2021
DOI: 10.3390/v13081463
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Mechanism of Hepatitis B Virus cccDNA Formation

Abstract: Hepatitis B virus (HBV) remains a major medical problem affecting at least 257 million chronically infected patients who are at risk of developing serious, frequently fatal liver diseases. HBV is a small, partially double-stranded DNA virus that goes through an intricate replication cycle in its native cellular environment: human hepatocytes. A critical step in the viral life-cycle is the conversion of relaxed circular DNA (rcDNA) into covalently closed circular DNA (cccDNA), the latter being the major templat… Show more

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Cited by 65 publications
(57 citation statements)
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References 151 publications
(232 reference statements)
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“…A number of small molecules have been shown in vitro to interfere with HBV‐DNA repair mechanisms. [ 80 ] Zinc finger nucleases can directly cleave specific sequences within cccDNA and transcription activator‐like effector nucleases can edit HBV genes or induce epigenetic modifications, thereby silencing cccDNA. [ 81 ] The CRISPR‐associated 9 system is a targeted nuclease that can directly cleave cccDNA, but it can also result in double‐strand breaks in the host genome, leading to pathological consequences.…”
Section: Future Therapies: Viral Targetsmentioning
confidence: 99%
“…A number of small molecules have been shown in vitro to interfere with HBV‐DNA repair mechanisms. [ 80 ] Zinc finger nucleases can directly cleave specific sequences within cccDNA and transcription activator‐like effector nucleases can edit HBV genes or induce epigenetic modifications, thereby silencing cccDNA. [ 81 ] The CRISPR‐associated 9 system is a targeted nuclease that can directly cleave cccDNA, but it can also result in double‐strand breaks in the host genome, leading to pathological consequences.…”
Section: Future Therapies: Viral Targetsmentioning
confidence: 99%
“…There the capsid shell disintegrates and releases the rcDNA genome, which is covalently linked to the viral P protein, into the nucleoplasm [ 29 ]. In a multi-step process involving host DNA replication and repair factors [ 30 , 31 , 32 ] rcDNA is then converted into the plasmid-like episomal covalently closed circular (ccc) DNA form.…”
Section: Functional Dynamics Of the Hbv Core Protein And Capsid In Virus Replicationmentioning
confidence: 99%
“…Currently, however, efficient direct antiviral therapies using nucleoside inhibitors are used for treatment in patients with chronic hepatitis B, which inhibit HBV replication but fail to induce protective HBV-specific immunity. The main reason for direct antiviral therapies to fail to achieve a cure from chronic hepatitis B, is the establishment of a persistent form in HBV-infected hepatocytes, the so-called covalently closed circular DNA (cccDNA) that serves as an extrachromosomal template for viral replication [6,7]. Despite successful control of HBV replication by direct antiviral drugs, treatment interruption is accompanied by re-activating cccDNA and initiation of viral replication, leading again to chronic viral hepatitis.…”
Section: The Challenge Of Chronic Viral Hepatitismentioning
confidence: 99%