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Viruses
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Hepatitis E: Molecular Virology, Pathogenesis, and Treatment
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Hepatitis E: Molecular Virology, Pathogenesis, and Treatment

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 13548

Special Issue Editor

Prof. Dr. Hiroaki Okamoto

E-Mail Website
Guest Editor
Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi, Japan
Interests: Hepatitis viruses; viral hepatitis; hepatitis E virus; molecular virology; pathogenesis; epidemiology; cell culture system; zoonosis; taxonomy

Special Issue Information

Dear Colleagues,

Hepatitis E virus (HEV), the causative agent of hepatitis E, is a leading cause of acute viral hepatitis worldwide and has emerged as a global public health concern in recent years. The first diagnosis of chronic hepatitis E in transplant recipients in 2008 profoundly changed our understanding of this pathogen. HEV belongs to the family Hepeviridae and subfamily Orthohepevirinae, which can proliferate in an ever-increasing range of susceptible hosts, including humans, pigs, wild boars, deer, rats, bats, birds and others. Although much progress has been made in our understanding of HEV, many gaps in our knowledge remain. There are many unanswered questions in the HEV life cycle. HEV causes a wide range of clinical manifestations and disease severities, but the underlying mechanisms remain largely unknown. No FDA-approved anti-HEV therapy is currently available. Only ribavirin and interferon α (IFN-α) are occasionally used as an off-label treatment. Thus, further research aimed at developing novel antivirals against HEV infection is urgently required.

This Special Issue of Viruses welcomes original research and review articles, which provide an up-to-date view of HEV virology, virus–host interactions, and the development of new therapies, including the HEV life cycle, zoonosis, cell culture systems, and animal models.

Prof. Dr. Hiroaki Okamoto
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HEV
  • HEV life cycle
  • HEV genotypes
  • model systems
  • zoonosis
  • pathogenesis
  • HEV-host interations
  • antivirals

Published Papers (7 papers)

