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Detection of Low Copy Number Integrated Viral DNA Formed by In Vitro Hepatitis B Infection
Published on: November 7, 2018
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Region-Specific Hepatitis B Virus Genome Exposure from Nucleocapsid Modulated by Capsid Linker Sequence and
Ji Xi1, Xiuji Cui1, Kuancheng Liu1
1Department of Microbiology and Immunology, The Pennsylvania State Universitygrid.29857.31 College of Medicine, Hershey, Pennsylvania, USA.
Journal of Virology
|April 7, 2022
Summary
Hepatitis B virus (HBV) uncoating exposes viral DNA, making it vulnerable to degradation or conversion to a nuclear form essential for infection. This DNA exposure, influenced by mutations and antivirals, impacts HBV persistence and cure strategies.
Area of Science:
- Virology
- Molecular Biology
- Hepatitis B Virus (HBV) Pathogenesis
Background:
- Hepatitis B virus (HBV) replication relies on its relaxed circular (RC) DNA genome within a nucleocapsid (NC).
- Uncoating, the release of RC DNA from the NC, is crucial for forming the nuclear covalently closed circular (CCC) DNA, the template for viral replication.
- The precise mechanisms of HBV uncoating and subsequent DNA fate remain incompletely understood.
Purpose of the Study:
- To investigate the role of HBV nucleocapsid (NC) structure and function in the uncoating process.
- To understand how HBV RC DNA is protected or exposed during uncoating.
- To explore the implications of DNA exposure during uncoating for HBV infection persistence and potential therapeutic interventions.
Main Methods:
- Analysis of HBV core (HBc) mutants with varying nuclear CCC DNA levels.
- Assessment of RC DNA protection against nucleases in cellular lysates and exogenous DNase treatments.
- Subcellular fractionation to identify DNA-degrading activities and DNase digestion to map DNA exposure sites on the NC.
Main Results:
- HBc mutants failed to protect RC DNA from degradation, unlike wild-type (wt) HBV, with degradation linked to membrane-associated nucleases.
- Region-specific exposure of RC DNA was observed in mutant NCs, wt NCs treated with a core inhibitor, and a subpopulation of untreated wt NCs.
- This site-specific DNA exposure suggests a competition between degradation and conversion to CCC DNA during uncoating.
Conclusions:
- HBV RC DNA is exposed in a region-specific manner during NC uncoating.
- This exposure can lead to DNA degradation or facilitate CCC DNA formation, influencing HBV infection establishment and persistence.
- Understanding this competition is critical for developing effective capsid-targeted antivirals and pursuing an HBV cure.
Keywords:
CCC DNAantiviralcapsidcccDNAcovalently closed circular DNAhepadnavirushepatitis B virusnucleasenucleocapsiduncoatingMore Related Videos
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