Hepatitis E Virus: Difference between revisions

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#REDIRECT [[Hepatitis E]]
__NOTOC__
{{Hepatitis E}}
 
{{About1|Hepatitis E}}
{{CMG}}; {{AE}} {{JS}}
 
==Overview==
The [[hepatitis E virus]] ([[HEV]]) is the causative agent of hepatitis E.  It is a member of the [[genus]] [[Hepevirus]] that belongs to the Hepeviridae family.  It is a nonenveloped, single-stranded positive-sense [[RNA]] virus.  The [[genome]] of [[HEV]] contains 3 [[Open reading frame]]s: [[ORF]] 1, [[ORF]] 2, and [[ORF]] 3.  The [[RNA]] [[genome]] acts as a template for [[viral replication]], structural and nonstructural [[protein synthesis]].  Five different [[genotype]]s have been identified, all belonging to the same [[serotype]]. Depending on the [[genotype]], epidemiological and clinical manifestations will be different: [[genotype]]s 1 and 2 only cause disease in humans, and are transmitted through water and [[fecal-oral route]], while [[genotype]]s 3 and 4 cause disease in animals, having humans as accidental hosts, and are transmitted through the consumption of undercook meat. The [[HEV]] replicates within the host cell's [[cytoplasm]], however, its [[cellular]] [[receptor]], and mechanism of entry remain unknown.
 
==Taxonomy==
[[Virus]]es; ssRNA viruses; ssRNA positive-strand viruses; Hepeviridae; [[Hepevirus]]; [[Hepatitis E virus]]<ref name=NCBI>{{cite web | title = Hepatitis E virus taxonomy | url = http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?id=12461 }}</ref>
 
==Biology==
{| style="float: right;"
| [[File:HEV.jpg|200px|thumb|none|Hepatitis E virus <SMALL>''[http://phil.cdc.gov/phil/details.asp Centers for Disease Control and Prevention]''<ref>{{Cite web | title = http://phil.cdc.gov/phil/details.asp | url = http://phil.cdc.gov/phil/details.asp}}</ref></SMALL>]]
|}
 
The viral particles are 27 to 34 [[nanometer]]s in diameter, [[nonenveloped]], and contain a single-strand of positive-sense [[RNA]] that is approximately 7200 bases in length, polyadenylated at the 3' terminus, and capped at the 5'terminus.<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref><ref name="pmid2107574">{{cite journal| author=Reyes GR, Purdy MA, Kim JP, Luk KC, Young LM, Fry KE et al.| title=Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis. | journal=Science | year= 1990 | volume= 247 | issue= 4948 | pages= 1335-9 | pmid=2107574 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2107574  }} </ref><ref name="pmid1926770">{{cite journal| author=Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE et al.| title=Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome. | journal=Virology | year= 1991 | volume= 185 | issue= 1 | pages= 120-31 | pmid=1926770 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1926770  }} </ref>
 
