{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:49:10Z","timestamp":1792622950343,"version":"4.5.0"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Hepatitis E virus (HEV) is a zoonotic pathogen causing hepatitis in both human and animal hosts, which is responsible for acute hepatitis E outbreaks worldwide. The 7.2 kb genome of the HEV encodes three well-defined open reading frames (ORFs), where the ORF2 translation product acts as the major virion component to form the viral capsid. In recent years, besides forming the capsid, more functions have been revealed for the HEV-ORF2 protein, and it appears that HEV-ORF2 plays multiple functions in both viral replication and pathogenesis. In this review, we systematically summarize the recent research advances regarding the function of the HEV-ORF2 protein such as application in the development of a vaccine, regulation of the innate immune response and cellular signaling, involvement in host tropism and participation in HEV pathogenesis as a novel secretory factor. Progress in understanding more of the function of HEV-ORF2 protein beyond the capsid protein would contribute to improved control and treatment of HEV infection.<\/jats:p>","DOI":"10.3389\/fmicb.2021.739124","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T17:32:21Z","timestamp":1633800741000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["The Hepatitis E Virus Open Reading Frame 2 Protein: Beyond Viral Capsid"],"prefix":"10.3389","volume":"12","author":[{"given":"Zhaobin","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinqian","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Nan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.virusres.2011.02.011","article-title":"Molecular virology of hepatitis E virus.","volume":"161","author":"Ahmad","year":"2011","journal-title":"Virus Res."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/s13062-015-0050-0","article-title":"Sequence analysis reveals a conserved extension in the capping enzyme of the alphavirus supergroup, and a homologous domain in nodaviruses.","volume":"10","author":"Ahola","year":"2015","journal-title":"Biol. Direct"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42737-2","article-title":"New insights into the ORF2 capsid protein, a key player of the hepatitis E virus lifecycle.","volume":"9","author":"Ankavay","year":"2019","journal-title":"Sci. Rep."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1016\/j.vaccine.2008.11.097","article-title":"Challenge studies in Rhesus monkeys immunized with candidate hepatitis E vaccines: DNA, DNA-prime-protein-boost and DNA-protein encapsulated in liposomes.","volume":"27","author":"Arankalle","year":"2009","journal-title":"Vaccine"},{"key":"B5","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.jviromet.2012.10.017","article-title":"Replication of hepatitis E virus in three-dimensional cell culture.","volume":"187","author":"Berto","year":"2013","journal-title":"J. Virol. Methods"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2012.7","article-title":"Molecular biology and replication of hepatitis E virus.","volume":"1","author":"Cao","year":"2012","journal-title":"Emerg. Microbes Infect"},{"key":"B7","doi-asserted-by":"publisher","first-page":"5073","DOI":"10.1016\/j.vaccine.2017.05.072","article-title":"A phase 1 randomized open-label clinical study to evaluate the safety and tolerability of a novel recombinant hepatitis E vaccine.","volume":"35","author":"Cao","year":"2017","journal-title":"Vaccine"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1099\/jgv.0.000478","article-title":"Hepatitis E virus (HEV)-1 harbouring HEV-4 non-structural protein (ORF1) replicates in transfected porcine kidney cells.","volume":"97","author":"Chatterjee","year":"2016","journal-title":"J. Gen. Virol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines8020178","article-title":"Synthetic Peptides Containing Three Neutralizing Epitopes of Genotype 4 Swine Hepatitis E Virus ORF2 induced Protection against Swine HEV Infection in Rabbit.","volume":"8","author":"Chen","year":"2020","journal-title":"Vaccines (Basel)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.3748\/wjg.v11.i25.3887","article-title":"C-terminal domain of hepatitis C virus core protein is essential for secretion.","volume":"11","author":"Choi","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005123","article-title":"The dual role of an ESCRT-0 component HGS in HBV transcription and naked capsid secretion.","volume":"11","author":"Chou","year":"2015","journal-title":"PLoS Pathog."