Hostname: page-component-848d4c4894-4hhp2 Total loading time: 0 Render date: 2024-05-31T08:49:49.431Z Has data issue: false hasContentIssue false
  • English
  • Français

Hepatitis B virus DNA methylation and its potential role in chronic hepatitis B

Published online by Cambridge University Press:  16 November 2022

Wei Feng Low Open the ORCID record for Wei Feng Low [Opens in a new window] ,
Yun Fong Ngeow ,
Jack Bee Chook Open the ORCID record for Jack Bee Chook [Opens in a new window] ,
Kok Keng Tee ,
Seng-Kai Ong ,
Suat Cheng Peh ,
Jan Jin Bong  and
Rosmawati Mohamed
Wei Feng Low
Affiliation:
Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia
Yun Fong Ngeow
Affiliation:
Department of Pre-clinical Sciences, Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Jalan Sungai Long, Bandar Sungai Long, Cheras 43000, Kajang, Malaysia
Jack Bee Chook*
Affiliation:
Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia
Kok Keng Tee
Affiliation:
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Jalan Universiti, 50603 Kuala Lumpur, Malaysia
Seng-Kai Ong
Affiliation:
Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia
Suat Cheng Peh
Affiliation:
Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan Universiti, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia
Jan Jin Bong
Affiliation:
Sunway Medical Centre, Jalan Lagoon Selatan, Bandar Sunway, 47500 Petaling Jaya, Selangor, Malaysia
Rosmawati Mohamed
Affiliation:
Department of Medicine, Faculty of Medicine, University of Malaya, Jalan Universiti, 50603 Kuala Lumpur, Malaysia
*
Author for correspondence: Jack Bee Chook, E-mail: jackbeec@sunway.edu.my
Get access Rights & Permissions [Opens in a new window]

Abstract

Hepatitis B virus (HBV) infection led to 66% liver deaths world-wide in year 2015. Thirty-seven per cent of these deaths were the result of chronic hepatitis B (CHB)-associated hepatocellular carcinoma (HCC). Although early diagnosis of HCC improves survival, early detection is rare. Methylation of HBV DNA including covalently closed circular DNA (cccDNA) is more often encountered in HCC cases than those in CHB and cirrhosis. Three typical CpG islands within the HBV genome are the common sites for methylation. The HBV cccDNA methylation affects the viral replication and protein expression in the course of infection and may associate with the disease pathogenesis and HCC development. We review the current findings in HBV DNA methylation that provide insights into its role in HCC diagnosis.

Keywords

Biomarkerchronic hepatitis Bcovalently closed circular DNACpG islandshepatitis B virushepatocellular carcinomamethylation
Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 25 , 2023 , e11
Check for updates
Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

World Health Organization (2017) Global hepatitis report 2017, 19 April 2017. Available at Global hepatitis report, 2017 (who.int).Google Scholar
Polaris Observatory Collaborators (2018) Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. The Lancet Gastroenterology and Hepatology 3, 383–403.CrossRefGoogle Scholar
Papatheodoridis, G et al. (2015) Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. Journal of Hepatology 62, 956–967.CrossRefGoogle ScholarPubMed
Su, TH et al. (2016) Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. Liver International 36, 1755–1764.CrossRefGoogle ScholarPubMed
Tu, T et al. (2020) The lived experience of chronic hepatitis B: a broader view of its impacts and why we need a cure. Viruses 12, 515.CrossRefGoogle ScholarPubMed
World Health Organization (2015) Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection, pp. 94–98.Google Scholar
Guan, R and Lui, HF (2011) Treatment of hepatitis B in decompensated liver cirrhosis. International Journal of Hepatology 918017, 1–11.CrossRefGoogle Scholar
