubMed 

    Google Scholar
     

  • D’Arienzo, V. et al. A PCR assay to quantify patterns of HBV transcription. J. Gen. Virol. 102, 001373 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Stadelmayer, B. et al. Full-length 5’RACE identifies all major HBV transcripts in HBV-infected hepatocytes and patient serum. J. Hepatol. 73, 40–51 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Altinel, K. et al. Single-nucleotide resolution mapping of hepatitis B virus promoters in infected human livers and hepatocellular carcinoma. J. Virol. 90, 10811–10822 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, S. C. et al. Efficacy of antiviral therapy and host-virus interactions visualised using serial liver sampling with fine-needle aspirates. JHEP Rep. 5, 100817 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harris, J. M. et al. Oxygen-dependent histone lysine demethylase 4 restricts hepatitis B virus replication. J. Biol. Chem. 300, 105724 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Testoni, B. et al. Evaluation of the HBV liver reservoir with fine needle aspirates. JHEP Rep. 5, 100841 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lumley, S. F. et al. Pan-genotypic probe-based enrichment to improve efficiency of Hepatitis B virus sequencing. bioRxiv, 2023.2002.2020.529276 (2023).

  • Ng, E. et al. An enrichment protocol and analysis pipeline for long read sequencing of the hepatitis B virus transcriptome. J. Gen. Virol. 104, 001856 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meier, M. A. et al. Ubiquitous expression of HBsAg from integrated HBV DNA in patients with low viral load. J. Hepatol. 75, 840–847 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Suslov, A. et al. Transition to HBeAg-negative chronic hepatitis B virus infection is associated with reduced cccDNA transcriptional activity. J. Hepatol. 74, 794–800 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Magri, A. et al. Inflammatory gene expression associates with hepatitis B virus cccDNA- but not integrant-derived transcripts in HBeAg negative disease. Viruses 14, 1070 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rossi, M. et al. Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro. Gut 72, 2123–2137 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Le Bert, N. et al. Effects of hepatitis B surface antigen on virus-specific and global T cells in patients with chronic hepatitis B virus infection. Gastroenterology 159, 652–664 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Wisskirchen, K. et al. Isolation and functional characterization of hepatitis B virus-specific T-cell receptors as new tools for experimental and clinical use. PLoS One 12, e0182936 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cornberg, M., Lok, A. S., Terrault, N. A., Zoulim, F. & Faculty, E.-A.H.T.E.C Guidance for design and endpoints of clinical trials in chronic hepatitis B – Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference(double dagger). J. Hepatol. 72, 539–557 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lok, A. S. F. Toward a Functional Cure for Hepatitis B. Gut Liver 18, 593–601 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Block, T. M. et al. New potent HBV replication inhibitors for the management of chronic hepatitis B are needed. Nat. Rev. Gastroenterol. Hepatol. 22, 150–151 (2025).

  • Ghany, M. G., Buti, M., Lampertico, P., Lee, H. M. & Faculty, A.-E.H.-H.T.E.C Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: report from the 2022 AASLD-EASL HBV-HDV treatment endpoints conference. Hepatology 78, 1654–1673 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Lim, C. S. et al. Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes. Micro. Genom. 7, mgen000492 (2021).


    Google Scholar
     

  • Tu, T., Budzinska, M. A., Vondran, F. W. R., Shackel, N. A. & Urban, S. Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via sodium taurocholate cotransporting polypeptide-dependent uptake of enveloped virus particles. J. Virol. 92, 11 (2018).

  • Ren, X. et al. Hepatitis B virus genotype and basal core promoter/precore mutations are associated with hepatitis B-related acute-on-chronic liver failure without pre-existing liver cirrhosis. J. Viral Hepat. 17, 887–895 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Derti, A. et al. A quantitative atlas of polyadenylation in five mammals. Genome Res. 22, 1173–1183 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anderson, M. et al. Circulating pregenomic hepatitis B virus RNA is primarily full-length in chronic hepatitis b patients undergoing nucleos(t)ide analogue therapy. Clin. Infect. Dis. 72, 2029–2031 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Testoni, B. et al. Quantification of circulating HBV RNA expressed from intrahepatic cccDNA in untreated and NUC treated patients with chronic hepatitis B. Gut 73, 659–667 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wooddell, C. I. et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci. Transl. Med 9, eaan0241 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Buuren, N. et al. Targeted long-read sequencing reveals clonally expanded HBV-associated chromosomal translocations in patients with chronic hepatitis B. JHEP Rep. 4, 100449 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chheda, U. et al. Factors affecting stability of RNA – temperature, length, concentration, pH, and buffering species. J. Pharm. Sci. 113, 377–385 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chapus, F. et al. Helicases DDX5 and DDX17 promote heterogeneity in HBV transcription termination in infected human hepatocytes. J. Hepatol. 81, 609–620 (2024).