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1086\/591970","article-title":"Time trend of the prevalence of hepatitis E antibodies among farmers and blood donors: a potential zoonosis in Denmark.","volume":"47","author":"Christensen","year":"2008","journal-title":"Clin. Infect Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1099\/vir.0.043711-0","article-title":"Rescue of a genotype 4 human hepatitis E virus from cloned cDNA and characterization of intergenotypic chimeric viruses in cultured human liver cells and in pigs.","volume":"93","author":"Cordoba","year":"2012","journal-title":"J. Gen. Virol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1016\/S1473-3099(08)70255-X","article-title":"Hepatitis E: an emerging infection in developed countries.","volume":"8","author":"Dalton","year":"2008","journal-title":"Lancet Infect Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nrneurol.2015.234","article-title":"Hepatitis E virus and neurological injury.","volume":"12","author":"Dalton","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1073\/pnas.1614955114","article-title":"Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles.","volume":"114","author":"Ding","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2985","DOI":"10.1021\/pr060171o","article-title":"Disorder and sequence repeats in hub proteins and their implications for network evolution.","volume":"5","author":"Dosztanyi","year":"2006","journal-title":"J. Proteome Res."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-9-S2-S1","article-title":"The unfoldomics decade: an update on intrinsically disordered proteins.","volume":"9","author":"Dunker","year":"2008","journal-title":"BMC Genomics"},{"key":"B19","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.virusres.2010.12.011","article-title":"Intergenotypic chimeric hepatitis E viruses (HEVs) with the genotype 4 human HEV capsid gene in the backbone of genotype 3 swine HEV are infectious in pigs.","volume":"156","author":"Feagins","year":"2011","journal-title":"Virus Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1146\/annurev-virology-031413-085359","article-title":"Naked viruses that aren\u2019t always naked: quasi-enveloped agents of acute Hepatitis.","volume":"1","author":"Feng","year":"2014","journal-title":"Annu. Rev. Virol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.jhep.2015.08.034","article-title":"Detection and assessment of infectivity of hepatitis E virus in urine.","volume":"64","author":"Geng","year":"2016","journal-title":"J. Hepatol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/0014-5793(91)81034-6","article-title":"Putative papain-related thiol proteases of positive-strand RNA viruses. Identification of rubi- and aphthovirus proteases and delineation of a novel conserved domain associated with proteases of rubi-, alpha- and coronaviruses.","volume":"288","author":"Gorbalenya","year":"1991","journal-title":"FEBS Lett."},{"key":"B23","doi-asserted-by":"publisher","first-page":"5919","DOI":"10.1128\/JVI.00046-06","article-title":"A bicistronic subgenomic mRNA encodes both the ORF2 and ORF3 proteins of hepatitis E virus.","volume":"80","author":"Graff","year":"2006","journal-title":"J. Virol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1128\/JVI.01219-07","article-title":"Mutations within potential glycosylation sites in the capsid protein of hepatitis E virus prevent the formation of infectious virus particles.","volume":"82","author":"Graff","year":"2008","journal-title":"J. Virol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1002\/hep.26636","article-title":"Chronic hepatitis E in an immunocompetent patient: a case report.","volume":"59","author":"Grewal","year":"2014","journal-title":"Hepatology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1038\/cr.2015.34","article-title":"Structural basis for the neutralization of hepatitis E virus by a cross-genotype antibody.","volume":"25","author":"Gu","year":"2015","journal-title":"Cell Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"12992","DOI":"10.1073\/pnas.0904848106","article-title":"Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding.","volume":"106","author":"Guu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.2903\/j.efsa.2017.4886","article-title":"Public health risks associated with hepatitis E virus (HEV) as a food-borne pathogen.","volume":"15","author":"Hazards","year":"2017","journal-title":"EFSA J."},{"key":"B29","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1099\/vir.0.83308-0","article-title":"Putative receptor-binding sites of hepatitis E virus.","volume":"89","author":"He","year":"2008","journal-title":"J. Gen. Virol."