Summary: Hepatitis delta virus delta antigen
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Hepatitis D Edit Wikipedia article
|Classification and external resources|
Hepatitis D (hepatitis delta) is a disease caused by the hepatitis D virus (HDV), a small spherical enveloped virusoid. This is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a subviral satellite because it can propagate only in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).
Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.
|Schematic representation of the hepatitis delta virus virion.|
|Group:||Group V ((−)ssRNA)|
|Species:||Hepatitis delta virus|
Structure and genome
|Hepatitis delta virus delta antigen|
oligomerization domain of hepatitis delta antigen
The HDV is a small, spherical virus with a 36 nm diameter. It has an outer coat containing three kinds of HBV envelope protein - large, medium, and small hepatitis B surface antigens - and host lipids surrounding an inner nucleocapsid. The nucleocapsid contains single-stranded, circular RNA of 1679 nucleotides and about 200 molecules of hepatitis D antigen (HDAg) for each genome. The central region of HDAg has been shown to bind RNA. Several interactions are also mediated by a coiled-coil region at the N terminus of HDAg. The hepatitis D circular genome is unique to animal viruses because of its high GC nucleotide content. The HDV genome exists as an enveloped, negative sense, single-stranded, closed circular RNA. Its nucleotide sequence is 70% self-complementary, allowing the genome to form a partially double-stranded, rod-like RNA structure. With a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals. It has been proposed that HDV may have originated from a class of plant pathogens called viroids, which are much smaller than viruses.
Like Hepatitis B, HDV gains entry into liver cells via the NTCP bile transporter. HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg. Mapping by mutagenesis of this domain has shown that amino acid residues 9–15 make up the receptor binding site. After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg Since the nucleocapsid does not contain an RNA polymerase to replicate the virus’ genome, the virus makes use of the cellular RNA polymerases. Initially just RNA pol II, now RNA polymerases I and III have also been shown to be involved in HDV replication Normally RNA polymerase II utilizes DNA as a template and produces mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known animal pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.
The RNA polymerases treat the RNA genome as double stranded DNA due to the folded rod-like structure it is in. Three forms of RNA are made; circular genomic RNA, circular complementary antigenomic RNA, and a linear polyadenylated antigenomic RNA, which is the mRNA containing the open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in the nucleolus, mediated by RNA Pol I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Pol II. HDV RNA is synthesized first as linear RNA that contains many copies of the genome. The genomic and antigenomic RNA contain a sequence of 85 nucleotides, the Hepatitis delta virus ribozyme, that acts as a ribozyme, which self-cleaves the linear RNA into monomers. These monomers are then ligated to form circular RNA.
There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity.
A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV is known to produce one protein, namely HDAg. It comes in two forms; a 27kDa large-HDAg, and a small-HDAg of 24kDa. The N-terminals of the two forms are identical, they differ by 19 more amino acids in the C-terminal of the large HDAg. Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg. However, editing by cellular enzyme adenosine deaminase-1 changes the stop codon to UGG, allowing the large-HDAg to be produced. Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection. HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication. HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles. Thus RNA editing by the cellular enzymes is critical to the virus’ life cycle because it regulates the balance between viral replication and virion assembly.
Antigenic Loop Infectivity
The HDV envelope protein has three of the HBV surface proteins anchored to it. The S region of the genome is most commonly expressed and its main function is to assemble subviral particles. HDV antigen proteins can combine with the viral genome to form a ribonucleoprotein (RNP) which when enveloped with the subviral particles can form viral-like particles that are almost identical to mature HDV, but they are not infectious. Researchers had concluded that the determinant of infectivity of HDV was within the N-terminal pre-S1 domain of the large protein (L). It was found to be a mediator in binding to the cellular receptor. Recently, researchers Georrges Abou Jaoudé and Camille Sureau published an article that studied the role of the antigenic loop, found in HDV envelope proteins, in the infectivity of the virus. The antigenic loop, like the N-terminal pre-S1 domain of the large protein, is exposed at the virion surface. Jaoudé and Sureau’s study provided evidence that the antigenic loop may be an important factor in HDV entry into the host cell and by mutating parts of the antigenic loop, the infectivity of HDV may be minimized.
