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| __NOTOC__
| | #REDIRECT[[Hepatitis D Virus]] |
| {{Hepatitis D}}
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| {{CMG}}; {{AOEIC}} {{VK}};
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| ==Overview==
| | [[Category:Emergency mdicine]] |
| | | [[Category:Disease]] |
| ==Taxonomy==
| | [[Category:Up-To-Date]] |
| ''[[Viruses]]''; ''[[Deltavirus]]''; ''[[Hepatitis delta virus]]''
| | [[Category:Infectious disease]] |
| | | [[Category:Hepatology]] |
| ==Biology==
| | [[Category:Gastroenterology]] |
| {| style="float: right;"
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| | [[File:Hep D virus.jpg|200px|thumb|none|Electron micrograph revealing the presence of hepatitis-B virus HBV "Dane particles", or virions. <SMALL>Courtesy: ''[http://www.who.int/en/ World Health Organization]''<ref>{{Cite web | title = http://www.who.int/en/ | url = http://www.who.int/en/}}</ref></SMALL>]]
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| ==Causes==
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| Hepatitis D virus(HDV) is the causative organism for Hepatitis D infection. HDV is only found in people who carry the hepatitis B virus. HDV may make a recent (acute) hepatitis B infection or an existing long-term (chronic) hepatitis B liver disease worse. It can even cause symptoms in people who carry hepatitis B virus but who never had symptoms. Hepatitis D infects about 15 million people worldwide. It occurs in 5% of people who carry hepatitis B.
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| Risk factors include:
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| * Abusing intravenous (IV) or injection drugs
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| * Being infected while pregnant (the mother can pass the virus to the baby)
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| * Carrying the hepatitis B virus
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| * Men having sexual intercourse with other men
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| * Receiving many blood transfusions
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| ===Virology===
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| '''Genome structure and similarities to viroids'''
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| The HDV genome exists as a negative sense, single-stranded, closed circular [[RNA]]. Because of a nucleotide sequence that is 70% self-complementary, the HDV genome forms a partially double stranded RNA structure that is described as rod-like.<ref>{{cite journal |author=Saldanha JA, Thomas HC, Monjardino JP |title=Cloning and sequencing of RNA of hepatitis delta virus isolated from human serum |journal=J. Gen. Virol. |volume=71 ( Pt 7) |issue= |pages=1603–6 |year=1990 |month=July |pmid=2374010 |url=http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=2374010 |doi=10.1099/0022-1317-71-7-1603}}</ref> With a genome of approximately 1700 nucleotides, HDV is the smallest "virus" known to infect animals.
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| It has been proposed that HDV may have originated from a class of plant viruses called [[viroids]].<ref>{{cite journal |author=Elena SF, Dopazo J, Flores R, Diener TO, Moya A |title=Phylogeny of viroids, viroidlike satellite RNAs, and the viroidlike domain of hepatitis delta virus RNA |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue=13 |pages=5631–4 |year=1991 |month=July |pmid=1712103 |pmc=51931 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1712103 |doi=10.1073/pnas.88.13.5631}}</ref> Evidence in support of this hypothesis stems from the fact that both HDV and viroids exist as single-stranded, closed circular RNAs that have rod-like structures. Likewise, both HDV and viroids contain RNA sequences that can assume catalytically active structures called ribozymes. During viral replication, these catalytic RNAs are required in order to produce unit length copies of the genome from longer RNA concatamers. Finally, neither HDV nor viroids encode their own polymerase. Instead, replication of HDV and viroids requires a host polymerase that can utilize RNA as a template.<ref>{{cite journal |author=Taylor JM |title=Replication of human hepatitis delta virus: recent developments |journal=Trends Microbiol. |volume=11 |issue=4 |pages=185–90 |year=2003 |month=April |pmid=12706997 |doi=10.1016/S0966-842X(03)00045-3}}</ref> RNA polymerase II has been implicated as the polymerase responsible for the replication of HDV.<ref>{{cite journal |author=Lehmann E, Brueckner F, Cramer P |title=Molecular basis of RNA-dependent RNA polymerase II activity |journal=Nature |volume=450 |issue=7168 |pages=445–9 |year=2007 |month=November |pmid=18004386 |doi=10.1038/nature06290}}</ref><ref>{{cite journal |author=Filipovska J, Konarska MM |title=Specific HDV RNA-templated transcription by pol II in vitro |journal=RNA |volume=6 |issue=1 |pages=41–54 |year=2000 |month=January |pmid=10668797 |pmc=1369892 |url=http://www.rnajournal.org/cgi/pmidlookup?view=long&pmid=10668797 |doi=10.1017/S1355838200991167}}</ref> 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 pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.