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1101\/2021.05.26.445820","article-title":"The fate of Hepatitis E virus capsid protein is regulated by an Arginine-Rich Motif.","author":"Hervouet","year":"2021","journal-title":"bioRxiv"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.00656","article-title":"Hepatitis E Virus ORF2 Inhibits RIG-I Mediated Interferon Response.","volume":"11","author":"Hingane","year":"2020","journal-title":"Front. Microbiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1111\/tra.12260","article-title":"Hepatitis E virus enters liver cells through a dynamin-2, clathrin and membrane cholesterol-dependent pathway.","volume":"16","author":"Holla","year":"2015","journal-title":"Traffic"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1056\/NEJMra1204512","article-title":"Hepatitis E.","volume":"367","author":"Hoofnagle","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"463","DOI":"10.3109\/10409238.2010.502516","article-title":"The ESCRT complexes.","volume":"45","author":"Hurley","year":"2010","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S1462399499001271","article-title":"Molecular biology and pathogenesis of hepatitis E virus.","volume":"1999","author":"Jameel","year":"1999","journal-title":"Expert. Rev. Mol. Med."},{"key":"B36","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1128\/jvi.70.1.207-216.1996","article-title":"Expression in animal cells and characterization of the hepatitis E virus structural proteins.","volume":"70","author":"Jameel","year":"1996","journal-title":"J. Virol."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025378","article-title":"Hepatitis E virus ORF2 protein activates the pro-apoptotic gene CHOP and anti-apoptotic heat shock proteins.","volume":"6","author":"John","year":"2011","journal-title":"PLoS One"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4225","DOI":"10.1128\/AEM.00951-16","article-title":"Thermal Stability of Hepatitis E Virus as Estimated by a Cell Culture Method.","volume":"82","author":"Johne","year":"2016","journal-title":"Appl. Environ. Microbiol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"12714","DOI":"10.1128\/JVI.00717-09","article-title":"Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection.","volume":"83","author":"Kalia","year":"2009","journal-title":"J. Virol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"173","DOI":"10.3201\/eid1702.100856","article-title":"Hepatitis E virus and neurologic disorders.","volume":"17","author":"Kamar","year":"2011","journal-title":"Emerg. Infect Dis."},{"key":"B41","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1097\/TP.0b013e318245f14c","article-title":"Hepatitis E virus and the kidney in solid-organ transplant patients.","volume":"93","author":"Kamar","year":"2012","journal-title":"Transplantation"},{"key":"B42","doi-asserted-by":"crossref","first-page":"S365","DOI":"10.1046\/j.1440-1746.17.s3.29.x","article-title":"DNA vaccination against hepatitis E virus infection in cynomolgus macaques.","volume":"17","author":"Kamili","year":"2002","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1111\/j.1365-2893.2011.01559.x","article-title":"Hepatitis E virus enters liver cells through receptor-dependent clathrin-mediated endocytosis.","volume":"19","author":"Kapur","year":"2012","journal-title":"J. Viral. Hepat."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1172\/JCI10323","article-title":"Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation.","volume":"106","author":"Kittlesen","year":"2000","journal-title":"J. Clin. Invest."},{"key":"B45","doi-asserted-by":"crossref","first-page":"8259","DOI":"10.1073\/pnas.89.17.8259","article-title":"Computer-assisted assignment of functional domains in the nonstructural polyprotein of hepatitis E virus: delineation of an additional group of positive-strand RNA plant and animal viruses.","volume":"89","author":"Koonin","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B46","doi-asserted-by":"publisher","first-page":"30653","DOI":"10.1074\/jbc.M002373200","article-title":"The long signal peptide isoform and its alternative processing direct the intracellular trafficking of interleukin-15.","volume":"275","author":"Kurys","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B47","doi-asserted-by":"publisher","first-page":"6367","DOI":"10.1128\/JVI.75.14.6367-6374.2001","article-title":"Molecular basis for the interaction of the hepatitis B virus core antigen with the surface immunoglobulin receptor on naive B cells.","volume":"75","author":"Lazdina","year":"2001","journal-title":"J. Virol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1053\/j.gastro.2015.10.048","article-title":"Chronic Infection With Camelid Hepatitis E Virus in a Liver Transplant Recipient Who Regularly Consumes Camel Meat and Milk.","volume":"150","author":"Lee","year":"2016","journal-title":"Gastroenterology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e02205","DOI":"10.1128\/JVI.02205-18","article-title":"Chicken