An, P et al. (2018) Host and viral genetic variation in HBV-related hepatocellular carcinoma. Frontiers in Genetics 19, 261.CrossRefGoogle Scholar
Dandri, M (2020) Epigenetic modulation in chronic hepatitis B virus infection. Seminars in Immunopathology 42, 173–185.CrossRefGoogle ScholarPubMed
Hung, TH et al. (2017) Association between complicated liver cirrhosis and the risk of hepatocellular carcinoma in Taiwan. PLoS One 12, e0181858.CrossRefGoogle ScholarPubMed
Seto, WK et al. (2018) Chronic hepatitis B virus infection. The Lancet 392, 2313–2324.CrossRefGoogle ScholarPubMed
Heimbach, JK et al. (2018) AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67, 358–380.CrossRefGoogle ScholarPubMed
Zhang, BH, Yang, BH and Tang, ZY (2004) Randomized controlled trial of screening for hepatocellular carcinoma. Journal of Cancer Research and Clinical Oncology 130, 417–422.CrossRefGoogle ScholarPubMed
Zhao, YJ, Ju, Q and Li, GC (2013) Tumor markers for hepatocellular carcinoma. Molecular and Clinical Oncology 1, 593–598.CrossRefGoogle ScholarPubMed
Beudeker, B and Boonstra, A (2020) Circulating biomarkers for early detection of hepatocellular carcinoma. Therapeutic Advances in Gastroenterology 13, 175628482093173.CrossRefGoogle ScholarPubMed
Johnson, PJ et al. (2013) The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiology, Biomarkers & Prevention 23, 144–153.CrossRefGoogle ScholarPubMed
Parikh, ND et al. (2020) Biomarkers for the early detection of hepatocellular carcinoma. Cancer Epidemiology, Biomarkers & Prevention 29, 2495–2503.CrossRefGoogle ScholarPubMed
Charostad, J et al. (2019) DNA methyltransferases in virus-associated cancers. Reviews in Medical Virology 29, e2022.CrossRefGoogle ScholarPubMed
Dong, X et al. (2017) Diagnostic value of the methylation of multiple gene promoters in serum in hepatitis B virus-related hepatocellular carcinoma. Disease Markers 2929381, 1–6.Google Scholar
Fernandez, AF et al. (2009) The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Research 19, 438–451.CrossRefGoogle ScholarPubMed
Jain, S et al. (2015) Comprehensive DNA methylation analysis of hepatitis B virus genome in infected liver tissues. Scientific Reports 22, 10478.CrossRefGoogle Scholar
Kaur, P et al. (2010) DNA methylation of hepatitis B virus (HBV) genome associated with the development of hepatocellular carcinoma and occult HBV infection. The Journal of Infectious Diseases 20, 700–704.CrossRefGoogle Scholar
Ye, C et al. (2016) Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma. International Journal of Oncology 49, 589–602.CrossRefGoogle ScholarPubMed
Zhang, ZM et al. (2020) Early diagnosis of hepatocellular carcinoma using machine learning method. Frontiers in Bioengineering and Biotechnology 8, 254.CrossRefGoogle ScholarPubMed
Lee, H et al. (2019) Hepatitis B virus X protein stimulates virus replication via DNA methylation of the C-1619 in covalently closed circular DNA. Molecules and Cells 42, 67–78.Google ScholarPubMed
Park, IY et al. (2007) Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology 132, 1476–1494.CrossRefGoogle ScholarPubMed
Lyko, F (2018) The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nature Reviews Genetics 19, 81–92.CrossRefGoogle Scholar
Caballero, A et al. (2018) Hepatitis B virus: the challenge of an ancient virus with multiple faces and a remarkable replication strategy. Antiviral Research 158, 34–44.CrossRefGoogle Scholar
Seeger, C and Mason, W (2015) Molecular biology of hepatitis B virus infection. Virology 479–480, 672–686.CrossRefGoogle ScholarPubMed
Chong, C et al. (2011) Dynamics of HBV cccDNA expression and transcription in different cell growth phase. Journal of Biomedical Science 18, 96.CrossRefGoogle ScholarPubMed