The genome of [[HEV]] contains 3 [[Open reading frame]]s:
*'''ORF1''' - encodes functional motifs and non-structural [[protein]] domains for [[replication]] and [[protein]] processing, including:<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref><ref name="pmid22537448">{{cite journal| author=Wedemeyer H, Pischke S, Manns MP| title=Pathogenesis and treatment of hepatitis e virus infection. | journal=Gastroenterology | year= 2012 | volume= 142 | issue= 6 | pages= 1388-1397.e1 | pmid=22537448 | doi=10.1053/j.gastro.2012.02.014 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22537448  }} </ref>
:*[[Cysteine]] [[protease]]
:*[[Methyltransferase]]
:*[[RNA]] [[helicase]]
:*[[RNA]]-dependent [[RNA]] [[polymerase]]
*'''ORF2''' - encodes the protein of the [[viral capsid]], with neutralizing [[epitopes]], responsible for:<ref name="pmid23013075">{{cite journal| author=Hoofnagle JH, Nelson KE, Purcell RH| title=Hepatitis E. | journal=N Engl J Med | year= 2012 | volume= 367 | issue= 13 | pages= 1237-44 | pmid=23013075 | doi=10.1056/NEJMra1204512 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23013075  }} </ref>
:*Assembly of [[virions]]<ref name="pmid9311793">{{cite journal| author=Li TC, Yamakawa Y, Suzuki K, Tatsumi M, Razak MA, Uchida T et al.| title=Expression and self-assembly of empty virus-like particles of hepatitis E virus. | journal=J Virol | year= 1997 | volume= 71 | issue= 10 | pages= 7207-13 | pmid=9311793 | doi= | pmc=PMC192060 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9311793  }} </ref>
:*Target cell interaction<ref name="pmid19812150">{{cite journal| author=Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S| title=Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection. | journal=J Virol | year= 2009 | volume= 83 | issue= 24 | pages= 12714-24 | pmid=19812150 | doi=10.1128/JVI.00717-09 | pmc=PMC2786843 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19812150  }} </ref>
:*[[Immunogenicity]]<ref name="pmid21068233">{{cite journal| author=Xing L, Wang JC, Li TC, Yasutomi Y, Lara J, Khudyakov Y et al.| title=Spatial configuration of hepatitis E virus antigenic domain. | journal=J Virol | year= 2011 | volume= 85 | issue= 2 | pages= 1117-24 | pmid=21068233 | doi=10.1128/JVI.00657-10 | pmc=PMC3020005 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21068233  }} </ref>
:*Mutations in the [[viral capsid]] may attenuate the [[HEV|virus]] and lead to the development of a [[vaccine]]
*'''ORF3''' - encodes a small protein involved in the [[morphogenesis]] and release of the [[virion]]s.<ref name="pmid19339479">{{cite journal| author=Yamada K, Takahashi M, Hoshino Y, Takahashi H, Ichiyama K, Nagashima S et al.| title=ORF3 protein of hepatitis E virus is essential for virion release from infected cells. | journal=J Gen Virol | year= 2009 | volume= 90 | issue= Pt 8 | pages= 1880-91 | pmid=19339479 | doi=10.1099/vir.0.010561-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19339479  }} </ref><ref name="pmid20610720">{{cite journal| author=Emerson SU, Nguyen HT, Torian U, Burke D, Engle R, Purcell RH| title=Release of genotype 1 hepatitis E virus from cultured hepatoma and polarized intestinal cells depends on open reading frame 3 protein and requires an intact PXXP motif. | journal=J Virol | year= 2010 | volume= 84 | issue= 18 | pages= 9059-69 | pmid=20610720 | doi=10.1128/JVI.00593-10 | pmc=PMC2937629 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20610720  }} </ref>
 
===Genotypes===
In order to study the [[biology]] of the [[virus]] and develop new treatment drugs, [[HEV]] must be grown in culture systems, such as:
*PLC/PRF/5 cell line of hepatic carcinoma, A549 cell line of lung carcinoma, and fecal samples from an infected patient<ref name="pmid17325363">{{cite journal| author=Tanaka T, Takahashi M, Kusano E, Okamoto H| title=Development and evaluation of an efficient cell-culture system for Hepatitis E virus. | journal=J Gen Virol | year= 2007 | volume= 88 | issue= Pt 3 | pages= 903-11 | pmid=17325363 | doi=10.1099/vir.0.82535-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17325363  }} </ref>
*HepG2/C3A cell line of hepatoma<ref name="pmid21262830">{{cite journal| author=Shukla P, Nguyen HT, Torian U, Engle RE, Faulk K, Dalton HR et al.| title=Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant. | journal=Proc Natl Acad Sci U S A | year= 2011 | volume= 108 | issue= 6 | pages= 2438-43 | pmid=21262830 | doi=10.1073/pnas.1018878108 | pmc=PMC3038723 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21262830  }} </ref>
 
