Host RNA circles and the origin of hepatitis delta virus

Table 1 Hypothesis for the origin of hepatitis delta virus

An acute hepatitis B virus (HBV) infection becomes chronic, spreading to virtually all the hepatocytes in the liver

HBV replication also involves transcription of many viral sequences some of which undergo splicing, with the potential to form stable RNA circles

A rare RNA circle is selected both because it has the rare capacity to undergo RNA directed replication using host polymerase(s) and because it expresses a short protein that is both intrinsically disordered (favoring multimerization) and positively-charged (favoring RNA binding)

Further replication and accumulation selects for increased efficiency, as facilitated by the encoded binding protein, which becomes the small delta antigen. The replicating RNA sequence undergoes many nucleotide changes, rendering it unrecognizable relative to HBV sequences. Such changes could be introduced by misincorporation during transcription and post-transcriptional RNA editing events

A site-specific post-transcriptional modification of the RNA by an RNA editing enzyme leads to translation of a C-terminal elongated second form of the protein, the large delta antigen which undergoes farnesylation. This farnesylation facilitates the binding of the hepatitis delta virus (HDV) ribonucleoprotein complexes to HBV envelope proteins, leading to the release of virus particles that can infect susceptible hepatocytes and undergo further rounds of replication. This, in the presence of HBV co-infection, leads to the release of more HDV

As listed above the hypothesis involves multiple steps, several of which would be rare events that have to be selected for. However, as separately enumerated in the text, there are other parameters that could favor such events.