The rise of the hepatitis E virus

View Large Image Figure ViewerDownload Hi-res image Download (PPT) It took 40 years for the hepatitis E virus (HEV) to grow from a suspected waterborne agent of hepatitis outbreaks in India,[1]Khuroo M.S. Study of an epidemic of non-A, non-B hepatitis: possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type.Am J Med. 1980; 68: 818-824Abstract Full Text PDF PubMed Scopus (575) Google Scholar to the most common cause of acute viral hepatitis worldwide, and a crucial issue for the European Association for the Study of the Liver.[2]European Association for the Study of the LiverElectronic address eee, European Association for the Study of the LEASL clinical practice guidelines on hepatitis E virus infection.J Hepatol. 2018; 68: 1256-1271Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar HEV belongs to the Hepeviridae: a family of viruses that can infect mammals, birds, and fish. Human pathogenic strains are found within the Orthohepevirus A species divided in genotypes: HEV-1 and -2 are restricted to humans; HEV-3 and -4 infect both humans and animals, and pigs are the main reservoir, along with deer, wild boars, and rabbits. Camel HEV-7 and rat HEV (the latter belonging to species Orthohepevirus C) may also be threats.[3]Smith D.B. Izopet J. Nicot F. Simmonds P. Jameel S. Meng X.J. et al.Update: proposed reference sequences for subtypes of hepatitis E virus (species Orthohepevirus A).J Gen Virol. 2020; 101: 692-698Crossref PubMed Scopus (194) Google Scholar HEV has a ~7.2 kb, single-stranded, positive-strand RNA genome that encodes 3 to 4 open reading frames (ORFs) and is surrounded by an icosahedral shell (see panel 1). ORF1 is translated from the genomic RNA and encodes non-structural protein domains required for replication. ORF2 and ORF3 overlap, and encode, respectively, the capsid protein and a phosphoprotein required for viral egress. An extra ORF4 protein promotes HEV-1 replication. HEV can present either as a ~30 nm, naked particle, or as a ~40 nm, quasi-enveloped virion (e-HEV). Both forms of HEV, the naked and the quasi-enveloped forms, are infectious.[4]Yin X. Ambardekar C. Lu Y. Feng Z. Distinct entry mechanisms for nonenveloped and quasi-enveloped hepatitis E viruses.J Virol. 2016; 90: 4232-4242Crossref PubMed Scopus (169) Google Scholar Bona fide exosome membranes surround e-HEV, and may facilitate, in a non-specific manner, extra-digestive tissue infections, including placenta, kidney cells, or neurons.[4]Yin X. Ambardekar C. Lu Y. Feng Z. Distinct entry mechanisms for nonenveloped and quasi-enveloped hepatitis E viruses.J Virol. 2016; 90: 4232-4242Crossref PubMed Scopus (169) Google Scholar However, evidence of replication of HEV outside of the liver or placenta is scarce. Most HEV infections are acquired enterically (see panel 2). HEV-1 and -2 are responsible for large, waterborne, fecal-oral outbreaks in endemic regions, such as Southeast Asia, Africa, and Mexico. HEV-3, and -4 account for the majority of sporadic infections in high-income countries and are transmitted by ingestion of infected food and contact with infected animals. HEV-1 and HEV-2 can also be transmitted from mother to fetus,[5]Bigna J.J. Modiyinji A.F. Nansseu J.R. Amougou M.A. Nola M. Kenmoe S. et al.Burden of hepatitis E virus infection in pregnancy and maternofoetal outcomes: a systematic review and meta-analysis.BMC Pregnancy Childbirth. 2020; 20: 426Crossref PubMed Scopus (24) Google Scholar and from person to person.[6]Teshale E.H. Grytdal S.P. Howard C. Barry V. Kamili S. Drobeniuc J. et al.Evidence of person-to-person transmission of hepatitis E virus during a large outbreak in Northern Uganda.Clin Infect Dis. 2010; 50: 1006-1010Crossref PubMed Scopus (125) Google Scholar Vertical transmission has not been reported for zoonotic HEV. All can be transmitted with blood transfusions, with a steady increase of reported cases of transfusion-transmitted HEV infections in blood donation recipients.[7]Bi H. Yang R. Wu C. Xia J. Hepatitis E virus and blood transfusion safety.Epidemiol Infect. 2020; 148: e158Crossref PubMed Scopus (34) Google Scholar HEV has recently been proposed to first replicate in intestinal cells and to be subsequently released as e-HEV into the portal bloodstream from where it can infect hepatocytes (see panel 3).[8]Marion O. Lhomme S. Nayrac M. Dubois M. Pucelle M. Requena M. et al.Hepatitis E virus replication in human intestinal cells.Gut. 2020; 69: 901-910Crossref PubMed Scopus (47) Google Scholar e-HEV is released at the basolateral side of hepatocytes to the bloodstream and infects extrahepatic cells.