Levrero, M et al. (2009) Control of cccDNA function in hepatitis B virus infection. Journal of Hepatology 51, 581–592.CrossRefGoogle ScholarPubMed
Mitra, B et al. (2018) Host functions used by hepatitis B virus to complete its life cycle: implications for developing host-targeting agents to treat chronic hepatitis B. Antiviral Research 158, 185–198.CrossRefGoogle ScholarPubMed
Wei, L and Ploss, A (2021) Mechanism of hepatitis B virus cccDNA formation. Viruses 13, 1463.CrossRefGoogle ScholarPubMed
Belloni, L et al. (2009) Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proceedings of the National Academy of Sciences of the United States of America 106, 19975–19979.CrossRefGoogle ScholarPubMed
He, ML et al. (2002) A new and sensitive method for the quantification of HBV cccDNA by real-time PCR. Biochemical and Biophysical Research Communications 295, 1102–1107.CrossRefGoogle ScholarPubMed
Ko, C et al. (2018) Hepatitis B virus genome recycling and de novo secondary infection events maintain stable cccDNA levels. Journal of Hepatology 69, 1231–1241.CrossRefGoogle ScholarPubMed
Xia, Y and Guo, H (2020) Hepatitis B virus cccDNA: formation, regulation and therapeutic potential. Antiviral Research 180, 104824.CrossRefGoogle ScholarPubMed
Zhang, D et al. (2019) Histone deacetylases and acetylated histone H3 are involved in the process of hepatitis B virus DNA replication. Life Sciences 15, 1–8.CrossRefGoogle Scholar
Velkov, S et al. (2018) The global hepatitis B virus genotype distribution approximated from available genotyping data. Genes (Basel) 9, 495.CrossRefGoogle ScholarPubMed
Lin, CL and Kao, JH (2017) Natural history of acute and chronic hepatitis B: the role of HBV genotypes and mutants. Best Practice and Research Clinical Gastroenterology 31, 249–255.CrossRefGoogle ScholarPubMed
Rajoriya, N et al. (2017) How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? Journal of Hepatology 67, 1281–1297.CrossRefGoogle ScholarPubMed
Tu, T et al. (2017) HBV DNA integration: molecular mechanisms and clinical implications. Viruses 9, 75.CrossRefGoogle ScholarPubMed
Wong, GL et al. (2013) Meta-analysis: the association of hepatitis B virus genotypes and hepatocellular carcinoma. Alimentary Pharmacology and Therapeutics 37, 517–526.CrossRefGoogle ScholarPubMed
Raffetti, E, Fattovich, G and Donato, F (2016) Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis. Liver International 36, 1239–1251.CrossRefGoogle ScholarPubMed
Ching, LK et al. (2016) Incidence of hepatocellular carcinoma according to hepatitis B virus genotype in Alaska native people. Liver International 36, 1507–1515.CrossRefGoogle ScholarPubMed
Gounder, PP et al. (2016) Hepatocellular carcinoma risk in Alaska native children and young adults with hepatitis B virus: retrospective cohort analysis. Journal of Pediatrics 178, 206–213.CrossRefGoogle Scholar
Yang, Y et al. (2018) Individual and combined effects of hepatitis B surface antigen level and viral load on liver cancer risk. Journal of Gastroenterology and Hepatology 33, 1131–1137.CrossRefGoogle ScholarPubMed
Sugiyama, M et al. (2006) Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens. Hepatology 44, 915–924.CrossRefGoogle ScholarPubMed
Yang, Y et al. (2015) Quantitative evaluation of hepatitis B virus mutations and hepatocellular carcinoma risk: a meta-analysis of prospective studies. Chinese Journal of Cancer Research 27, 497–508.Google Scholar
Yang, Z et al. (2016) Naturally occurring basal core promoter A1762T/G1764A dual mutations increase the risk of HBV-related hepatocellular carcinoma: a meta-analysis. Oncotarget 7, 12525–12536.CrossRefGoogle ScholarPubMed
Chuon, C et al. (2019) High possibility of hepatocarcinogenesis in HBV genotype C1 infected Cambodians is indicated by 340 HBV C1 full-genomes analysis from GenBank. Science Reports 9, 12186.CrossRefGoogle ScholarPubMed