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Research

Jump to: Review, Other

17 pages, 5333 KiB  
Article
Quantification of Hepatitis E Virus ORF2 Protein by a Novel Sandwich ELISA
by Sakthivel Subramaniam, Rafaelle Fares-Gusmao and David R. McGivern
Viruses 2024, 16(3), 393; https://doi.org/10.3390/v16030393 - 02 Mar 2024
Viewed by 813
Abstract
Hepatitis E virus (HEV) causes acute hepatitis in humans, which can progress to chronicity in immunosuppressed individuals. Almost all reported HEV infections are caused by Paslahepevirus balayani genotypes 1–4. The structural ORF2 protein is the major antigen detected in the blood of HEV-infected individuals. [...] Read more.
Hepatitis E virus (HEV) causes acute hepatitis in humans, which can progress to chronicity in immunosuppressed individuals. Almost all reported HEV infections are caused by Paslahepevirus balayani genotypes 1–4. The structural ORF2 protein is the major antigen detected in the blood of HEV-infected individuals. ELISA assays to detect IgM antibodies to HEV are the first-line diagnostic tests; however, they showed variable performance with frequently discordant results. A qualitative HEV antigen (ORF2) ELISA is currently available for research use. Here, we report a novel quantitative sandwich ELISA to measure HEV ORF2 protein in 3 matrix types. An optimal pair of capture and detection antibodies was selected among 12 unique combinations tested. A sandwich ELISA protocol was developed using these mAbs and biotin–streptavidin technology. The protocol was further optimized to quantify ORF2 antigen in different matrices by interpolating from a standard curve with a linear range of 3.17 to 50.8 femtomoles/mL. Using this method, ORF2 protein was detected in the cell culture medium of Huh7 cells as early as 2–3 days after transfection with HEV genome RNA and in a medium of human hepatocytes infected with HEV. ORF2 antigen was readily detected in the first 2 weeks post-HEV infection in gerbil sera. In immunosuppressed gerbils, ORF2 was detected up to 6 weeks, and the levels were significantly higher between 3 and 6 weeks post-infection. HEV ORF2 antigen levels showed a strong positive correlation with HEV RNA levels in both cell culture medium and gerbil sera. Our novel sandwich ELISA detected at least 7.3 femtomoles/mL ORF2 protein in human plasma spiked with cell culture propagated HEV and detected ORF2 protein in human plasma samples that tested positive for HEV RNA but negative for anti-HEV antibodies. Further, the assay was nonreactive, with negative human plasma, and HBV or HCV-positive human plasma demonstrating specificity. Overall, our ORF2 antigen ELISA will be useful for quantifying ORF2 antigen in cell culture medium, gerbil serum, and human plasma. Further studies are warranted to evaluate its utility in HEV clinical diagnosis. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment)
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50 pages, 5562 KiB  
Article
Virus–Host Protein Interaction Network of the Hepatitis E Virus ORF2-4 by Mammalian Two-Hybrid Assays
by Laura Corneillie, Irma Lemmens, Karin Weening, Amse De Meyer, Freya Van Houtte, Jan Tavernier and Philip Meuleman
Viruses 2023, 15(12), 2412; https://doi.org/10.3390/v15122412 - 12 Dec 2023
Viewed by 2195
Abstract
Throughout their life cycle, viruses interact with cellular host factors, thereby influencing propagation, host range, cell tropism and pathogenesis. The hepatitis E virus (HEV) is an underestimated RNA virus in which knowledge of the virus–host interaction network to date is limited. Here, two [...] Read more.
Throughout their life cycle, viruses interact with cellular host factors, thereby influencing propagation, host range, cell tropism and pathogenesis. The hepatitis E virus (HEV) is an underestimated RNA virus in which knowledge of the virus–host interaction network to date is limited. Here, two related high-throughput mammalian two-hybrid approaches (MAPPIT and KISS) were used to screen for HEV-interacting host proteins. Promising hits were examined on protein function, involved pathway(s), and their relation to other viruses. We identified 37 ORF2 hits, 187 for ORF3 and 91 for ORF4. Several hits had functions in the life cycle of distinct viruses. We focused on SHARPIN and RNF5 as candidate hits for ORF3, as they are involved in the RLR-MAVS pathway and interferon (IFN) induction during viral infections. Knocking out (KO) SHARPIN and RNF5 resulted in a different IFN response upon ORF3 transfection, compared to wild-type cells. Moreover, infection was increased in SHARPIN KO cells and decreased in RNF5 KO cells. In conclusion, MAPPIT and KISS are valuable tools to study virus–host interactions, providing insights into the poorly understood HEV life cycle. We further provide evidence for two identified hits as new host factors in the HEV life cycle. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment)
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12 pages, 880 KiB  
Article
Evidence of a Link between Hepatitis E Virus Exposure and Glomerulonephritis Development
by Mohamed A. El-Mokhtar, Ayat M. Kamel, Ehsan M. W. El-Sabaa, Sahar A. Mandour, Ahmed Shawkat Abdelmohsen, Abdelmajeed M. Moussa, Eman H. Salama, Sahar Aboulfotuh, Lobna Abdel-Wahid, Essam M. Abdel Aziz, Nashwa Mostafa A. Azoz, Ibrahim M. Sayed and Amal A. Elkhawaga
Viruses 2023, 15(6), 1379; https://doi.org/10.3390/v15061379 - 15 Jun 2023
Cited by 3 | Viewed by 1270
Abstract
Viruses can trigger glomerulonephritis (GN) development. Hepatitis viruses, especially Hepatitis C virus and Hepatitis B viruses, are examples of the viruses that trigger GN initiation or progression. However, the proof of a correlation between GN and Hepatitis E virus infection is not clear. [...] Read more.
Viruses can trigger glomerulonephritis (GN) development. Hepatitis viruses, especially Hepatitis C virus and Hepatitis B viruses, are examples of the viruses that trigger GN initiation or progression. However, the proof of a correlation between GN and Hepatitis E virus infection is not clear. Some studies confirmed the development of GN during acute or chronic HEV infections, mainly caused by genotype 3. While others reported that there is no relation between HEV exposure and GN development. A recent study showed that a reduced glomerular filtration rate was developed in 16% of acute HEV genotype 1 (HEV-1) infections that returned to normal during recovery. HEV-1 is endemic in Egypt with a high seroprevalence among villagers and pregnant women. There is no available data about a link between HEV and GN in Egypt. Methods: GN patients (n = 43) and matched healthy subjects (n = 36) enrolled in Assiut University hospitals were included in this study. Blood samples were screened for hepatotropic pathogens. Tests for HEV markers such as HEV RNA and anti-HEV antibodies (IgM and IgG) were performed. Laboratory parameters were compared in HEV-seropositive and HEV-seronegative GN patients. Results: Anti-HEV IgG was detected in 26 (60.5%) out of 43 GN patients. HEV seroprevalence was significantly higher in GN than in healthy controls, suggesting that HEV exposure is a risk factor for GN development. None of the GN patients nor the healthy subjects were positive for anti-HEV IgM or HEV RNA. There was no significant difference between seropositive and seronegative GN patients in terms of age, gender, albumin, kidney function profiles, or liver transaminases. However, anti-HEV IgG positive GN patients had higher bilirubin levels than anti-HEV IgG negative GN patients. HEV-seropositive GN patients had a significantly elevated AST level compared to HEV-seropositive healthy subjects. Conclusion: exposure to HEV infection could be complicated by the development of GN. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment)
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Review

