Origin of hepatitis delta virus

Abstract

This article addresses some of the questions relating to how hepatitis delta virus (HDV), an agent so far unique in the animal world, might have arisen. HDV was discovered in patients infected with hepatitis B virus (HBV). It generally makes HBV infections more damaging to the liver. It is a subviral satellite agent that depends upon HBV envelope proteins for its assembly and ability to infect new cells. In other aspects of replication, HDV is both independent of and very different from HBV. In addition, the small single-stranded circular RNA genome of HDV, and its mechanism of replication, demonstrate an increasing number of similarities to the viroids - a large family of helper-independent subviral agents that cause pathogenesis in plants.

Figure 1. Comparison of hepatitis δ virus RNAs with those of a viroid

There are three stable HDV RNAs that accumulate during replication. The genome, which is the RNA assembled into new virus particles, and its exact complement, the antigenome, are approximately 1700 nucleotides in length, with a circular conformation and the ability, based on approximately 74% intramolecular base pairing, to fold into an unbranched rod-like structure. Both genome and antigenome contain their own ribozyme domain, of approximately 85 nucleotides (yellow box). The antigenome contains the open reading frame for the δ antigen (blue box), but this protein is actually translated from a third RNA, the mRNA, which is linear, less than full length, 5′-capped and 3′-polyadenylated. Also indicated are the RNAs of a plant viroid, ASBVd. This approximately 250-nucleotide long RNA and its exact complement are indicated as plus and minus, even though there is no coding capacity. As with HDV, RNAs can be circular and have the ability to fold intramolecularly. While the RNAs of ASBVd may be almost rod-like, the RNAs of other viroids can have more complicated folding. For viroids such as potato spindle tuber viroid, the circular conformation is only found for the plus RNA. ASBVd: Avocado sunblotch viroid; HDV: Hepatitis δ virus.

Figure 2. Possible primed transcription of hepatitis δ virus RNA

The example shown is for an antigenomic RNA template. (A) Indicates cleavage, which may be via a cellular exonuclease or even polymerase II in association with transcription factor IIS [75]. (B) The 3′-OH produced by the cleavage allows back-priming (or fold-back priming). This occurs in vitro with phage phi6 polymerase [Taylor J et al., Unpublished Data]. (C)Indicates leader-priming (or in situ priming), which has been reported in vitro with polymerase II [74,75]. Note that (B & C) produce different chimeras of genomic RNA transcript linked to antigenomic RNA template.