Molecular studies of [[HEV]] lead to the classification of the [[HEV|virus]] into 4 [[genotype]]s:<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref><ref name="pmid18992406">{{cite journal| author=Dalton HR, Bendall R, Ijaz S, Banks M| title=Hepatitis E: an emerging infection in developed countries. | journal=Lancet Infect Dis | year= 2008 | volume= 8 | issue= 11 | pages= 698-709 | pmid=18992406 | doi=10.1016/S1473-3099(08)70255-X | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18992406  }} </ref><ref name="pmid16175650">{{cite journal| author=Lu L, Li C, Hagedorn CH| title=Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis. | journal=Rev Med Virol | year= 2006 | volume= 16 | issue= 1 | pages= 5-36 | pmid=16175650 | doi=10.1002/rmv.482 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16175650  }} </ref><ref name="pmid12907011">{{cite journal| author=Tei S, Kitajima N, Takahashi K, Mishiro S| title=Zoonotic transmission of hepatitis E virus from deer to human beings. | journal=Lancet | year= 2003 | volume= 362 | issue= 9381 | pages= 371-3 | pmid=12907011 | doi=10.1016/S0140-6736(03)14025-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12907011  }} </ref><ref name="pmid20695796">{{cite journal| author=Colson P, Borentain P, Queyriaux B, Kaba M, Moal V, Gallian P et al.| title=Pig liver sausage as a source of hepatitis E virus transmission to humans. | journal=J Infect Dis | year= 2010 | volume= 202 | issue= 6 | pages= 825-34 | pmid=20695796 | doi=10.1086/655898 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20695796  }} </ref><ref name="pmid22537448">{{cite journal| author=Wedemeyer H, Pischke S, Manns MP| title=Pathogenesis and treatment of hepatitis e virus infection. | journal=Gastroenterology | year= 2012 | volume= 142 | issue= 6 | pages= 1388-1397.e1 | pmid=22537448 | doi=10.1053/j.gastro.2012.02.014 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22537448  }} </ref><ref name="pmid15984321">{{cite journal| author=Goens SD, Perdue ML| title=Hepatitis E viruses in humans and animals. | journal=Anim Health Res Rev | year= 2004 | volume= 5 | issue= 2 | pages= 145-56 | pmid=15984321 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15984321  }} </ref><ref name="pmid20040046">{{cite journal| author=Meng XJ| title=Recent advances in Hepatitis E virus. | journal=J Viral Hepat | year= 2010 | volume= 17 | issue= 3 | pages= 153-61 | pmid=20040046 | doi=10.1111/j.1365-2893.2009.01257.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20040046  }} </ref><ref name="pmid21316404">{{cite journal| author=Meng XJ| title=From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. | journal=Virus Res | year= 2011 | volume= 161 | issue= 1 | pages= 23-30 | pmid=21316404 | doi=10.1016/j.virusres.2011.01.016 | pmc=PMC3126906 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21316404  }} </ref>
 
{| style="border: 2px solid #DCDCDC; font-size: 90%; width: 50%;"
|+ '''Genotypes'''
|-
! style="width: 75px; background: #4479BA; text-align: center;"|{{fontcolor|#FFF|Genotype}}
! style="width: 200px; background: #4479BA; text-align: center;"| {{fontcolor|#FFF|Characteristics}}
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''HEV1'''
| style="background: #DCDCDC; padding: 5px;"|
*Restricted to humans
*Responsible for [[epidemic]] hepatitis
*Water-borne disease in developing countries
*[[Fecal-oral route]] of [[transmission]]
*Predominant in Asia ([[endemic]] and [[epidemic]])
*Classified in 4 subgenotypes
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''HEV2'''
| style="background: #DCDCDC; padding: 5px;"|
*Restricted to humans
*Responsible for [[epidemic]] hepatitis
*Water-borne disease in developing countries
*[[Fecal-oral route]] of [[transmission]]
*Predominant in Central America and Africa
*Classified in 2 subgenotypes
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''HEV3'''
| style="background: #DCDCDC; padding: 5px;"|
*Infects humans (accidental host) and other mammalian species, such as pigs, deer, shellfish and rodents ([[zoonosis]])
*Responsible for autochthonous hepatitis E in developed and developing countries
*Worldwide distribution
*Consumption of undercooked pork
*Classified in 3 subgenotypes
*Important [[zoonotic]] [[transmission]]
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''HEV4'''
| style="background: #DCDCDC; padding: 5px;"|
*Infects humans (accidental host) and other mammalian species, such as pigs, deer, shellfish and rodents ([[zoonosis]])
*Responsible for autochthonous hepatitis E in developed and developing countries
*Most frequent in southeast Asia
*Consumption of undercooked pork
*Classified in 7 subgenotypes
*Important [[zoonotic]] [[transmission]]
 