[9]Gouilly J. Chen Q. Siewiera J. Cartron G. Levy C. Dubois M. et al.Genotype specific pathogenicity of hepatitis E virus at the human maternal-fetal interface.Nat Commun. 2018; 9: 4748Crossref PubMed Scopus (80) Google Scholar When released at the apical side, bile salts dissolve eHEV quasi-membranes, and naked virions are excreted in the stool. eHEV can also be shed in urine. During the incubation phase, HEV evades the immune response by disrupting interferon production and signaling, producing high amounts of glycosylated ORF2, and hiding in a quasi-envelope not neutralized by anti-HEV antibodies.[10]Lhomme S. Migueres M. Abravanel F. Marion O. Kamar N. Izopet J. Hepatitis E virus: how it escapes host innate immunity.Vaccines. 2020; 8: 422Crossref Scopus (11) Google Scholar Most HEV contacts result in asymptomatic infections and cause a self-limiting illness that lasts a few weeks. Acute liver failure has been reported in 0.5 to 4% of patients in endemic areas, and the risk is higher in people with pre-existing liver disease,[11]Acharya S.K. Sharma P.K. Singh R. Mohanty S.K. Madan K. Jha J.K. et al.Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death.J Hepatol. 2007; 46: 387-394Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar children,[1]Khuroo M.S. Study of an epidemic of non-A, non-B hepatitis: possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type.Am J Med. 1980; 68: 818-824Abstract Full Text PDF PubMed Scopus (575) Google Scholar and pregnant women infected with HEV-1 and HEV-2 (see panel 4).[12]Pérez-Gracia M.T. Suay-García B. Mateos-Lindemann M.L. Hepatitis E and pregnancy: current state.Rev Med Virol. 2017; 27e1929Crossref PubMed Scopus (150) Google Scholar Mutations in the helicase domain of HEV-3 have been associated with increased virulence.[13]Takahashi K. Okamoto H. Abe N. Kawakami M. Matsuda H. Mochida S. et al.Virulent strain of hepatitis E virus genotype 3, Japan.Emerging Infect Dis. 2009; 15: 704Crossref PubMed Scopus (45) Google Scholar In immunocompromised persons, including transplant recipients and lymphopenic hosts, zoonotic HEV infections may progress to chronic hepatitis, cirrhosis, and liver-related death.[14]Kamar N. Selves J. Mansuy J.M. Ouezzani L. Peron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1106) Google Scholar Liver damage is immune-mediated (see panel 5). HEV-specific T cell and serological anti-HEV responses are generally detected. Many extrahepatic manifestations are reported in HEV-infected patients.[15]Pischke S. Hartl J. Pas S.D. Lohse A.W. Jacobs B.C. Van der Eijk A.A. Hepatitis E virus: infection beyond the liver?.J Hepatol. 2017; 66: 1082-1095Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Neurological and renal manifestations are the most consistently reported and include neuralgic amyotrophy, Guillain–Barré syndrome, acute kidney injury, and glomerular disease. Molecular mimicry and cryoglobuminemia could account for these disorders. There is no approved drug for HEV (see panel 6). If reduction of immunosuppression does not lead to HEV clearance in patients with chronic hepatitis E, ribavirin treatment is recommended.[2]European Association for the Study of the LiverElectronic address eee, European Association for the Study of the LEASL clinical practice guidelines on hepatitis E virus infection.J Hepatol. 2018; 68: 1256-1271Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar Non-responding liver transplant patients can be treated with interferon-alpha.[2]European Association for the Study of the LiverElectronic address eee, European Association for the Study of the LEASL clinical practice guidelines on hepatitis E virus infection.J Hepatol. 2018; 68: 1256-1271Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar The benefit of antiviral treatment in other settings, including extrahepatic manifestations and acute liver failure, has not been demonstrated. An HEV vaccine is licensed in China. The authors received no financial support to produce this manuscript. VM: figure and text; JPSP, AM: figure; AMR: figure and text; all authors approved the final versions of the text and the figure. The authors have no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. The authors thank Miss Agathe Mallet for the Vitruvian man. They also thank Doctor Carmen Navas Jiménez, Professor Stanislas Pol and Professor Philippe Sogni for their comments on the figure and the manuscript. The following is the supplementary data to this article: Download .pdf (.2 MB) Help with pdf files Multimedia component 1