Figure 2.

HDV life cycle. (1) HDV life cycle starts with HDV virions attachment to heparan sulfate proteoglycans (HSPG), including Glypican 5 (GPC5), at the hepatocyte surface. L-HBsAg pre-S1 region then binds to HBV/HDV specific receptor, the bile acid transporter NTCP. Viral particle enters the cell through endocytosis and viral RNP is freed in the cytoplasm. (2) Both forms of HDAg contain a nuclear localization signal that induces viral RNP translocation to the nucleus. (3) In the nucleus, HDAg mRNA transcription is done by RNA polymerase II. HDAg mRNA is then exported in the cytoplasm where it is translated to produce the small form of HDAg (S-HDAg). (4) During the first step of replication, HDV genomic RNA serves as a template for antigenomic RNA production, probably done by RNA polymerase I. (5) Antigenomic RNA is recognized by RNA polymerase II to produce new genomic RNAs. (6) Antigenomic RNA is edited by ADAR1 enzyme, suppressing S-HDAg stop codon. (7) Edited antigenomic RNA is replicated into genomic RNA, then inducing the transcription of edited HDAg mRNA that is exported in the cytoplasm where it leads to the production of the large form of HDAg (L-HDAg). (8) L-HDAg contains a prenylation site that is farnesylated by a cellular farnesyltransferase before being translocated to the nucleus. (9) Both forms of HDAg interact with newly synthesized genomic RNA to form new viral ribonucleoproteins (RNP) that are exported to the cytoplasm. (10) Viral RNPs interact, through their farnesylated cystein in L-HDAg, with the cytosolic part of HBsAg at the endoplasmic reticulum surface, thus inducing their envelopment. (11) HDV virions are then secreted form the infected cell. The different steps targeted by antiviral treatments are indicated. Represented cell is also infected by HBV, indicated by its cccDNA or its integrated genome, but its life cycle is not depicted.