Highlighting the Gaps in Understanding Hepatitis E

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Researchers suggest that the hepatitis E virus remains a worldwide threat because more needs to be investigated about its transmission.

Although hepatitis E virus (HEV) is the most common cause of acute viral hepatitis, much is unknown about its mechanisms, transmission pathways, and treatments. As more research is conducted, investigators have identified important gaps in knowledge that future studies need to explore.1,2

Knowledge Gaps in HEV Assembly and Release
The current understanding of HEV’s lifecycle is incomplete, which is the first roadblock to finding an effective treatment. In a review, Xiaohu Ju, PhD, and Qiang Ding, PhD,3 highlight the gaps in knowledge that exist in understanding HEV assembly and release. In particular, these gaps are:

  • the detailed mechanism of reciprocal interaction between viral and host factors for assembly and release
  • the exact mechanism of capsid and genomic interaction for assembling viral particles, as well as the location where this takes place
  • the method by which the membrane-associated, quasi-enveloped form (eHEV) acquires the host-derived membrane
  • the biochemical composition of the infectious HEV particle
  • the role of open reading frame 3 (ORF3) in the release process

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Despite their targeted research questions, Dr Ju and Dr Ding note that research will be hindered by the limitations of current technology. Currently, the cells used to produce infectious viruses in cell culture models are derived from hepatocellular carcinoma and thus do not have many of the typical characteristics of hepatocytes in vivo.

“An experimental system that can produce large amounts of highly purified infectious HEV particles is urgently required for structural investigations,” they wrote.

On a more positive note, Dr Ju and Dr Ding highlighted the development of a long-term 3-dimensional organoid culture system for human primary hepatocytes, which they say will be an integral tool for studying HEV.

Targets for Antiviral Research

Worldwide, HEV is the most common cause of acute viral hepatitis. Every year, HEV accounts for 20 million infections and 70,000 deaths.4 Despite the significant impact of HEV, there is no direct-acting antiviral treatment available.

ORF2 plays key roles in HEV assembly, which has made it an attractive target for the development of an antiviral agent. Dr Ju and Dr Ding believe that the genomic RNA binding of ORF2 may be the key. An antiviral could potentially target the RNA elements in the 5′ end of the genomic RNA, which would prevent its interactions with ORF2. The development of compounds of peptides that disrupt this process would inhibit viral particle assembly.

Another possible target for antiviral agents is the oligomerization of ORF2, which forms an icosahedral capsid that encapsulates genomic RNA. The development of compounds that block or misdirect capsid assembly would suppress virion production.

New Discoveries of HEV Presentation in Immunocompetent Patients

The clinical presentation of HEV has significant heterogeneity between developing and developed countries. Of the 8 HEV genotypes, HEV1-4 can infect humans. HEV1 an HEV2 are anthroponotic pathogens that can cause waterborne outbreaks in developing countries, while HEV3 and HEV4 are zoonotic.

A study by Oliver Viera-Segura and colleagues showed that HEV is still often overlooked as a diagnosis.5 In adult patients in Mexico with a non-identified infectious etiological agent, the researchers discovered that 30.26% were infected with HEV. Of note, the researchers found that none of these patients presented with the typical symptoms of acute hepatitis, although they did have altered liver function.

In an opinion piece, Santiago Mirazo, PhD, and Juan Arbiza, PhD, of the Universidad de la República de Uruguay, Montevideo, considered the next steps in light of these results. The data suggests that the infection dynamics of HEV may be more complicated than previously thought, and the researchers believe that more research is needed to determine the clinical phenotype of HEV in at-risk populations.

“Prompt recognition of the infection, supported by adequate molecular and serological testing and an early intervention of those groups of patients remains key to achieve effective management,”4 Doctors Mirazo and Arbiza wrote.

Autochthonous HEV In Developed Countries

Previously, HEV in developed countries was seen as something brought over from developing countries. However, a surveillance report of all countries in the European Union (excluding Liechtenstein) suggests that autochthonous HEV in high-income countries is more common than previously thought.

The survey, conducted by Dr Esther J. Aspinall of Glasgow Caledonian University, Scotland, and colleagues, found that from 2005 to 2015, 87% (13,511/15,525) HEV cases reported in Europe were considered locally acquired. The percentage of autochthonous cases increased from 43% to 73% per year from 2006 to 2011 to 89% to 97% per year from 2012 to 2015. Only 9 to 36 cases per year could be attributed to travel outside of the European Union.

In industrialized countries, there is a growing body of evidence that links zoonotic HEV transmission to consuming contaminated foods or coming into direct contact with infected animals.6 Waterborne transmission in developed countries has been linked to contaminated irrigation water used in the production chain of fruits and vegetables as well as contaminated environmental water.

Because HEV is only now being considered autochthonous in developed countries, more studies are needed to elucidate the routes of transmission.

Looking Forward

Despite its prevalence, HEV is poorly understood in terms of its assembly, transmission, and treatment routes. Until more research is conducted, HEV will continue to be a significant worldwide health burden.


1. Aspinall EJ, Couturier E, Faber M, et al. Hepatitis E virus infection in Europe: surveillance and descriptive epidemiology of confirmed cases, 2005 to 2015. Euro Surveill. 2017;22(26):pii=30561.

2. Capai L, Charrel R, Falchi A. Hepatitis E in high-income countries: what do we know? And what are the knowledge gaps? Viruses. 2018;10(6):E285.

3. Ju X, Ding Q. Hepatitis E virus assembly and release. Viruses. 2019;11(6):539.

4. Mirazo S, Arbiza J. Hepatitis E and chronic liver damage in apparently immunocompetent individuals: now what? Ann Hepatol. 2019;18:539-540.

5. Viera-Segura O, Realpe M, Panduro A, et al. First detection of hepatitis E virus genotype 3 as a common infectious agent in patients with chronic liver damage in Mexico. Ann Hepatol. 2019;18(4):571-577.

6. Webb GW, Dalton HR. Hepatitis E: an underestimated emerging threat. Ther Adv Infectious Dis. 2019;6:1-18.