The routes of transmission of hepatitis D are similar to those for hepatitis B. Infection is largely restricted to persons at high risk of hepatitis B infection, particularly injecting drug users and persons receiving clotting factor concentrates. Worldwide more than 15 million people are co-infected. HDV is rare in most developed countries, and is mostly associated with intravenous drug use. However, HDV is much more common in the immediate Mediterranean region, sub-Saharan Africa, the Middle East, and the northern part of South America. In all, about 20 million people may be infected with HDV.
Treatment and prevention
Latest evidence suggests that Pegylated interferon alpha is effective in reducing the viral load and the effect of the disease during the time the drug is given, but the benefit generally stops if the drug is discontinued. The efficiency of the pegylated interferon treatment does not usually exceed ~20%.
Hepatitis D virus was first reported in the mid-1977 as a nuclear antigen in patients infected with HBV who had severe liver disease. This nuclear antigen was then thought to be a hepatitis B antigen and was called the delta antigen. Subsequent experiments in chimpanzees showed that the hepatitis delta antigen (HDAg) was a structural part of a pathogen that required HBV infection to replicate. The entire genome was cloned and sequenced in 1986. It was subsequently placed in its own genus: Deltavirus.
Three genotypes (I–III) were originally described. Genotype I has been isolated in Europe, North America, Africa and some Asia. Genotype II has been found in Japan, Taiwan, and Yakutia (Russia). Genotype III has been found exclusively in South America (Peru, Colombia, and Venezuela). Some genomes from Taiwan and the Okinawa islands have been difficult to type but have been placed in genotype 2. However it is now known that there are at least 8 genotypes of this virus (HDV-1 to HDV-8). Phylogenetic studies suggest an African origin for this pathogen.
An analysis of 36 strains of genotype 3 estimated that the most recent common ancestor of these strains originated around 1930. This genotype spread exponentially from early 1950s to the 1970s in South America. The substitution rate was estimated to be 1.07×10−3 substitutions per site per year.
Another study found an overall evolution rate of 3.18 x 10×10−3 substitutions per site per year. The mutation rate varied with position : the hypervariable region evolved faster (4.55 x 10×10−3 substitutions per site per year) than the hepatitis delta antigen coding region (2.60 x 10×10−3 substitutions per site per year) and the autocatalytic region (1.11 x 10×10−3 substitutions per site per year).
A third study suggested a mutation rate between 9.5x10×10−3 to 1.2x10×10−3 substitutions/site/year.
Genotype 8 has also been isolated from South America. This genotype is usually only found in Africa and may have been imported into South America during the slave trade.
Genotypes, with the exception of type 1, appear to be restricted to certain geographical areas: HDV-2 (previously HDV-IIa) is found in Japan, Taiwan and Yakoutia, Russia; HDV-4 (previously HDV-IIb) in Japan and Taiwan; HDV-3 in the Amazonian region; HDV-5, HDV-6, HDV-7 and HDV-8 in Africa.
- GB virus C
- Hepatitis A
- Hepatitis B, Hepatitis B Virus
- Hepatitis C, Hepatitis C Virus
- Hepatitis E, Hepatitis E Virus
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Hepatitis delta virus delta antigen Provide feedback
The hepatitis delta virus (HDV) encodes a single protein, the hepatitis delta antigen (HDAg). The central region of this protein has been shown to bind RNA . Several interactions are also mediated by a coiled-coil region at the N terminus of the protein .
Poisson F, Roingeard P, Baillou A, Dubois F, Bonelli F, Calogero RA, Goudeau A; , J Gen Virol 1993;74:2473-2478.: Characterization of RNA-binding domains of hepatitis delta antigen. PUBMED:8245865 EPMC:8245865
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002506The Hepatitis delta virus (HDV) encodes a single protein, the hepatitis delta antigen (HDAg). The central region of this protein has been shown to bind RNA [PUBMED:8245865]. Several interactions are also mediated by a coiled-coil region at the N terminus of the protein [PUBMED:9687364].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||host cell nucleus (GO:0042025)|
|Molecular function||RNA binding (GO:0003723)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Seed source:||Pfam-B_808 (release 4.0)|
|Number in seed:||1|
|Number in full:||3|
|Average length of the domain:||156.30 aa|
|Average identity of full alignment:||68 %|
|Average coverage of the sequence by the domain:||86.21 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||18|
|Download:||download the raw HMM for this family|
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In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the HDV_ag domain has been found. There are 5 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
Loading structure mapping...