organic Anion-Transporting polypeptide 1A2, a novel Avian Hepatitis E Virus (HEV) ORF2-Interacting protein, is involved in avian HEV infection.","volume":"93","author":"Li","year":"2019","journal-title":"J. Virol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"12999","DOI":"10.1128\/JVI.79.20.12999-13006.2005","article-title":"Essential elements of the capsid protein for self-assembly into empty virus-like particles of hepatitis E virus.","volume":"79","author":"Li","year":"","journal-title":"J. Virol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.1016\/j.vaccine.2004.11.064","article-title":"A bacterially expressed particulate hepatitis E vaccine: antigenicity, immunogenicity and protectivity on primates.","volume":"23","author":"Li","year":"","journal-title":"Vaccine"},{"key":"B52","doi-asserted-by":"publisher","first-page":"3400","DOI":"10.1074\/jbc.M410361200","article-title":"Mutational analysis of essential interactions involved in the assembly of hepatitis E virus capsid.","volume":"280","author":"Li","year":"","journal-title":"J. Biol. Chem."},{"key":"B53","doi-asserted-by":"crossref","first-page":"7207","DOI":"10.1128\/jvi.71.10.7207-7213.1997","article-title":"Expression and self-assembly of empty virus-like particles of hepatitis E virus.","volume":"71","author":"Li","year":"1997","journal-title":"J. Virol."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/v11111050","article-title":"The Capsid Protein of Hepatitis E Virus Inhibits Interferon Induction via Its N-terminal Arginine-Rich Motif.","volume":"11","author":"Lin","year":"2019","journal-title":"Viruses"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02930","article-title":"beta-TrCP Restricts Lipopolysaccharide (LPS)-Induced Activation of TRAF6-IKK Pathway Upstream of IkappaBalpha Signaling.","volume":"9","author":"Liu","year":"2018","journal-title":"Front. Immunol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"8240","DOI":"10.1128\/jvi.75.17.8240-8250.2001","article-title":"Nonenveloped nucleocapsids of hepatitis C virus in the serum of infected patients.","volume":"75","author":"Maillard","year":"2001","journal-title":"J. Virol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1006\/prep.1996.0099","article-title":"Purification of a soluble hepatitis E open reading frame 2-derived protein with unique antigenic properties.","volume":"8","author":"McAtee","year":"1996","journal-title":"Protein Expr. Purif."},{"key":"B58","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1055\/s-0033-1338113","article-title":"Zoonotic and foodborne transmission of hepatitis E virus.","volume":"33","author":"Meng","year":"2013","journal-title":"Semin. Liver Dis."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005695","article-title":"Expanding Host Range and Cross-Species Infection of Hepatitis E Virus.","volume":"12","author":"Meng","year":"2016","journal-title":"PLoS Pathog."},{"key":"B60","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1053\/j.gastro.2017.09.020","article-title":"Hepatitis E Virus Lifecycle and Identification of 3 Forms of the ORF2 Capsid Protein.","volume":"154","author":"Montpellier","year":"2018","journal-title":"Gastroenterology"},{"key":"B61","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.virusres.2011.03.015","article-title":"Structure of hepatitis E viral particle.","volume":"161","author":"Mori","year":"2011","journal-title":"Virus Res."},{"key":"B62","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1099\/vir.0.025791-0","article-title":"A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells.","volume":"92","author":"Nagashima","year":"2010","journal-title":"J. Gen. Virol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"2838","DOI":"10.1099\/vir.0.035378-0","article-title":"Tumour susceptibility gene 101 and the vacuolar protein sorting pathway are required for the release of hepatitis E virions.","volume":"92","author":"Nagashima","year":"","journal-title":"J. Gen. Virol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1099\/vir.0.025791-0","article-title":"A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells.","volume":"92","author":"Nagashima","year":"","journal-title":"J. Gen. Virol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1007\/s00705-013-1912-3","article-title":"The membrane on the surface of hepatitis E virus particles is derived from the intracellular membrane and contains trans-Golgi network protein 2.","volume":"159","author":"Nagashima","year":"2014","journal-title":"Arch. Virol."},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005521","article-title":"Endoplasmic Reticulum Stress Induced Synthesis of a Novel Viral Factor Mediates Efficient Replication of Genotype-1 Hepatitis E Virus.","volume":"12","author":"Nair","year":"2016","journal-title":"PLoS Pathog."},{"key":"B67","doi-asserted-by":"publisher","first-page":"4999","DOI":"10.3390\/v6124999","article-title":"Interferon induction by RNA viruses and antagonism by viral pathogens.","volume":"6","author":"Nan","year":"2014","journal-title":"Viruses"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.02396","article-title":"Zoonotic Hepatitis E Virus: an ignored risk for public health.","volume":"8","author":"Nan","year":"","journal-title":"Front. Microbiol."},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01758","article-title":"Interplay between janus kinase\/signal transducer and activator of transcription signaling activated by type i interferons and viral antagonism.","volume":"8","author":"Nan","year":"","journal-title":"Front. Immunol."},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.01419","article-title":"Molecular Biology and Infection of Hepatitis E Virus.","volume":"7","author":"Nan","year":"2016","journal-title":"Front. Microbiol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1128\/JVI.02205-13","article-title":"Hepatitis E virus genotype 1 infection of swine kidney cells in vitro is inhibited at multiple levels.","volume":"88","author":"Nguyen","year":"2014","journal-title":"J. Virol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1002\/rmv.678","article-title":"Efficient cell culture systems for hepatitis E virus strains in feces and circulating blood.","volume":"21","author":"Okamoto","year":"2011","journal-title":"Rev. Med. Virol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1099\/vir.0.066142-0","article-title":"Hepatitis E Virus (HEV) Protease: a Chymotrypsin-like Enzyme that Processes both Non-structural (pORF1) and Capsid (pORF2) Protein.","volume":"95","author":"Paliwal","year":"2014","journal-title":"J. Gen. Virol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.virusres.2013.07.020","article-title":"Molecular characterization of hepatitis E virus ORF1 gene supports a papain-like cysteine protease (PCP)-domain activity.","volume":"178","author":"Parvez","year":"2013","journal-title":"Virus Res."},{"key":"B75","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.gene.2015.04.026","article-title":"The hepatitis E virus ORF1 \u2018X-domain\u2019 residues form a putative macrodomain protein\/Appr-1\u201d-pase catalytic-site, critical for viral RNA replication.","volume":"566","author":"Parvez","year":"2015","journal-title":"Gene"},{"key":"B76","doi-asserted-by":"publisher","first-page":"915","DOI":"10.2217\/fmb-2017-0016","article-title":"The hepatitis E virus nonstructural polyprotein.","volume":"12","author":"Parvez","year":"2017","journal-title":"Future Microbiol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.coviro.2014.12.006","article-title":"Zoonotic origin of hepatitis E.","volume":"10","author":"Pavio","year":"2015","journal-title":"Curr. Opin. Virol."},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2020.197868","article-title":"Multivesicular body sorting and the exosomal pathway are required for the release of rat hepatitis E virus from infected cells.","volume":"278","author":"Primadharsini","year":"2020","journal-title":"Virus Res."},{"key":"B79","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1128\/JVI.01854-08","article-title":"Deletions of the hypervariable region (HVR) in open reading frame 1 of hepatitis E virus do not abolish virus infectivity: evidence for attenuation of HVR deletion mutants in vivo.","volume":"83","author":"Pudupakam","year":"2009","journal-title":"J. Virol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"10031","DOI":"10.1128\/JVI.00763-11","article-title":"Mutational analysis of the hypervariable region of hepatitis e virus reveals its involvement in the efficiency of viral RNA replication.","volume":"85","author":"Pudupakam","year":"2011","journal-title":"J. Virol."},{"key":"B81","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1016\/S0264-410X(03)00100-2","article-title":"Pre-clinical immunogenicity and efficacy trial of a recombinant hepatitis E vaccine.","volume":"21","author":"Purcell","year":"2003","journal-title":"Vaccine"},{"key":"B82","doi-asserted-by":"publisher","first-page":"10186","DOI":"10.1128\/JVI.01374-12","article-title":"Evolution of the hepatitis E virus polyproline region: order from disorder.","volume":"86","author":"Purdy","year":"2012","journal-title":"J. Virol."