HBV CccDNA: The Molecular Reservoir of Hepatitis B Persistence and Challenges to Achieve Viral Eradication

Overview

Journal Biomolecules

Publisher MDPI

Date 2025 Jan 25

PMID 39858456

Authors

Andre Boonstra

Gulce Sari

Affiliations

Soon will be listed here.

Abstract

Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is effective in the suppression of viral activity but generally requires lifelong treatment. They fail to eradicate the HBV viral reservoir, called covalently closed circular DNA (cccDNA), which replicates in the nucleus of liver cells. The cccDNA serves as the sole template for viral replication, as it generates the pregenomic RNA (pgRNA) necessary for producing new viral genomes. This stable form of viral DNA can reactivate the virus when treatment is stopped. HBV cccDNA is therefore one of the main challenges in curing chronic HBV infections. By targeting steps such as cccDNA formation, capsid assembly, or particle secretion, researchers continue to seek ways to interfere with HBV replication and to reduce its persistence, ultimately to eradicate HBV as a global health problem. This review provides an overview of what is currently known about cccDNA formation and biogenesis and the ongoing efforts to target and eradicate it to cure chronic HBV infections.

References

Gerlich W, ROBINSON W . Hepatitis B virus contains protein attached to the 5' terminus of its complete DNA strand. Cell. 1980; 21(3):801-9. DOI: 10.1016/0092-8674(80)90443-2. View

Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X . Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014; 343(6176):1221-8. PMC: 6309542. DOI: 10.1126/science.1243462. View

Yang B, Li B, Jia L, Jiang Y, Wang X, Jiang S . 3D landscape of Hepatitis B virus interactions with human chromatins. Cell Discov. 2020; 6(1):95. PMC: 7769987. DOI: 10.1038/s41421-020-00218-1. View

Alcantara F, Tang H, McLachlan A . Functional characterization of the interferon regulatory element in the enhancer 1 region of the hepatitis B virus genome. Nucleic Acids Res. 2002; 30(9):2068-75. PMC: 113846. DOI: 10.1093/nar/30.9.2068. View

Wong G, Gane E, Lok A . How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?. J Hepatol. 2022; 76(6):1249-1262. DOI: 10.1016/j.jhep.2021.11.024. View

Wursthorn K, Lutgehetmann M, Dandri M, Volz T, Buggisch P, Zollner B . Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B. Hepatology. 2006; 44(3):675-84. DOI: 10.1002/hep.21282. View

Liang T . Hepatitis B: the virus and disease. Hepatology. 2009; 49(5 Suppl):S13-21. PMC: 2809016. DOI: 10.1002/hep.22881. View

Brakenhoff S, de Knegt R, van Campenhout M, van der Eijk A, Brouwer W, van Bommel F . End-of-treatment HBsAg, HBcrAg and HBV RNA predict the risk of off-treatment ALT flares in chronic hepatitis B patients. J Microbiol Immunol Infect. 2022; 56(1):31-39. DOI: 10.1016/j.jmii.2022.06.002. View

Tsukuda S, Watashi K . Hepatitis B virus biology and life cycle. Antiviral Res. 2020; 182:104925. DOI: 10.1016/j.antiviral.2020.104925. View

10.

Rabe B, Glebe D, Kann M . Lipid-mediated introduction of hepatitis B virus capsids into nonsusceptible cells allows highly efficient replication and facilitates the study of early infection events. J Virol. 2006; 80(11):5465-73. PMC: 1472160. DOI: 10.1128/JVI.02303-05. View

11.

Stadler D, Kachele M, Jones A, Hess J, Urban C, Schneider J . Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20. EMBO Rep. 2021; 22(6):e49568. PMC: 8183418. DOI: 10.15252/embr.201949568. View

12.

Hu J, Liu K . Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application. Viruses. 2017; 9(3). PMC: 5371811. DOI: 10.3390/v9030056. View

13.

Decorsiere A, Mueller H, van Breugel P, Abdul F, Gerossier L, Beran R . Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature. 2016; 531(7594):386-9. DOI: 10.1038/nature17170. View

14.

Wei L, Ploss A . Mechanism of Hepatitis B Virus cccDNA Formation. Viruses. 2021; 13(8). PMC: 8402782. DOI: 10.3390/v13081463. View

15.

Kramvis A, Chang K, Dandri M, Farci P, Glebe D, Hu J . A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol. 2022; 19(11):727-745. PMC: 9298709. DOI: 10.1038/s41575-022-00649-z. View

16.

Montanari N, Ramirez R, Aggarwal A, van Buuren N, Doukas M, Moon C . Multi-parametric analysis of human livers reveals variation in intrahepatic inflammation across phases of chronic hepatitis B infection. J Hepatol. 2022; 77(2):332-343. DOI: 10.1016/j.jhep.2022.02.016. View

17.

Rabe B, Vlachou A, Pante N, Helenius A, Kann M . Nuclear import of hepatitis B virus capsids and release of the viral genome. Proc Natl Acad Sci U S A. 2003; 100(17):9849-54. PMC: 187862. DOI: 10.1073/pnas.1730940100. View

17.

Liu S, Huang Q, Zhou B, Guo H, Sun J . REPLY. Hepatology. 2020; 73(5):2076-2077. DOI: 10.1002/hep.31515. View

18.

Beudeker B, Osmani Z, van Oord G, Groothuismink Z, de Knegt R, Hoogenboezem R . Association of HBsAg levels with differential gene expression in NK, CD8 T, and memory B cells in treated patients with chronic HBV. JHEP Rep. 2024; 6(2):100980. PMC: 10835465. DOI: 10.1016/j.jhepr.2023.100980. View

19.

Liem K, Fung S, Wong D, Yim C, Noureldin S, Chen J . Limited sustained response after stopping nucleos(t)ide analogues in patients with chronic hepatitis B: results from a randomised controlled trial (Toronto STOP study). Gut. 2019; 68(12):2206-2213. DOI: 10.1136/gutjnl-2019-318981. View