Wahyuni, RM et al. (2019) Analysis of hepatitis B virus genotype and gene mutation in patients with advanced liver disease in East Kalimantan, Indonesia. Biomedical Reports 10, 303–310.Google ScholarPubMed
Sung, WK et al. (2012) Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nature Genetics 44, 765–769.CrossRefGoogle ScholarPubMed
Yang, L et al. (2018) Molecular characterization of HBV DNA integration in patients with hepatitis and hepatocellular carcinoma. Journal of Cancer 9, 3225–3235.CrossRefGoogle ScholarPubMed
Tu, T et al. (2018) 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. Journal of Virology 92, e02007–17.CrossRefGoogle Scholar
Jones, P (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews Genetics 13, 484–492.CrossRefGoogle ScholarPubMed
Moore, LD, Le, T and Fan, G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38, 23–38.CrossRefGoogle ScholarPubMed
Hou, Z et al. (2015) CpG islands of hepatitis B virus genome isolated from Chinese patients. Gene 561, 261–267.CrossRefGoogle ScholarPubMed
Xue, Y et al. (2016) Characteristics of CpG islands and their quasispecies of full-length hepatitis B virus genomes from patients at different phases of infection. SpringerPlus 5, 1630.CrossRefGoogle ScholarPubMed
Zhang, Y et al. (2013) Comparative analysis of CpG islands among HBV genotypes. PloS ONE 8, e56711.CrossRefGoogle ScholarPubMed
Guo, YH et al. (2011) HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state. Epigenetics 6, 720–726.CrossRefGoogle Scholar
Zhong, C et al. (2017) CpG methylation participates in regulation of hepatitis B virus gene expression in host sperm and sperm-derived embryos. Epigenomics 9, 123–125.CrossRefGoogle ScholarPubMed
Héberlé, É and Bardet, AF (2019) Sensitivity of transcription factors to DNA methylation. Essays in Biochemistry 63, 727–741.Google ScholarPubMed
Lambert, SA et al. (2018) The human transcription factors. Cell 172, 650–665.CrossRefGoogle ScholarPubMed
Koumbi, L and Karayiannis, P (2016) The epigenetic control of hepatitis B virus modulates the outcome of infection. Frontiers in Microbiology 6, 1491.CrossRefGoogle ScholarPubMed
Hoelzer, K, Shackelton, LA and Parrish, CR (2008) Presence and role of cytosine methylation in DNA viruses of animals. Nucleic Acids Research 36, 2825–2837.CrossRefGoogle ScholarPubMed
Kim, JW et al. (2011) Replicative activity of hepatitis B virus is negatively associated with methylation of covalently closed circular DNA in advanced hepatitis B virus infection. Intervirology 54, 316–325.CrossRefGoogle ScholarPubMed
Yin, Y et al. (2017) Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science (New York, N.Y.) 356, p.eaaj2239.CrossRefGoogle ScholarPubMed
Brezgin, S et al. (2019) Replenishment of hepatitis B virus cccDNA pool is restricted by baseline expression of host restriction factors in vitro. Microorganisms 7, 533.CrossRefGoogle ScholarPubMed
Vivekanandan, P et al. (2010) Hepatitis B virus replication induces methylation of both host and viral DNA. Journal of Virology 84, 4321–4329.CrossRefGoogle ScholarPubMed
Zeisel, MB, Guerrieri, F and Levrero, M (2021) Host epigenetic alterations and hepatitis B virus-associated hepatocellular carcinoma. Journal of Clinical Medicine 10, 1715.CrossRefGoogle ScholarPubMed
Tian, Y et al. (2013) Hepatitis B virus X protein induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis. Molecular and Cellular Biology 33, 2810–2816.CrossRefGoogle ScholarPubMed
Watanabe, Y et al. (2015) DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences. Genome Research 25, 328–337.CrossRefGoogle ScholarPubMed
Wang, Z, Wang, W and Wang, L (2020) Epigenetic regulation of covalently closed circular DNA minichromosome in hepatitis B virus infection. Biophysics Reports 6, 115–126.CrossRefGoogle Scholar