  • Yuen, M. F. et al. Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Nat. Med. 27, 1725–1734 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kramvis, A. & Kew, M. C. Relationship of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy. J. Viral Hepat. 12, 456–464 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Washizaki, A. et al. Neutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen. Nat. Commun. 13, 5207 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gout, J. F., Thomas, W. K., Smith, Z., Okamoto, K. & Lynch, M. Large-scale detection of in vivo transcription errors. Proc. Natl. Acad. Sci. USA 110, 18584–18589 (2013).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Avellon, A. & Echevarria, J. M. Frequency of hepatitis B virus ‘a’ determinant variants in unselected Spanish chronic carriers. J. Med Virol. 78, 24–36 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Norder, H., Courouce, A. M. & Magnius, L. O. Molecular basis of hepatitis B virus serotype variations within the four major subtypes. J. Gen. Virol. 73, 3141–3145 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scholtes, C. et al. Performance of the cobas(R) HBV RNA automated investigational assay for the detection and quantification of circulating HBV RNA in chronic HBV patients. J. Clin. Virol. 150-151, 105150 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Butler, E. K. et al. Hepatitis B virus serum DNA and RNA levels in nucleos(t)ide analog-treated or untreated patients during chronic and acute infection. Hepatology 68, 2106–2117 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Degasperi, E. et al. Differential HBV RNA and HBcrAg patterns in untreated patients with chronic hepatitis delta. J. Hepatol. 82, 1004–1011 (2024).

  • Tombacz, D. et al. Long-read assays shed new light on the transcriptome complexity of a viral pathogen. Sci. Rep. 10, 13822 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Balazs, Z. et al. long-read sequencing of human cytomegalovirus transcriptome reveals RNA isoforms carrying distinct coding potentials. Sci. Rep. 7, 15989 (2017).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gu, Z. et al. Hepatitis B virus enhancer 1 activates preS1 and preS2 promoters of integrated HBV DNA impairing HBsAg secretion. JHEP Rep. 6, 101144 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qian, Z. et al. HBV integrations reshaping genomic structures promote hepatocellular carcinoma. Gut 73, 1169–1182 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tu, T. & Jilbert, A. R. Detection of hepatocyte clones containing integrated hepatitis B virus DNA using inverse nested PCR. Methods Mol. Biol. 1540, 97–118 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, C. L. et al. HBV DNA integration into telomerase or MLL4 genes and TERT promoter point mutation as three independent signatures in subgrouping HBV-related HCC with distinct features. Liver Cancer 13, 41–55 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seydel, C. Beyond cell atlases: spatial biology reveals mechanisms behind disease. Nat. Biotechnol. 43, 841–844 (2025).

  • Li, D., Hamadalnil, Y. & Tu, T. Hepatitis B viral protein HBx: roles in viral replication and hepatocarcinogenesis. Viruses 16, 1361 (2024).

  • Hernandez, S. et al. Canonical and divergent N-terminal HBx isoform proteins unveiled: characteristics and roles during HBV replication. Biomedicines 9, 1701 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Iden, M. et al. Multi-omics mapping of human papillomavirus integration sites illuminates novel cervical cancer target genes. Br. J. Cancer 125, 1408–1419 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Z. et al. Long-read sequencing reveals the structural complexity of genomic integration of HPV DNA in cervical cancer cell lines. BMC Genom.25, 198 (2024).

    Article 
    CAS 

    Google Scholar
     

  • Santiago, J. C. et al. Variation within major internal repeats of KSHV in vivo. Virus Evol. 9, vead034 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fulop, A. et al. Integrative profiling of Epstein-Barr virus transcriptome using a multiplatform approach. Virol. J. 19, 7 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wright, C. J., Smith, C. W. J. & Jiggins, C. D. Alternative splicing as a source of phenotypic diversity. Nat. Rev. Genet 23, 697–710 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McCoullough, L. C. et al. The in vitro replication phenotype of hepatitis B virus (HBV) splice variants Sp3 and Sp9 and their impact on wild-type HBV replication. J. Virol. 98, e0153823 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Velkov, S., Ott, J. J., Protzer, U. & Michler, T. The global hepatitis B virus genotype distribution approximated from available genotyping data. Genes (Basel) 9, 495 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Hou, J. et al. Prevalence of naturally occurring surface gene variants of hepatitis B virus in nonimmunized surface antigen-negative Chinese carriers. Hepatology 34, 1027–1034 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wettengel, J. M. et al. Rapid and robust continuous purification of high-titer hepatitis B virus for in vitro and in vivo applications. Viruses 13, 1503 (2021).

  • Belloni, L. et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc. Natl. Acad. Sci. USA 106, 19975–19979 (2009).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dobrica, M. O. et al. CTCF regulates hepatitis B virus cccDNA chromatin topology. J Gen Virol 105, 001939 (2024).

  • Tsukuda, S. et al. The N6-methyladenosine demethylase ALKBH5 regulates the hypoxic HBV transcriptome. PLoS Pathog. 20, e1011917 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, H. Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics 34, 3094–3100 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lawrence, M. et al. Software for computing and annotating genomic ranges. PLoS Comput Biol. 9, e1003118 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Garrido-Martin, D., Palumbo, E., Guigo, R. & Breschi, A. ggsashimi: Sashimi plot revised for browser- and annotation-independent splicing visualization. PLoS Comput. Biol. 14, e1006360 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Minh, B. Q. et al. IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol. Biol. Evol. 37, 1530–1534 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kalyaanamoorthy, S., Minh, B. Q., Wong, T. K. F., von Haeseler, A. & Jermiin, L. S. ModelFinder: fast model selection for accurate phylogenetic estimates. Nat. Methods 14, 587–589 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

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