Hepatitis delta virus (HDV) was first discovered in 1977 among a group of patients infected with hepatitis B virus (HBV). Subsequent studies revealed that HDV is a replication-defective virus which requires a helper virus, HBV, to supply the hepatitis B surface antigen (HBsAg) for virion assembly and infectivity. Being a human pathogen, HDV infection may lead to progressive chronic liver disease and occasional fulminant hepatitis in patients coinfected or superinfected with HBV. In recent years, the incidence of new HDV infections has significantly declined in some parts of the world due to HBV vaccination. However, investigation of the HDV replication cycle has raised many issues which molecular biologists are interested in.
Unlike other RNA satellite viruses which rely on the RNA-dependent RNA polymerase (RdRp) provided by the coexisting helper virus for genome replication, the dependence of HDV on HBV is limited to the supply of HBsAg for the production of HDV viral particle. Similar to plant viroids which do not encode RdRp, HDV undergoes robust RNA replication autonomously once inside the cells. Thus, it is certain that HDV and plant viroids have to replicate their RNA genome using a cellular enzyme(s). Unlike plant viroids which do not encode any protein, HDV encodes a protein, hepatitis delta antigen (HDAg), which is intimately involved in its RNA replication. In addition, HDV RNA not only has to replicate itself but also needs to transcribe a subgenomic mRNA species coding for HDAg. The transcription of the HDAg-encoding mRNA has all of the hallmarks of the cellular mRNA transcription except for the nature of the template (DNA versus RNA). Therefore, distinct from plant viroids, HDV represents a hybrid of the conventional DNA-dependent transcription and the unique RNA-dependent RNA synthesis in the absence of an RdRP. To coordinate with this sophisticated and unique RNA amplification process in mammalian cells, HDAg plays important regulatory roles which will be reviewed herein. Additionally, the nature of the enzyme involved in HDV RNA replication will also be addressed.
This review article examines the HDV RNA replication cycle, with emphasis on the function of HDAg in modulating RNA replication and the nature of the enzyme involved: