Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance

Figures & data

Figure 1 The replication cycle of HBV. HBV virions bind to the receptor NTCP on hepatocytes and are internalized. Nucleocapsids are released into the cytoplasm and then translocated to the nucleus, where the genome is converted into cccDNA through a poorly understood mechanism, most likely via the DNA repair mechanism. The HBV cccDNA serves as the template for transcription of the pregenomic and subgenomic RNAs. The pregenomic RNA is the template for both reverse transcription and translation of polymerase and core proteins. The polymerase binds to the packaging signal of the pregenomic RNA, and both of them are incorporated into the viral capsid, inside which RC-DNA is generated through reverse transcription. The resulting RC-DNA can either be enveloped in ER and secreted as progeny virions or be recycled back to the nucleus for cccDNA amplification. ER, endoplasmic reticulum; NTCP, sodium taurocholate cotransporting polypeptide.

Table 1 Current antiviral treatments and potential strategies that may eliminate persistent cccDNA

	Mode of action	Specific cccDNA degradation	Killing of infected hepatocytes
NA	Inhibition of HBV polymerase	No	No
IFN-α	Immune modulation	Yes (in a high dose)	Yes (indirectly in some patients)
	Inhibition of HBV replication
	Epigenetic regulation of the transcriptional activity of cccDNA
	Upregulation of APOBEC activity for cccDNA hypermutation and degradation
LTβR agonist	Upregulation of APOBEC3B activity for cccDNA hypermutation and degradation	Yes	No
Adoptive T-cell therapy (T cells expressing chimeric antigen receptor)	T cell immune response against HBV-infected hepatocytes	No	Yes
Genome editing tools (ZFNs, TALENs, CRISPR/Cas9)	Site-specific cleavage of HBV cccDNA	Yes	No

Abbreviations: LTβR, lymphotoxin-β-receptor; TALEN, transcription activator-like effector nuclease; ZFN, zinc-finger nuclease; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) systems.