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| ===Life Cycle===
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| To replicate efficiently, a [[virus]] requires the cooperation of the host cell at all stages of the replicative cycle:<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref> | |
| #Attachment
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| #Penetration
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| #Uncoating
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| #Provision of appropriate metabolic conditions for the synthesis of viral macromolecules
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| #Final assembly of viral subunits
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| #Release of new virions
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| *[[HDV]] also requires the presence of a helper [[hepadnavirus]] to provide the [[protein]] components for its own envelope. How HDV enters hepatocytes is still not known, but it may involve the interaction between HBsAg-L and a cellular receptor. The incoming [[HDV]] [[RNA]] is then transported into the [[nucleus]], probably by the small form of delta antigen, ''HDAg-S''. Binding of HDAg to RNA also protects the HDV RNAs from degradation.<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref>
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| *HDV RNA replication is carried out by cellular [[RNA]] [[polymerase]] II, without a DNA intermediate, and without the help of HBV.
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| *RNA transcription is regulated:<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref>
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| :*''Initially'' - mRNA(s) is(are) transcribed from the incoming minus-strand genome
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| :*''Later'' - after the translation of the [[mRNA]] to make essential replication proteins, there is a switch in the mode of [[RNA]]-directed [[RNA synthesis]] to facilitate replication of the RNA [[genome]]
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| *Translation of the 800 b RNA transcript yields:<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref><ref name="pmid9573243">{{cite journal| author=Dingle K, Bichko V, Zuccola H, Hogle J, Taylor J| title=Initiation of hepatitis delta virus genome replication. | journal=J Virol | year= 1998 | volume= 72 | issue= 6 | pages= 4783-8 | pmid=9573243 | doi= | pmc=PMC110015 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9573243 }} </ref><ref name="pmid7574482">{{cite journal| author=Lai MM| title=The molecular biology of hepatitis delta virus. | journal=Annu Rev Biochem | year= 1995 | volume= 64 | issue= | pages= 259-86 | pmid=7574482 | doi=10.1146/annurev.bi.64.070195.001355 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7574482 }} </ref><ref name="pmid1548764">{{cite journal| author=Ryu WS, Bayer M, Taylor J| title=Assembly of hepatitis delta virus particles. | journal=J Virol | year= 1992 | volume= 66 | issue= 4 | pages= 2310-5 | pmid=1548764 | doi= | pmc=PMC289026 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1548764 }} </ref>
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| :*''Small (p24) form of HDAg (HDAg-S)'' - transactivator of [[HDV]] [[RNA]] replication
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| :*''Large (p27) form of HDAg (HDAg-L)'' - inhibits [[RNA synthesis]] and initiates [[virion]] assembly with HBsAg.
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| * [[HDV]] particles include:
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| :*HBsAg
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| :*HDAg-S
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| :*HDAg-L | |
| :*RNA
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| These elements are only assembled in the presence of the hepatitis B virus (helper virus).
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| <!--
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| The receptor that HDV recognizes on human hepatocytes has not been identified; however it is thought to be the same as the HBV receptor because both viruses have the same outer coat.<ref>{{cite journal|last=Barrera|first=A|coauthors=Guerra, B, Notvall, L, Lanford, RE|title=Mapping of the Hepatitis B Virus Pre-S1 Domain Involved in Receptor Recognition|journal=Journal of virology|date=2005 Aug|volume=79|issue=15|pages=9786–98|pmid=16014940|doi=10.1128/JVI.79.15.9786-9798.2005|pmc=1181564}}</ref> HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg.<ref>{{cite journal|last=Engelke|first=M|coauthors=Mills, K, Seitz, S, Simon, P, Gripon, P, Schnölzer, M, Urban, S|title=Characterization of a hepatitis B and hepatitis delta virus receptor binding site|journal=Hepatology (Baltimore, Md.)|date=2006 Apr|volume=43|issue=4|pages=750–60|pmid=16557545|doi=10.1002/hep.21112}}</ref> Mapping by mutagenesis of this domain has shown that aminoacid residues 9-15 make up the receptor binding site.