},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035974","article-title":"The hepatitis E virus polyproline region is involved in viral adaptation.","volume":"7","author":"Purdy","year":"2012","journal-title":"PLoS One"},{"key":"B84","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/jmv.1890410118","article-title":"Preliminary evidence that a trpE-HEV fusion protein protects cynomolgus macaques against challenge with wild-type hepatitis E virus (HEV).","volume":"41","author":"Purdy","year":"1993","journal-title":"J. Med. Virol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1006\/prep.1997.0817","article-title":"Structural characterization of recombinant hepatitis E virus ORF2 proteins in baculovirus-infected insect cells.","volume":"12","author":"Robinson","year":"1998","journal-title":"Protein Expr. Purif."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1002\/hep.510300429","article-title":"Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates.","volume":"30","author":"Sabile","year":"1999","journal-title":"Hepatology"},{"key":"B87","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1046\/j.1365-2249.2003.02204.x","article-title":"Non-enveloped HCV core protein as constitutive antigen of cold-precipitable immune complexes in type II mixed cryoglobulinaemia.","volume":"133","author":"Sansonno","year":"2003","journal-title":"Clin. Exp. Immunol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"913","DOI":"10.5812\/kowsar.1735143X.768","article-title":"HEV-Capsid Protein Interacts With Cytochrome P4502C8 and Retinol-Binding Protein 4.","volume":"11","author":"Shen","year":"2011","journal-title":"Hepat. Mon."},{"key":"B89","doi-asserted-by":"publisher","first-page":"2438","DOI":"10.1073\/pnas.1018878108","article-title":"Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant.","volume":"108","author":"Shukla","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B90","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1099\/vir.0.068429-0","article-title":"Consensus proposals for classification of the family Hepeviridae.","volume":"95","author":"Smith","year":"2014","journal-title":"J. Gen. Virol."},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2091-13-7","article-title":"The ORF2 glycoprotein of hepatitis E virus inhibits cellular NF-kappaB activity by blocking ubiquitination mediated proteasomal degradation of IkappaBalpha in human hepatoma cells.","volume":"13","author":"Surjit","year":"2012","journal-title":"BMC Biochem"},{"key":"B92","doi-asserted-by":"publisher","first-page":"10847","DOI":"10.1074\/jbc.M110.217653","article-title":"Extracellular hepatitis C virus core protein activates STAT3 in human monocytes\/macrophages\/dendritic cells via an IL-6 autocrine pathway.","volume":"286","author":"Tacke","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1128\/JCM.02002-09","article-title":"Hepatitis E Virus (HEV) strains in serum samples can replicate efficiently in cultured cells despite the coexistence of HEV antibodies: characterization of HEV virions in blood circulation.","volume":"48","author":"Takahashi","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/0042-6822(91)90760-9","article-title":"Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome.","volume":"185","author":"Tam","year":"1991","journal-title":"Virology"},{"key":"B95","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1099\/vir.0.82535-0","article-title":"Development and evaluation of an efficient cell-culture system for Hepatitis E virus.","volume":"88","author":"Tanaka","year":"2007","journal-title":"J. Gen. Virol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"3504","DOI":"10.1016\/j.vaccine.2015.05.065","article-title":"A novel linear neutralizing epitope of hepatitis E virus.","volume":"33","author":"Tang","year":"2015","journal-title":"Vaccine"},{"key":"B97","doi-asserted-by":"publisher","first-page":"3563","DOI":"10.1002\/jmv.26226","article-title":"Dissecting the potential role of hepatitis E virus ORF1 nonstructural gene in cross-species infection by using intergenotypic chimeric viruses.","volume":"92","author":"Tian","year":"2020","journal-title":"J. Med. Virol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/prot.1107","article-title":"Structured disorder and conformational selection.","volume":"44","author":"Tsai","year":"2001","journal-title":"Proteins"},{"key":"B99","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1073\/pnas.89.2.559","article-title":"Characterization of a prototype strain of hepatitis E virus.","volume":"89","author":"Tsarev","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B100","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1212\/WNL.0000000000000112","article-title":"Neuralgic amyotrophy and hepatitis E virus infection.","volume":"82","author":"van Eijk","year":"2014","journal-title":"Neurology"},{"key":"B101","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.1016\/j.vaccine.2014.02.025","article-title":"Bacteria expressed hepatitis E virus capsid proteins maintain virion-like epitopes.","volume":"32","author":"Wei","year":"2014","journal-title":"Vaccine"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20137-2","article-title":"Dimerization: a structural feature for the protection of hepatitis E virus capsid protein against trypsinization.","volume":"8","author":"Wei","year":"2018","journal-title":"Sci. Rep."