Moon, IY et al. (2019) MicroRNA-20 induces methylation of hepatitis B virus covalently closed circular DNA in human hepatoma cells. Molecular Medicine Reports 20, 2285–2293.Google ScholarPubMed
Park, HK et al. (2013) Short hairpin RNA induces methylation of hepatitis B virus covalently closed circular DNA in human hepatoma cells. Biochemical and Biophysical Research Communications 436, 152–155.CrossRefGoogle ScholarPubMed
Sun, CT et al. (2001) Transcription repression of human hepatitis B virus genes by negative regulatory element-binding protein/SON. The Journal of Biological Chemistry 276, 24059–24067.CrossRefGoogle ScholarPubMed
Chou, YC et al. (2005) Evaluation of transcriptional efficiency of hepatitis B virus covalently closed circular DNA by reverse transcription-PCR combined with the restriction enzyme digestion method. Journal of Virology 79, 1813–1823.CrossRefGoogle ScholarPubMed
Lucifora, J et al. (2011) Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. Journal of Hepatology 55, 996–1003.CrossRefGoogle ScholarPubMed
Moon, IY and Kim, JW (2018) Epigenetic regulation of hepatitis B virus replication. Chromatin Epigenetics, 294. doi: 10.5772/intechopen.81711.Google Scholar
Pollicino, T et al. (2006) Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology 130, 823–837.CrossRefGoogle ScholarPubMed
Guerrieri, F et al. (2017) Genome-wide identification of direct Hbx genomic targets. BMC Genomics 18, 187.CrossRefGoogle ScholarPubMed
Cohen, D et al. (2010) Hepatitis B virus activates deoxynucleotide synthesis in nondividing hepatocytes by targeting the R2 gene. Hepatology 51, 1538–1546.CrossRefGoogle ScholarPubMed
Ricardo-Lax, I et al. (2018) A short HBV RNA region induces RNR-R2 expression in non-cycling cells and in primary human hepatocytes. bioRxiv 458679.CrossRefGoogle Scholar
Murphy, CM et al. (2016) Hepatitis B virus X protein promotes degradation of SMC5/6 to enhance HBV replication. Cell Reports 16, 2846–2854.CrossRefGoogle ScholarPubMed
Sekiba, K et al. (2019) Inhibition of HBV transcription from cccDNA with nitazoxanide by targeting the HBx–DDB1 interaction. Cellular and Molecular Gastroenterology and Hepatology 7, 297–312.CrossRefGoogle ScholarPubMed
Vivekanandan, P, Thomas, D and Torbenson, M (2008) Hepatitis B viral DNA is methylated in liver tissues. Journal of Viral Hepatology 15, 103–107.Google ScholarPubMed
Zhang, Y et al. (2014) Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection. PLoS One 9, e110442.CrossRefGoogle ScholarPubMed
Chong, CK et al. (2017) Role of hepatitis B core protein in HBV transcription and recruitment of histone acetyltransferases to cccDNA minichromosome. Antiviral Research 144, 1–7.CrossRefGoogle ScholarPubMed
Vivekanandan, P, Thomas, D and Torbenson, M (2009) Methylation regulates hepatitis B viral protein expression. The Journal of Infectious Diseases 199, 1286–1291.CrossRefGoogle ScholarPubMed
Huang, Q et al. (2021) 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. Hepatology 73, 41–52.CrossRefGoogle ScholarPubMed
Guo, Y et al. (2009) Evidence that methylation of hepatitis B virus covalently closed circular DNA in liver tissues of patients with chronic hepatitis B modulates HBV replication. Journal of Medical Virology 81, 1177–1183.CrossRefGoogle ScholarPubMed
Nakamura, T et al. (2020) Effect of viral DNA methylation on expression of hepatitis B virus proteins depends on the virus genotype. Virus Genes 56, 439–447.CrossRefGoogle ScholarPubMed
Graumann, F et al. (2015) Genomic methylation inhibits expression of hepatitis B virus envelope protein in transgenic mice: a non-infectious mouse model to study silencing of HBV surface antigen genes. PLoS One 10, e0146099.CrossRefGoogle ScholarPubMed
Choi, J et al. (2019) Longitudinal assessment of three serum biomarkers to detect very early-stage hepatocellular carcinoma. Hepatology 69, 1983–1994.CrossRefGoogle ScholarPubMed