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''HEV5'''
| style="background: #DCDCDC; padding: 5px;"|
*Recently identified in birds (''Avian HEV'')
|}
 
Despite the [[epidemiological]] and clinical differences, the different [[genotype]]s are thought to belong to one same [[serotype]], after studies with cross-[[neutralization]].<ref name="pmid21642534">{{cite journal| author=Tang X, Yang C, Gu Y, Song C, Zhang X, Wang Y et al.| title=Structural basis for the neutralization and genotype specificity of hepatitis E virus. | journal=Proc Natl Acad Sci U S A | year= 2011 | volume= 108 | issue= 25 | pages= 10266-71 | pmid=21642534 | doi=10.1073/pnas.1101309108 | pmc=PMC3121834 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21642534  }} </ref>  Evidence shows that [[HEV]] has evolved and adapted to a series of hosts, until finally being able to [[infect]] humans. [[HEV]] subgenotypes in humans and pigs have been associated, also suggesting [[zoonotic]] [[transmission]].<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref><ref name="pmid19116067">{{cite journal| author=Legrand-Abravanel F, Mansuy JM, Dubois M, Kamar N, Peron JM, Rostaing L et al.| title=Hepatitis E virus genotype 3 diversity, France. | journal=Emerg Infect Dis | year= 2009 | volume= 15 | issue= 1 | pages= 110-4 | pmid=19116067 | doi=10.3201/eid1501.080296 | pmc=PMC2660688 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19116067  }} </ref><ref name="pmid21203540">{{cite journal| author=Purdy MA, Khudyakov YE| title=Evolutionary history and population dynamics of hepatitis E virus. | journal=PLoS One | year= 2010 | volume= 5 | issue= 12 | pages= e14376 | pmid=21203540 | doi=10.1371/journal.pone.0014376 | pmc=PMC3006657 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21203540  }} </ref>
 
===Life Cycle===
The [[hepatitis E virus]] replicates in the [[cytoplasm]] of the host cell. The [[genomic]] [[RNA]] serves as template chain for [[replication]] and encodes nonstructural [[proteins]], while subgenomic [[RNA]] produces [[capsid]] proteins.  Different recombination events may lead to changes in [[viral replication]], tissue [[tropism]] and [[pathogenesis]] of the [[HEV|virus]].<ref name="pmid23013075">{{cite journal| author=Hoofnagle JH, Nelson KE, Purcell RH| title=Hepatitis E. | journal=N Engl J Med | year= 2012 | volume= 367 | issue= 13 | pages= 1237-44 | pmid=23013075 | doi=10.1056/NEJMra1204512 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23013075  }} </ref>
 
==Tropism==
Hepatitis D shows [[tropism]] for [[hepatocytes]], however, the host [[cell receptor]] has not been identified.<ref name="pmid19812150">{{cite journal| author=Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S| title=Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection. | journal=J Virol | year= 2009 | volume= 83 | issue= 24 | pages= 12714-24 | pmid=19812150 | doi=10.1128/JVI.00717-09 | pmc=PMC2786843 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19812150  }} </ref>
==Natural Reservoir==
The [[natural reservoir]] of [[HEV]] is yet to be identified.  Different observations have suggested different reservoirs:
*Prolonged fecal shedding from patients with history of the disease has been suggested. However, the duration of viral shedding in feces is not compatible with this hypothesis.<ref name="pmid11009149">{{cite journal| author=Aggarwal R, Kini D, Sofat S, Naik SR, Krawczynski K| title=Duration of viraemia and faecal viral excretion in acute hepatitis E. | journal=Lancet | year= 2000 | volume= 356 | issue= 9235 | pages= 1081-2 | pmid=11009149 | doi=10.1016/S0140-6736(00)02737-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11009149  }} </ref>
*Environmental reservoir was suggested following detection of [[HEV]] in sewages.<ref name="pmid17935174">{{cite journal| author=Ippagunta SK, Naik S, Sharma B, Aggarwal R| title=Presence of hepatitis E virus in sewage in Northern India: frequency and seasonal pattern. | journal=J Med Virol | year= 2007 | volume= 79 | issue= 12 | pages= 1827-31 | pmid=17935174 | doi=10.1002/jmv.21017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17935174  }} </ref>
*Continuous fecal shedding from [[asymptomatic]] patients was suggested as a form of maintenance of the [[HEV|virus]], contaminating water supplies.<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref>
*The existence of an animal reservoir is supported by the detection of anti-[[HEV]] antibodies in different animal species.<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref>
 
