Hepatitis B virus pathogenesis: Fresh insights into hepatitis B virus RNA

Abstract

Hepatitis B virus (HBV) is still a worldwide health concern. While divergent factors are involved in its pathogenesis, it is now clear that HBV RNAs, principally templates for viral proteins and viral DNAs, have diverse biological functions involved in HBV pathogenesis. These functions include viral replication, hepatic fibrosis and hepatocarcinogenesis. Depending on the sequence similarities, HBV RNAs may act as sponges for host miRNAs and may deregulate miRNA functions, possibly leading to pathological consequences. Some parts of the HBV RNA molecule may function as viral-derived miRNA, which regulates viral replication. HBV DNA can integrate into the host genomic DNA and produce novel viral-host fusion RNA, which may have pathological functions. To date, elimination of HBV-derived covalently closed circular DNA has not been achieved. However, RNA transcription silencing may be an alternative practical approach to treat HBV-induced pathogenesis. A full understanding of HBV RNA transcription and the biological functions of HBV RNA may open a new avenue for the development of novel HBV therapeutics.

Keywords: Genome integration; Hepatic fibrosis; Hepatitis B virus; Hepatitis B virus RNA; Hepatocellular carcinoma; MicroRNA; Smc5/6; Viral replication.

Figure 1

Hepatitis B virus genome structure. The 3.2-kb partially double-stranded relaxed circular DNA genome of the hepatitis B virus (HBV) is shown in the center. The surrounding colored arrows indicate the locations of the four overlapping open-reading frames. The black arrows show the viral mRNA. Pol: Polymerase; DR1: Direct repeat 1; DR2: Direct repeat 2.

Figure 2

The life cycle of the hepatitis B virus. Hepatitis B virus (HBV) virions infect hepatocytes, and then rcDNA enters the nucleus and is converted to covalently closed circular DNA (cccDNA). Structural maintenance of chromosomes 5 and 6 (Smc5/6) can silence cccDNA, but HBV regulatory protein X (HBx) hijacks the Cullin 4-ROC1 RING E3 ubiquitin ligase (CRL4) complexes by binding to damage-specific DNA-binding protein 1 (DDB1) to target Smc5/6 for ubiquitination. Smc5/6 is consequently degraded by the proteasome, and cccDNA can then be transcribed. Transcribed HBV pregenomic RNA (pgRNA) is co-packaged with reverse transcriptase in capsids and is normally (~90%) reverse-transcribed into rcDNA, while double stranded linear DNA (dslDNA) is rarely (10%) synthesized depending on the binding region of the RNA primer. dslDNA can be integrated into the host cell genome, and virus-human chimeric RNA can be transcribed from integrated HBV DNA. After reverse transcription, the mature nucleocapsids can either be secreted as virions or cycle to the nucleus to add to the cccDNA pool.

Figure 3

Hepatitis B virus-related RNAs alone have diverse effects on the host. Hepatitis B virus (HBV) mRNAs and HBV-miR-3 are transcribed from cccDNA, while viral-human chimeric RNAs are transcribed from integrated HBV DNA. These RNAs, except HBV-CCNA2, have complementary lesion(s) to cellular micro RNAs (miRNAs) and act as miRNA sponges, in turn triggering upregulated expression of the miRNA target and resulting in the induction of HBV pathogenesis. HBV-CCNA2 promotes tumor development through the newly synthesized chimeric transcript, which has new splice sites in the pre-mRNA produced by viral DNA integration.