Leerapun, A et al. (2007) The utility of lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population. Clinical Gastroenterology and Hepatology 5, 394–402.CrossRefGoogle Scholar
Singhal, A et al. (2012) Molecular and serum markers in hepatocellular carcinoma: predictive tools for prognosis and recurrence. Critical Reviews in Oncology/Hematology 82, 116–140.CrossRefGoogle ScholarPubMed
Toyoda, H et al. (2006) Prognostic significance of simultaneous measurement of three tumor markers in patients with hepatocellular carcinoma. Clinical Gastroenterology and Hepatology 4, 111–117.CrossRefGoogle ScholarPubMed
Zacharakis, G, Aleid, A and Aldossari, K (2018) New and old biomarkers of hepatocellular carcinoma. Hepatoma Research 4, 65.CrossRefGoogle Scholar
Zhou, L, Liu, J and Luo, F (2006) Serum tumor markers for detection of hepatocellular carcinoma. World Journal of Gastroenterology 12, 1175.CrossRefGoogle ScholarPubMed
Debruyne, EN and Delanghe, JR (2008) Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications. Clinica Chimica Acta 395, 19–26.CrossRefGoogle ScholarPubMed
Marrero, JA et al. (2009) Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 137, 110–118.CrossRefGoogle ScholarPubMed
Huang, JT et al. (2018) A highly sensitive and robust method for hepatitis B virus covalently closed circular DNA detection in single cells and serum. The Journal of Molecular Diagnostics 20, 334–343.CrossRefGoogle ScholarPubMed
Lebossé, F et al. (2020) Quantification and epigenetic evaluation of the residual pool of hepatitis B covalently closed circular DNA in long-term nucleoside analogue-treated patients. Scientific Reports 10, 21097.CrossRefGoogle ScholarPubMed
Minosse, C et al. (2016) Simple and reliable method to quantify the hepatitis B viral load and replicative capacity in liver tissue and blood leukocytes. Hepatitis Monthly 16, e28751.CrossRefGoogle ScholarPubMed
Singla, B et al. (2014) Levels of hepatitis B virus replicative intermediate in serum samples of chronic hepatitis B patients. Molecular Biology Reports 41, 4689–4696.CrossRefGoogle ScholarPubMed
Wong, DK et al. (2004) Quantitation of covalently closed circular hepatitis B virus DNA in chronic hepatitis B patients. Hepatology 40, 727–737.CrossRefGoogle ScholarPubMed
Yuen, MF et al. (2005) Effect of lamivudine therapy on the serum covalently closed-circular (ccc) DNA of chronic hepatitis B infection. The American Journal of Gastroenterology 100, 1099–1103.CrossRefGoogle Scholar
Wong, DK et al. (2006) Quantification of hepatitis B virus covalently closed circular DNA in patients with hepatocellular carcinoma. Journal of Hepatology 45, 553–559.CrossRefGoogle ScholarPubMed
Takkenberg, RB et al. (2010) Detection of hepatitis B virus covalently closed circular DNA in paraffin-embedded and cryo-preserved liver biopsies of chronic hepatitis B patients. European Journal of Gastroenterology & Hepatology 22, 952–960.CrossRefGoogle ScholarPubMed
Cabrerizo, M et al. (2000) Molecular analysis of hepatitis B virus DNA in serum and peripheral blood mononuclear cells from hepatitis B surface antigen–negative cases. Hepatology 32, 116–123.CrossRefGoogle ScholarPubMed
Liu, MC et al. (2004) Dynamic analysis of hepatitis B virus DNA and its antigens in 2.2.15 cells. Journal of Viral Hepatitis 11, 124–129.Google ScholarPubMed
Hsu, CW et al. (2021) Hepatitis B virus covalently closed circular DNA predicts postoperative liver cancer metastasis independent of virological suppression. Cancers 13, 538.CrossRefGoogle ScholarPubMed
Chen, Y, Sze, J and He, M (2004) HBV cccDNA in patients’ sera as an indicator for HBV reactivation and an early signal of liver damage. World Journal of Gastroenterology 10, 82–85.CrossRefGoogle Scholar