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Type Species |
(HDV) |
Virions of Hepatitis delta virus (HDV) are roughly spherical with an average diameter of 36 to 43 nm and no identified surface projections (Fig. 1). They consist of an outer envelope containing lipid and all three envelope proteins of the co-infecting helper hepadnavirus (see below), and an inner nucleocapsid of 19 nm comprising the RNA genome of HDV and approximately 70 copies of the only HDV-encoded protein, known as delta antigen (HDAg). HDAg exists in two forms (large HDAg; L-HDAg, p27 and small HDAg; S-HDAg, p24) which differ only by a 19-aa C-terminal extension. Virions contain roughly equimolar amounts of L-HDAg and S-HDAg in close association with virion RNA. Nucleocapsid symmetry has not been confirmed. Nucleocapsids can be released by treatment of virions with non-ionic detergent and dithiothreitol.
Physicochemical and Physical Properties
None reported.
The genome consists of a single molecule of circular negative sense ssRNA about 1.7 kb in length. Due to a high degree (~70%) of intramolecular base pairing this has the potential to fold on itself forming an unbranched rod-like structure. Both genomic and antigenomic RNA species can function as a ribozyme to carry out self-cleavage and self-ligation. The above properties make this genome unique and distinct from all other known animal viruses.
HDV RNA encodes one known protein HDAg (see above). The two HDAg species arise via an RNA editing event mediated by the cellular enzyme dsRNA adenosine deaminase, in which the UAG stop codon for S-HDAg is converted to UGG, thereby allowing read-through translation giving rise to L-HDAg. Both HDAg species are multi-functional with domains identified that result in (from the N-terminus) (1) dimerisation via a coiled coil structure; (2) nuclear localisation via a bipartite signal; (3) RNA binding via two arginine-rich motifs. In addition, L-HDAg has a domain, which includes a prenylation site responsible for packaging. The two HDAg species play distinct roles in replication; S-HDAg is essential for HDV replication while L-HDAg inhibits replication but is essential for packaging.
The remaining structural proteins of the HDV virion consist of the surface proteins and glycoproteins of the helper hepadnavirus located in the HDV envelope.
Not characterized.
Not characterized.
Genomic Organization and Replication
It is assumed that attachment, entry and uncoating of HDV may be similar to the steps that occur with the helper hepadnavirus, although very little is known. Genome replication involves RNA-directed RNA synthesis carried out by host cell RNA polymerase II in the nucleus. It occurs by a double rolling circle mechanism that generates oligomeric forms of each complementarity, which then undergo site specific autocatalytic cleavage and ligation to generate circular genomic and antigenomic monomers (Fig. 2).
Only one HDV mRNA species has been identified, coding for HDAg. In transfected cells only S-HDAg is made initially and L-HDAg appears subsequently as a result of the RNA editing event described above. Editing is now also recognised to occur in infected chimpanzees and woodchucks.
As HDV assembly requires the envelope proteins of a helper hepadnavirus, its assembly pathway is likely to overlap with that of the helper virus. In dually transfected cells, L-HDAg must be present for delta antigen-containing particles to be released, while S-HDAg is packaged if present in the cell, but is not essential for particle formation. Full size, or deleted, HDV RNA molecules are incorporated if present in the cell, as long as they are capable of folding into rod-like structures. In cells undergoing HDV RNA replication this process is highly specific for genomic RNA, while in cells expressing but not replicating HDV RNA, either sense can be assembled.
Full replication of HDV requires the presence of a helper hepadnavirus to provide envelope proteins, and it can therefore be considered as a subviral satellite virus. Natural HDV infection is found only in humans with HBV as helper virus. However, it can be transmitted to chimpanzees if accompanied by Hepatitis B virus (HBV), and experimental transmission of HDV to woodchucks has also been achieved using woodchuck hepatitis virus as helper virus.
Helper independent HDV infection has also been seen in human liver transplant recipients and in experimental woodchuck infection. In this situation, “latent” persistent HDV infection with little or no virus release can be rescued by subsequent HBV reactivation or reinfection. Transmission of HDV to laboratory mice has been reported leading to a single round of HDV genome replication in hepatocytes but no further replication presumably due to the absence of helper virus.
Transmission of HDV in man occurs by similar routes to HBV although in many parts of the world transmission by parenteral contact (e.g., sharing of intravenous needles) is more prominent than sexual or vertical routes. If transmission occurs to an individual with chronic HBV infection, this situation is termed superinfection and HDV infection usually then persists. On the other hand, if both HDV and HBV are simultaneously transmitted to a naive host the situation is termed co-infection and both infections are usually transient. HDV distribution is world-wide, but the proportion of HBV carriers who also have chronic HDV infection varies greatly between 0% and 60% in different geographical areas.
Clinical sequelae of acute and chronic HDV infection are variable and cover a similar spectrum to HBV alone, including acute hepatitis, chronic active hepatitis, cirrhosis, fulminant acute hepatitis and hepatocellular carcinoma. However, the frequency of severe sequelae and their rates of progression are significantly higher in chronic HDV infection than in chronic HBV infection alone. A subacute rapidly progressive form of HDV superinfection has been seen in HBV carriers in Venezuela, and other forms of severe acute and chronic hepatitis D, often fatal, occur in indigenous populations of Venezuela, Colombia, Brazil and Peru.
List of Species Demarcation Criteria in the Genus
Not applicable. Only one species in the genus. A study of 14 independent isolates of HDV revealed up to 40% variation in nucleotide sequence with some geographical clustering. Studies of nucleotide homologies have distinguished genotype 1 (USA, Europe, China), genotype 2 (Japan) and genotype 3 (S. America).
Official virus species names are in italics. Tentative virus species names, alternative names ( ), strains or serotypes are not italicized. Virus name and assigned abbreviation ( ) are:
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Hepatitis delta virus |
(HDV) |
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HDV genotype 1 (USA, Europe, China) |
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HDV genotype 2 (Japan) |
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HDV genotype 3 (S. America) |
Tentative Species in the Genus
None reported.
Phylogenetic Relationships within the Genus
Not applicable.
Several features of HDV (genome structure, RNA-RNA transcription using RNA polymerase II, and autocatalytic RNA sites) are similar to properties of viroids. However, unlike viroids, HDV possesses a larger genome, encodes a functional protein and requires a specific hepadnavirus helper function.
HDV also possesses some features in common with ssRNA satellites of plants, including B type mRNA satellites and D type circular RNA satellites (“virusoids”), and also (in terms of the satellite-helper relationship) with ssRNA satellite viruses chronic bee-paralysis virus associated satellite and tobacco necrosis virus satellite.
However, on the basis of genome size and structure, mode of replication, protein coding strategy, structure of virion and satellite-helper virus relationship, none of the above examples warrant inclusion in a distinct family together with HDV.
Delta: A novel antigen in HBV infected tissue, unrelated to previously described HBV antigens, was named delta antigen (Ag) by Rizzetto, Canese, Arico, Crivelli, Bonino, Trepo and Verme, 1977.
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