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| __NOTOC__
| | #REDIRECT[[Hepatitis D Virus]] |
| {{Hepatitis D}}
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| {{CMG}}; {{AE}} {{JS}} {{JM}}
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| ==Overview==
| | [[Category:Emergency mdicine]] |
| The [[hepatitis D virus]] belongs to the genus [[Deltavirus]]. Its [[genome]] consists of a single circular [[RNA]] molecule (ssRNA), with a high degree of complementarity, which gives it the ability to survive at high temperatures. Its life cycle requires cooperation with the host cell at all stages, including: attachment, penetration, uncoating, provision of adequate metabolic conditions, assembly and release of new [[virions]]. The [[replication]] cycle also requires the presence of an [[hepadnavirus]] to provide the [[protein]] components for the new [[HDV]] envelopes. The [[HDV]] is composed by the following particles: [[HBsAg]]; HDAg-S; HDAg-L; and [[RNA]]. Different HDV [[genotype]]s have been associated with different courses of the disease. The [[virus]] has [[tropism]] for [[hepatocytes]] and humans are its own [[natural reservoir]].
| | [[Category:Disease]] |
| | | [[Category:Up-To-Date]] |
| ==Taxonomy==
| | [[Category:Infectious disease]] |
| ''[[Viruses]]''; ''[[Deltavirus]]''; ''[[Hepatitis delta virus]]''
| | [[Category:Hepatology]] |
| | | [[Category:Gastroenterology]] |
| ==Biology==
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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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| The [[hepatitis D virus]] belongs to the genus [[Deltavirus]]. Its [[genome]] is a single, negative stranded, circular [[RNA]] molecule nearly 1.7 kb in length containing about 60% C+G. A high degree of intramolecular complementarity allows about 70% of the [[nucleotides]] to be basepaired to each other to form an unbranched, double-stranded, stable, rod-shaped structure.<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="pmid2198992">{{cite journal| author=Monjardino JP, Saldanha JA| title=Delta hepatitis. The disease and the virus. | journal=Br Med Bull | year= 1990 | volume= 46 | issue= 2 | pages= 399-407 | pmid=2198992 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2198992 }} </ref> Because the viral [[genome]] is double-stranded, the [[virus]] is relatively stable, being able to survive dry heat at 60°C for 30h. The [[genome]] of [[HDV]] is unrelated to the [[genome]]s of [[hepadnavirus]]es, of which [[hepatitis B virus]] (HBV) is a member.<ref name="pmid24843434">{{cite journal| author=Nakamura A, Osonoi T, Terauchi Y| title=Relationship between urinary sodium excretion and pioglitazone-induced edema. | journal=J Diabetes Investig | year= 2010 | volume= 1 | issue= 5 | pages= 208-11 | pmid=24843434 | doi=10.1111/j.2040-1124.2010.00046.x | pmc=PMC4020723 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24843434 }} </ref> [[HDV]] is a replication defective, helper ([[HBV]]) dependent ssRNA virus that requires the surface antigen of [[HBV]] ([[HBsAg]]) for the "encapsidation" of its own [[genome]]. The envelope [[proteins]] on the outer surface of [[HDV]] are entirely provided by [[HBV]].<ref name="pmid3627276">{{cite journal| author=Makino S, Chang MF, Shieh CK, Kamahora T, Vannier DM, Govindarajan S et al.| title=Molecular cloning and sequencing of a human hepatitis delta (delta) virus RNA. | journal=Nature | year= 1987 | volume= 329 | issue= 6137 | pages= 343-6 | pmid=3627276 | doi=10.1038/329343a0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3627276 }} </ref><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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| The outer envelope of [[HDV]] particles contains [[lipids]] and the three forms (S, M, and L) of [[HBsAg|HBV surface antigen]] ([[HBsAg]]), but predominantly the major form of [[HBsAg]] with very few middle (pre S1) and large (pre S2) proteins. The internal [[nucleocapsid]] structure of HDV is composed of the viral single stranded RNA [[genome]] and about 60 copies of delta antigen, the only [[HDV]]-encoded protein.<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 does not [[infect]] established tissue culture cell lines. Complete [[viral replication]] cycles in vitro are limited to primary [[hepatocytes]] that are coinfected with a [[hepadnavirus]] or cotransfected with [[hepadnavirus]] [[cDNA]].<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</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>
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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 [[viral replication]] cycle. These stages include:<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref> | |
| #Atthment
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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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| [[Hepatitis D virus]] requires the presence of an helper [[hepadnavirus]] to provide the [[protein]] components for its own envelope. How [[HDV]] enters [[hepatocytes]] is still unknown, however, it may involve the interaction between ''HBsAg-L'' and the [[HBV]] cellular receptor. This assumption is due to the similarities between the outer coats of these two [[virus]]es.<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref> After entering the host cell, the virus loses its coat.<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref> The incoming [[HDV]] [[RNA]] is then transported into the [[nucleus]], probably by the small form of viral delta antigen, ''HDAg-S''. Binding of HDAg to [[RNA]] also protects the [[HDV]] [[RNA]]s from cellular 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 or help from [[HBV]]. During the replication of the HDV [[genome]] three forms of [[RNA]] are produced:
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| *Circular [[genomic]] [[RNA]]
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| *Circular complementary antigenomic [[RNA]]
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| *Linear polyadenylated antigenomic [[RNA]] - [[mRNA]] containing the open reading frame for the HDAg.
