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

Abstract

Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV). Extensive research over the past decades has unveiled the important role of cccDNA in the natural history and antiviral treatment of chronic HBV infection. cccDNA can persist in patients recovering from acute HBV infection for decades. This explains why HBV reactivation occasionally occurs in patients with resolved hepatitis B receiving intensive immunosuppressive agents. In addition, although advances in antiviral treatment dramatically improve the adverse outcomes of chronic hepatitis B (CHB), accumulating evidence demonstrates that current antiviral treatments alone, be they nucleos(t)ide analogs (NAs) or interferon (IFN), fail to cure most CHB patients because of the persistent cccDNA. NA suppresses HBV replication by directly inhibiting viral polymerase, while IFN enhances host immunity against HBV infection. Viral rebound often occurs after discontinuation of antiviral treatment. The loss of cccDNA can be induced by non-cytolytic destruction of cccDNA or immune-mediated killing of infected hepatocytes. It is known that NA has no direct effect on viral transcription or cccDNA stability. Therefore, the long half-life of hepatocytes leads to a very slow decline in cccDNA in patients under antiviral therapy. Novel antiviral agents targeting cccDNA or cccDNA-containing hepatocytes are thus required for curing chronic HBV infection.

Keywords: chronic hepatitis B; covalently closed circular DNA; hepatitis B virus; interferon; nucleos(t)ide analog.

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.