==References==
{{reflist|2}}
 
[[Category:Hepatitis|E]]
[[Category:Viruses]]
[[Category:Infectious disease]]
[[Category:Gastroenterology]]

Revision as of 19:22, 6 August 2015

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This page is about clinical aspects of the disease.  For microbiologic aspects of the causative organism(s), see Hepatitis E.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

The hepatitis E virus (HEV) is the causative agent of hepatitis E. It is a member of the genus Hepevirus that belongs to the Hepeviridae family. It is a nonenveloped, single-stranded positive-sense RNA virus. The genome of HEV contains 3 Open reading frames: ORF 1, ORF 2, and ORF 3. The RNA genome acts as a template for viral replication, structural and nonstructural protein synthesis. Five different genotypes have been identified, all belonging to the same serotype. Depending on the genotype, epidemiological and clinical manifestations will be different: genotypes 1 and 2 only cause disease in humans, and are transmitted through water and fecal-oral route, while genotypes 3 and 4 cause disease in animals, having humans as accidental hosts, and are transmitted through the consumption of undercook meat. The HEV replicates within the host cell's cytoplasm, however, its cellular receptor, and mechanism of entry remain unknown.

Taxonomy

Viruses; ssRNA viruses; ssRNA positive-strand viruses; Hepeviridae; Hepevirus; Hepatitis E virus[1]

Biology

Hepatitis E virus Centers for Disease Control and Prevention[2]

The viral particles are 27 to 34 nanometers in diameter, nonenveloped, and contain a single-strand of positive-sense RNA that is approximately 7200 bases in length, polyadenylated at the 3' terminus, and capped at the 5'terminus.[3][4][5]

The genome of HEV contains 3 Open reading frames:

Genotypes

In order to study the biology of the virus and develop new treatment drugs, HEV must be grown in culture systems, such as:

  • PLC/PRF/5 cell line of hepatic carcinoma, A549 cell line of lung carcinoma, and fecal samples from an infected patient[13]
  • HepG2/C3A cell line of hepatoma[14]

Molecular studies of HEV lead to the classification of the virus into 4 genotypes:[3][15][16][17][18][6][19][20][21]

Genotypes
Genotype Characteristics
HEV1
HEV2
  • Restricted to humans
  • Responsible for epidemic hepatitis
  • Water-borne disease in developing countries
  • Fecal-oral route of transmission
  • Predominant in Central America and Africa
  • Classified in 2 subgenotypes
HEV3
  • Infects humans (accidental host) and other mammalian species, such as pigs, deer, shellfish and rodents (zoonosis)
  • Responsible for autochthonous hepatitis E in developed and developing countries
  • Worldwide distribution
  • Consumption of undercooked pork
  • Classified in 3 subgenotypes
  • Important zoonotic transmission
HEV4
  • Infects humans (accidental host) and other mammalian species, such as pigs, deer, shellfish and rodents (zoonosis)
  • Responsible for autochthonous hepatitis E in developed and developing countries
  • Most frequent in southeast Asia
  • Consumption of undercooked pork
  • Classified in 7 subgenotypes
  • Important zoonotic transmission
HEV5
  • Recently identified in birds (Avian HEV)