<ref>{{cite journal|last=Schulze|first=A|coauthors=Schieck, A, Ni, Y, Mier, W, Urban, S|title=Fine Mapping of Pre-S Sequence Requirements for Hepatitis B Virus Large Envelope Protein-Mediated Receptor Interaction|journal=Journal of virology|date=2010 Feb|volume=84|issue=4|pages=1989–2000|pmid=20007265|doi=10.1128/JVI.01902-09|pmc=2812397}}</ref> After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg<ref>{{cite journal|last=Xia|first=YP|coauthors=Yeh, CT, Ou, JH, Lai, MM|title=Characterization of nuclear targeting signal of hepatitis delta antigen: nuclear transport as a protein complex|journal=Journal of virology|date=1992 Feb|volume=66|issue=2|pages=914–21|pmid=1731113|pmc=240792}}</ref> 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,<ref>{{cite journal|author=Lehmann E, Brueckner F, Cramer P|title=Molecular basis of RNA-dependent RNA polymerase II activity|journal=Nature|volume=450|issue=7168|pages=445–9|year=2007|month=November|pmid=18004386|doi=10.1038/nature06290}}</ref><ref>{{cite journal|author=Filipovska J, Konarska MM|title=Specific HDV RNA-templated transcription by pol II in vitro|journal=RNA|volume=6|issue=1|pages=41–54|year=2000|month=January|pmid=10668797|pmc=1369892|url=http://www.rnajournal.org/cgi/pmidlookup?view=long&pmid=10668797|doi=10.1017/S1355838200991167}}</ref> now RNA polymerases I and III have also been shown to be involved in HDV replication<ref>{{cite journal|last=Greco-Stewart|first=VS|coauthors=Schissel, E, Pelchat, M|title=The hepatitis delta virus RNA genome interacts with the human RNA polymerases I and III|journal=Virology|date=2009-03-30|volume=386|issue=1|pages=12–5|pmid=19246067|doi=10.1016/j.virol.2009.02.007}}</ref>
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| 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 pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.
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| 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 nucleous, mediated by RNA Pol I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Pol II.<ref>{{cite journal|last=Li|first=YJ|coauthors=Macnaughton, T, Gao, L, Lai, MM|title=RNA-Templated Replication of Hepatitis Delta Virus: Genomic and Antigenomic RNAs Associate with Different Nuclear Bodies|journal=Journal of virology|date=2006 Jul|volume=80|issue=13|pages=6478–86|pmid=16775335|doi=10.1128/JVI.02650-05|pmc=1488965}}</ref> 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 that acts as a [[ribozyme]], which self-cleaves the linear RNA into monomers. This monomers are then ligated to form circular RNA <ref>{{cite journal|last=Branch|first=AD|coauthors=Benenfeld, BJ, Baroudy, BM, Wells, FV, Gerin, JL, Robertson, HD|title=An ultraviolet-sensitive RNA structural element in a viroid-like domain of the hepatitis delta virus|journal=Science|date=1989-02-03|volume=243|issue=4891|pages=649–52|pmid=2492676|doi=10.1126/science.2492676}}</ref><ref>{{cite journal|last=Wu|first=HN|coauthors=Lin, YJ, Lin, FP, Makino, S, Chang, MF, Lai, MM|title=Human hepatitis delta virus RNA subfragments contain an autocleavage activity|journal=Proceedings of the National Academy of Sciences of the United States of America|date=1989 Mar|volume=86|issue=6|pages=1831–5|pmid=2648383|pmc=286798|doi=10.1073/pnas.86.6.1831}}</ref>
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| There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity.
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| '''The Delta Antigens'''
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| A significant difference between viroids and HDV is that, while viroids produce no proteins, HDV produces two proteins called the small and large delta antigens (HDAg-S and HDAg-L, respectively). These two proteins are produced from a single open reading frame. They are identical for 195 amino acids and differ only by the presence of an additional 19 amino acids at the C-terminus of HDAg-L. 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 is required for 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.
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| '''Evolution'''
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| 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 not known that there are at least 8 genotypes of this virus (HDV-1 to HDV-8).<ref name=Celik2011>{{cite journal |author=Celik I, Karataylı E, Cevik E, ''et al.'' |title=Complete genome sequences and phylogenetic analysis of hepatitis delta viruses isolated from nine Turkish patients |journal=Arch. Virol. |volume=156 |issue=12 |pages=2215–20 |year=2011 |month=December |pmid=21984217 |doi=10.1007/s00705-011-1120-y }}</ref>Phylogenetic studies suggest an African origin for this pathogen.<ref name=Radjef2004>Radjef N, Gordien E, Ivaniushina V, Gault E, Anaïs P, Drugan T, Trinchet JC, Roulot D, Tamby M, Milinkovitch MC, Dény P (2004) Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades. J Virol 78(5):2537-2544</ref>
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| ==References==
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| {{reflist|2}}
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| [[Category:Hepatitis|D]] | |
| [[Category:Viruses]]
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| [[Category:Needs overview]]
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| {{WH}}
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| {{WS}}
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