As briefly outlined in Chapter 4, Part I, HDV appears to be absolutely dependent on coinfec-tion with hepatitis B virus (HBV) for spread. Despite this, there are a significant number of cases where it can be inferred that an individual was infected with HDV without any evidence of active or prior HBV infection.
The HDV genome, shown in Fig. 15.12, has very significant similarities with plant viroid RNAs! It is difficult to come up with a convincing scenario that explains how a plant pathogen could become associated with a human hepatitis virus that has certain important similarities to retroviruses (see Chapter 21). The HDV particles are enveloped with a membrane containing the three envelope glycoproteins of HBV. Within the envelope is the HDV nucleocapsid containing a covalently closed, circular, single-stranded 1.7-kb RNA molecule of negative-sense orientation complexed with multiple copies of the major gene product of this RNA, the delta antigen.
The circular RNA can form base pairs within itself, forming a rod-like structure reminiscent of plant viroid agents (see below). The delta antigen contains three major structural domains. There are two RNA-binding domains, a nuclear localization signal, and a multimerization domain characteristic of members of proteins in the leucine zipper family. Many of these proteins are known to have a role in regulating transcription.
Self cleavage site
RNA editing site i
I Sense genome (300,000 copies per liver cell)
Self-cleavage or interrupted replication
Cellular RNA polymerase
Self-cleavage or interrupted replication
Open reading frame for small delta antigen
(+) Sense antigenome (50,000 copies per liver cell)
(600 copies per liver cell)
Fig. 15.12 The three RNAs of hepatitis delta virus found in infected liver cells. The genomic negative-sense RNA, which is replicated by means of RNA polymerase II, encodes the antigenomic positive-sense RNA, which is the template for genomes, and a subgenomic positive-sense mRNA. This mRNA is cleaved from the antigenomic RNA by RNA self-cleavage. Further, the RNA can be edited by cellular enzymes so that the first translational terminator can be altered. With such edited RNA, a protein 19 amino acids larger than that expressed from unedited RNA is produced.
After entry and uncoating, the genome and associated delta antigen are transported to the nucleus of the cell where the replicative cycle begins. The delta virus genome is transcribed and replicated by host cell RNA polymerase II! This is truly unique in animal virus systems, and is a major exception to the rule that cells cannot copy RNA into RNA. Somehow this agent has evolved to co-opt one of the three host RNA polymerases for this job.
RNA is transcribed into an antigenome that is positive sense and also a covalently closed circle. Transcription also generates a subgenomic mRNA that is capped and polyadenylated and is translated into the delta antigen. The generation of the subgenomic mRNA may occur by transcription that does not continue to generate the full antigenomic template for transcription of further genomic RNA. Alternatively, it may be generated by the circular RNA acting as a ribozyme that autocatalytically cleaves itself into a linear form. This latter, rather bizarre mechanism is known to be the way that unit-length genomic RNA is generated from circular intermediates generated during the replication process. The term ribozyme was invented by Thomas Cech to explain the fact that in splicing of fungal pre-mRNAs, the RNA molecules can assume a structure so that they can hydrolyze an internal phosphodiester bond without the mediation of any protein at all. He was awarded the Nobel Prize for this discovery.
The delta antigen comes in two forms, a small version (195 amino acids) and a somewhat larger version (214 amino acids). The two forms differ by 19 amino acids, and translation of the larger form results from an RNA editing reaction that changes a UAG stop codon into a UGG. This editing suppresses the termination codon and allows continued translation. The short form of the delta antigen is required for genome replication while the long form suppresses replication and promotes virus assembly.
HDV is spread by blood contamination and causes a pathology much like that of other hepatitis viruses, resulting in liver damage. The severity of this disease results from coinfection with HBV or superinfection of an HBV-positive patient with HDV. In this latter situation, fatality rates can be as high as 20% and virtually all survivors have chronic hepatitis.
While HDV pathology requires coinfection with HBV, this does not explain occurrence and spread of the virus. The virus is found in indigenous populations of South America and is prevalent in Europe, Africa, and the Middle East, but is relatively uncommon in Asia, where there is a high frequency of endemic HBV infections. There may be some way the virus can be maintained and spread without HBV, or it may be able to replicate asymptomatically in some hosts who are also asymptomatically infected with HBV.
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