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| Synthesis of ''antigenomic [[RNA]]'' occurs in the [[nucleus]], mediated by [[RNA polymerase I]], whereas synthesis of ''genomic RNA'' takes place in the [[nucleoplasm]], mediated by RNA Polymerase 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> The translation of the [[HDV]] [[mRNA]] 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)'' - after translated in the [[cytoplasm]], returns to the [[nucleus]] to support transcription
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| *''Large (p27) form of HDAg (HDAg-L)'' - inhibitor of [[RNA synthesis]] and initiator of [[virion]] assembly with [[HBsAg]]
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| The [[HDV]] particle is composed by:
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| * [[HBsAg]]
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| * HDAg-S
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| * HDAg-L
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| * [[RNA]]
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| These elements are only assembled in the presence of the [[hepatitis B virus]], which works as an helper [[virus]]. [[HBsAg]] and HDAg-L are necessary and sufficient for [[viral]] assembly. [[HDV]] RNA or HDAg-S, despite present, are not required for this phase. The primary initiation event for [[HDV]] assembly is the interaction of HDAg-L with [[HBsAg]]. HDAg is localized in the [[nuclei]] while [[HBsAg]] is present in the [[cytoplasm]] of the [[infected]] cells. In the [[nucleus]], complexes of small and large HDAg, and new fragments of [[RNA]] are formed. These are then transferred to the Golgi membranes, where they will be conjugated with [[hepatitis B virus]] envelope proteins, thereby forming the final virion.<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref><ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref><ref name="pmid9621000">{{cite journal| author=Modahl LE, Lai MM| title=Transcription of hepatitis delta antigen mRNA continues throughout hepatitis delta virus (HDV) replication: a new model of HDV RNA transcription and replication. | journal=J Virol | year= 1998 | volume= 72 | issue= 7 | pages= 5449-56 | pmid=9621000 | doi= | pmc=PMC110180 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9621000 }} </ref><ref>{{cite book | last = Fields | first = Bernard | title = Fields virology | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2013 | isbn = 1451105630 }}</ref>
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| ===Genotypes===
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| The sequence of [[RNA]] in the genome of HDV has great variability. Genotyping techniques have shown the existence of more than 8 different genotypes of HDV.<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref>
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| Different HDV genotypes have been associated with different courses of natural history. Different studies have shown that:<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref>
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| * Patients with genotype 1 have severe outcomes and lower remission rates than those with HDV genotype 2
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| * Genotype 1 commonly leads to a wide range of manifestations of the disease, making it hard to establish a relationship between natural history and genotype
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| * Genotype 3 is associated with outbreaks of florid hepatitis, leading to liver failure and death, in South America
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| * Mild liver disease is often associated with HDV genotype 4
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| * In Japan there is a variant of the HDV genotype 4 prone to the development of cirrhosis
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| ==Tropism==
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| Hepatitis D shows [[tropism]] for [[hepatocytes]].
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| ==Natural Reservoir==
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| Humans are the only known [[natural reservoir]] of [[hepatitis D virus]], in nature. However, when in the presence of [[hepatitis B virus]], or woodchuck hepatitis virus, [[HDV]] can be experimentally transmitted to chimpanzees and woodchucks, respectively.<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=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref><ref name="pmid2198992">{{cite journal| author=Monjardino JP, Saldanha JA| title=Delta hepatitis. The disease and the virus. | journal=Br Med Bull | year= 1990 | volume= 46 | issue= 2 | pages= 399-407 | pmid=2198992 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2198992 }} </ref><ref name="pmid2778877">{{cite journal| author=Sureau C, Taylor J, Chao M, Eichberg JW, Lanford RE| title=Cloned hepatitis delta virus cDNA is infectious in the chimpanzee. | journal=J Virol | year= 1989 | volume= 63 | issue= 10 | pages= 4292-7 | pmid=2778877 | doi= | pmc=PMC251044 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2778877 }} </ref>
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| ==References==
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| {{reflist|2}}
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