Fig. 5

The interplay between canonical and extracellular vesicle-mediated HDV life cycle. The canonical life cycle of HDV initiates with the binding of the virus to the hepatocyte membrane receptor NTCP through the HBV surface proteins (HBsAg). Following membrane fusion, facilitated by an as-yet-unknown mechanism likely similar to that of HBV, the ribonucleoprotein (RNP) complex containing the HDV genome is released and transported to the nucleus. Genomic ( +) RNA serves as the template for mRNAs encoding HDAg, specifically SHDAg. Genome replication occurs through a double rolling circle amplification mechanism, generating anti-genomic (-) and genomic ( +) RNAs. During replication, host adenosine deaminase acting on RNA 1 (ADAR1) edits anti-genomic RNA, generating a second mRNA coding for the elongated LHDAg. Progeny HDV-RNAs assemble into RNPs containing SHDAg and LHDAg in the nucleus and then bud into the host endoplasmic reticulum (ER) where HBsAg proteins localize. LHDAg interacts with the HBsAg proteins for the acquisition of the HBV envelope, leading to virion release. Details regarding the exosomal HDV life cycle remain unclear. However, reports indicate the presence of HDV-RNA in exosomes enriched with CD63 and CD81 surface markers, as well as the ESCRT machinery component TSG101. Although the proposed interconnection between the canonical and exosomal HDV life cycle is depicted, further investigations are warranted for solidification. The question mark denotes an unknown or unclear process and molecular mechanism