Despite the epidemiological and clinical differences, the different genotypes are thought to belong to one same serotype, after studies with cross-neutralization.[22] Evidence shows that HEV has evolved and adapted to a series of hosts, until finally being able to infect humans. HEV subgenotypes in humans and pigs have been associated, also suggesting zoonotic transmission.[3][23][24]

Life Cycle

The hepatitis E virus replicates in the cytoplasm of the host cell. The genomic RNA serves as template chain for replication and encodes nonstructural proteins, while subgenomic RNA produces capsid proteins. Different recombination events may lead to changes in viral replication, tissue tropism and pathogenesis of the virus.[7]

Tropism

Hepatitis D shows tropism for hepatocytes, however, the host cell receptor has not been identified.[9]

Natural Reservoir

The natural reservoir of HEV is yet to be identified. Different observations have suggested different reservoirs:

  • Prolonged fecal shedding from patients with history of the disease has been suggested. However, the duration of viral shedding in feces is not compatible with this hypothesis.[25]
  • Environmental reservoir was suggested following detection of HEV in sewages.[26]
  • Continuous fecal shedding from asymptomatic patients was suggested as a form of maintenance of the virus, contaminating water supplies.[27]
  • The existence of an animal reservoir is supported by the detection of anti-HEV antibodies in different animal species.[27]