},{"key":"B103","year":"2014","journal-title":"Hepatitis E Vaccine Pipeline."},{"key":"B104","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.3201\/eid2212.160979","article-title":"New Hepatitis E Virus Genotype in Bactrian Camels, Xinjiang, China, 2013.","volume":"22","author":"Woo","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"B105","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.meegid.2015.11.006","article-title":"Role of asparagine at position 562 in dimerization and immunogenicity of the hepatitis E virus capsid protein.","volume":"37","author":"Xu","year":"2016","journal-title":"Infect. Genet. Evol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"12986","DOI":"10.1073\/pnas.0903699106","article-title":"Biological and immunological characteristics of hepatitis E virus-like particles based on the crystal structure.","volume":"106","author":"Yamashita","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B107","doi-asserted-by":"publisher","first-page":"4232","DOI":"10.1128\/JVI.02804-15","article-title":"Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses.","volume":"90","author":"Yin","year":"2016","journal-title":"J. Virol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"4773","DOI":"10.1073\/pnas.1721345115","article-title":"Origin, antigenicity, and function of a secreted form of ORF2 in hepatitis E virus infection.","volume":"115","author":"Yin","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B109","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1007\/s00894-010-0794-5","article-title":"Homology model and potential virus-capsid binding site of a putative HEV receptor Grp78.","volume":"17","author":"Yu","year":"2011","journal-title":"J. Mol. Model."},{"key":"B110","doi-asserted-by":"crossref","first-page":"4074","DOI":"10.1128\/JVI.73.5.4074-4082.1999","article-title":"Mutational analysis of glycosylation, membrane translocation, and cell surface expression of the hepatitis E virus ORF2 protein.","volume":"73","author":"Zafrullah","year":"1999","journal-title":"J. Virol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"2186","DOI":"10.1002\/jmv.24570","article-title":"Asialoglycoprotein receptor facilitates infection of PLC\/PRF\/5 cells by HEV through interaction with ORF2.","volume":"88","author":"Zhang","year":"2016","journal-title":"J. Med. Virol."},{"key":"B112","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S0264-410X(01)00399-1","article-title":"Immunogenicity and protective efficacy of a vaccine prepared from 53 kDa truncated hepatitis E virus capsid protein expressed in insect cells.","volume":"20","author":"Zhang","year":"2001","journal-title":"Vaccine"},{"key":"B113","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1128\/cdli.4.4.423-428.1997","article-title":"Expression, characterization, and immunoreactivities of a soluble hepatitis E virus putative capsid protein species expressed in insect cells.","volume":"4","author":"Zhang","year":"1997","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"B114","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.vetmic.2015.08.016","article-title":"Antigenic properties of avian hepatitis E virus capsid protein.","volume":"180","author":"Zhao","year":"2015","journal-title":"Vet. Microbiol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1016\/j.vaccine.2018.03.005","article-title":"Characterization of capsid protein (p495) of hepatitis E virus expressed in Escherichia coli and assembling into particles in vitro.","volume":"36","author":"Zheng","year":"2018","journal-title":"Vaccine"},{"key":"B116","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1099\/vir.0.019323-0","article-title":"Role of heat-shock protein 90 in hepatitis E virus capsid trafficking.","volume":"91","author":"Zheng","year":"2010","journal-title":"J. Gen. Virol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.739124\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T17:32:34Z","timestamp":1633800754000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.739124\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,7]]},"references-count":116,"alternative-id":["10.3389\/fmicb.2021.739124"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.739124","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,7]]},"article-number":"739124"}}