Replication of the hepatitis B virus (HBV) is peculiar for a DNA virus, because it passes through an RNA intermediate that is then copied back into DNA, and because the infected cell releases large numbers of non-infective decoy particles made of HBsAg. Two features of the genome explain the rest of the cycle: the HBV genome is a small, partially double-stranded DNA circle, and the virus brings its own reverse transcriptase.
The replication cycle
HBV attaches to the hepatocyte surface through its surface antigen, which binds the sodium taurocholate cotransporting polypeptide (NTCP), a bile-salt transporter that the virus has adopted as its entry receptor. After entry, only the genome and the core proteins of the capsid reach the cytoplasm. The partially double-stranded genome then travels to the nucleus, where host-cell DNA polymerase completes the second strand into a fully double-stranded circle.
That completed DNA is transcribed by host-cell machinery from several different initiation points, producing a set of overlapping messenger RNAs:
| mRNA | Encodes |
|---|---|
| 3500 bp | HBeAg, HBcAg, the polymerase, and the template for reverse transcription |
| 2400 bp | HBsAg-S, HBsAg-M and HBsAg-L |
| 2100 bp | HBsAg-S and HBsAg-M |
| 900 bp | protein X, a transactivator that promotes HBV replication |
In the cytosol, the viral reverse transcriptase finally copies one of these mRNAs back into DNA — the step that gives HBV its RNA intermediate.
The pre-S regions of the S strand carry several genes, among them a receptor for albumin and a receptor for proteins on the hepatocyte surface. Antibodies against the pre-S regions exist, but they have no clinical relevance.
HBeAg and HBcAg come from the same strand, the C strand. If translation starts from the C part of the gene the product is HBcAg, and if it starts upstream, from the pre-C part, the product is HBeAg. HBcAg remains inside the hepatocyte while HBeAg is released from it, so HBeAg is a good marker of the replication state of HBV in the body: it is released into the blood, which makes it easy to measure.
The P gene of the HBV genome encodes the HBV DNA polymerase, which carries both DNA-dependent DNA polymerase and RNA-dependent reverse transcriptase activity. The virion released from the host cell contains the ~3.2 kb partially double-stranded DNA genome, which after entry is completed in the nucleus into covalently closed circular DNA (cccDNA) and serves as the template for the next round of transcription.