References

  1. ↑ "Hepatitis E virus taxonomy".
  2. ↑ "http://phil.cdc.gov/phil/details.asp". External link in |title= (help)
  3. ↑ 3.0 3.1 3.2 3.3 Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J; et al. (2012). "Hepatitis E." Lancet. 379 (9835): 2477–88. doi:10.1016/S0140-6736(11)61849-7. PMID 22549046.
  4. ↑ Reyes GR, Purdy MA, Kim JP, Luk KC, Young LM, Fry KE; et al. (1990). "Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis". Science. 247 (4948): 1335–9. PMID 2107574.
  5. ↑ Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE; et al. (1991). "Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome". Virology. 185 (1): 120–31. PMID 1926770.
  6. ↑ 6.0 6.1 Wedemeyer H, Pischke S, Manns MP (2012). "Pathogenesis and treatment of hepatitis e virus infection". Gastroenterology. 142 (6): 1388–1397.e1. doi:10.1053/j.gastro.2012.02.014. PMID 22537448.
  7. ↑ 7.0 7.1 Hoofnagle JH, Nelson KE, Purcell RH (2012). "Hepatitis E." N Engl J Med. 367 (13): 1237–44. doi:10.1056/NEJMra1204512. PMID 23013075.
  8. ↑ Li TC, Yamakawa Y, Suzuki K, Tatsumi M, Razak MA, Uchida T; et al. (1997). "Expression and self-assembly of empty virus-like particles of hepatitis E virus". J Virol. 71 (10): 7207–13. PMC 192060. PMID 9311793.
  9. ↑ 9.0 9.1 Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S (2009). "Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection". J Virol. 83 (24): 12714–24. doi:10.1128/JVI.00717-09. PMC 2786843. PMID 19812150.
  10. ↑ Xing L, Wang JC, Li TC, Yasutomi Y, Lara J, Khudyakov Y; et al. (2011). "Spatial configuration of hepatitis E virus antigenic domain". J Virol. 85 (2): 1117–24. doi:10.1128/JVI.00657-10. PMC 3020005. PMID 21068233.
  11. ↑ Yamada K, Takahashi M, Hoshino Y, Takahashi H, Ichiyama K, Nagashima S; et al. (2009). "ORF3 protein of hepatitis E virus is essential for virion release from infected cells". J Gen Virol. 90 (Pt 8): 1880–91. doi:10.1099/vir.0.010561-0. PMID 19339479.
  12. ↑ Emerson SU, Nguyen HT, Torian U, Burke D, Engle R, Purcell RH (2010). "Release of genotype 1 hepatitis E virus from cultured hepatoma and polarized intestinal cells depends on open reading frame 3 protein and requires an intact PXXP motif". J Virol. 84 (18): 9059–69. doi:10.1128/JVI.00593-10. PMC 2937629. PMID 20610720.
  13. ↑ Tanaka T, Takahashi M, Kusano E, Okamoto H (2007). "Development and evaluation of an efficient cell-culture system for Hepatitis E virus". J Gen Virol. 88 (Pt 3): 903–11. doi:10.1099/vir.0.82535-0. PMID 17325363.
  14. ↑ Shukla P, Nguyen HT, Torian U, Engle RE, Faulk K, Dalton HR; et al. (2011). "Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant". Proc Natl Acad Sci U S A. 108 (6): 2438–43. doi:10.1073/pnas.1018878108. PMC 3038723. PMID 21262830.
  15. ↑ Dalton HR, Bendall R, Ijaz S, Banks M (2008). "Hepatitis E: an emerging infection in developed countries". Lancet Infect Dis. 8 (11): 698–709. doi:10.1016/S1473-3099(08)70255-X. PMID 18992406.
  16. ↑ Lu L, Li C, Hagedorn CH (2006). "Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis". Rev Med Virol. 16 (1): 5–36. doi:10.1002/rmv.482. PMID 16175650.
  17. ↑ Tei S, Kitajima N, Takahashi K, Mishiro S (2003). "Zoonotic transmission of hepatitis E virus from deer to human beings". Lancet. 362 (9381): 371–3. doi:10.1016/S0140-6736(03)14025-1. PMID 12907011.
  18. ↑ Colson P, Borentain P, Queyriaux B, Kaba M, Moal V, Gallian P; et al. (2010). "Pig liver sausage as a source of hepatitis E virus transmission to humans". J Infect Dis. 202 (6): 825–34. doi:10.1086/655898. PMID 20695796.
  19. ↑ Goens SD, Perdue ML (2004). "Hepatitis E viruses in humans and animals". Anim Health Res Rev. 5 (2): 145–56. PMID 15984321.
  20. ↑ Meng XJ (2010). "Recent advances in Hepatitis E virus". J Viral Hepat. 17 (3): 153–61. doi:10.1111/j.1365-2893.2009.01257.x. PMID 20040046.
  21. ↑ Meng XJ (2011). "From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety". Virus Res. 161 (1): 23–30. doi:10.1016/j.virusres.2011.01.016. PMC 3126906. PMID 21316404.
  22. ↑ Tang X, Yang C, Gu Y, Song C, Zhang X, Wang Y; et al. (2011). "Structural basis for the neutralization and genotype specificity of hepatitis E virus". Proc Natl Acad Sci U S A. 108 (25): 10266–71. doi:10.1073/pnas.1101309108. PMC 3121834. PMID 21642534.
  23. ↑ Legrand-Abravanel F, Mansuy JM, Dubois M, Kamar N, Peron JM, Rostaing L; et al. (2009). "Hepatitis E virus genotype 3 diversity, France". Emerg Infect Dis. 15 (1): 110–4. doi:10.3201/eid1501.080296. PMC 2660688. PMID 19116067.
  24. ↑ Purdy MA, Khudyakov YE (2010). "Evolutionary history and population dynamics of hepatitis E virus". PLoS One. 5 (12): e14376. doi:10.1371/journal.pone.0014376. PMC 3006657. PMID 21203540.
  25. ↑ Aggarwal R, Kini D, Sofat S, Naik SR, Krawczynski K (2000). "Duration of viraemia and faecal viral excretion in acute hepatitis E." Lancet. 356 (9235): 1081–2. doi:10.1016/S0140-6736(00)02737-9. PMID 11009149.
  26. ↑ Ippagunta SK, Naik S, Sharma B, Aggarwal R (2007). "Presence of hepatitis E virus in sewage in Northern India: frequency and seasonal pattern". J Med Virol. 79 (12): 1827–31. doi:10.1002/jmv.21017. PMID 17935174.
  27. ↑ 27.0 27.1 Aggarwal R, Jameel S (2011). "Hepatitis E." Hepatology. 54 (6): 2218–26. doi:10.1002/hep.24674. PMID 21932388.
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