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18 pages, 6662 KiB  
Review
Three Distinct Reporter Systems of Hepatitis E Virus and Their Utility as Drug Screening Platforms
by Putu Prathiwi Primadharsini, Shigeo Nagashima, Takashi Nishiyama and Hiroaki Okamoto
Viruses 2023, 15(10), 1989; https://doi.org/10.3390/v15101989 - 23 Sep 2023
Viewed by 1539
Abstract
The hepatitis E virus (HEV) is increasingly acknowledged as the primary cause of acute hepatitis. While most HEV infections are self-limiting, cases of chronic infection and fulminant hepatitis necessitate the administration of anti-HEV medications. However, there is a lack of specific antiviral drugs [...] Read more.
The hepatitis E virus (HEV) is increasingly acknowledged as the primary cause of acute hepatitis. While most HEV infections are self-limiting, cases of chronic infection and fulminant hepatitis necessitate the administration of anti-HEV medications. However, there is a lack of specific antiviral drugs designed for HEV, and the currently available drug (ribavirin) has been associated with significant adverse effects. The development of innovative antiviral drugs involves targeting distinct steps within the viral life cycle: the early step (attachment and internalization), middle step (translation and RNA replication), and late step (virus particle formation and virion release). We recently established three HEV reporter systems, each covering one or two of these steps. Using these reporter systems, we identified various potential drug candidates that target different steps of the HEV life cycle. Through rigorous in vitro testing using our robust cell culture system with the genotype 3 HEV strain (JE03-1760F/P10), we confirmed the efficacy of these drugs, when used alone or in combination with existing anti-HEV drugs. This underscores their significance in the quest for an effective anti-HEV treatment. In the present review, we discuss the development of the three reporter systems, their applications in drug screening, and their potential to advance our understanding of the incompletely elucidated HEV life cycle. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment)
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26 pages, 22535 KiB  
Review
Discovery of Hepatitis E and Its Impact on Global Health: A Journey of 44 Years about an Incredible Human-Interest Story
by Mohammad Sultan Khuroo
Viruses 2023, 15(8), 1745; https://doi.org/10.3390/v15081745 - 15 Aug 2023
Cited by 1 | Viewed by 2963
Abstract
The story of the discovery of hepatitis E originated in the late 1970s with my extreme belief that there was a hidden saga in the relationship between jaundice and pregnancy in developing countries and the opportunity for a massive epidemic of viral hepatitis, [...] Read more.
The story of the discovery of hepatitis E originated in the late 1970s with my extreme belief that there was a hidden saga in the relationship between jaundice and pregnancy in developing countries and the opportunity for a massive epidemic of viral hepatitis, which hit the Gulmarg Kashmir region in November 1978. Based on data collected from a door-to-door survey, the existence of a new disease, epidemic non-A, non-B hepatitis, caused by a hitherto unknown hepatitis virus, was announced. This news was received by the world community with hype and skepticism. In the early 1980s, the world watched in awe as an extreme example of human self-experimentation led to the identification of VLP. In 1990, a cDNA clone from the virus responsible for epidemic non-A, non-B hepatitis was isolated. Over the years, we traversed three eras of ambiguity, hope, and hype of hepatitis E research and conducted several seminal studies to understand the biology of HEV and manifestations of hepatitis E. Many milestones have been reached on the long and winding road of hepatitis E research to understand the structure, biology, and diversity of the agent, changing the behavior of the pathogen in developed countries, and the discovery of a highly effective vaccine. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment)
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22 pages, 2328 KiB  
Review
Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations
by Busara Songtanin, Adebayo J. Molehin, Kevin Brittan, Wuttiporn Manatsathit and Kenneth Nugent
Viruses 2023, 15(6), 1389; https://doi.org/10.3390/v15061389 - 17 Jun 2023
Cited by 6 | Viewed by 2759
Abstract
According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are four main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water [...] Read more.
According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are four main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal–oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans via undercooked meat. Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients. The majority of patients with HEV infection are asymptomatic and usually have spontaneous viral clearance without treatment. However, infection in immunocompromised individuals can lead to chronic HEV infection. Both acute and chronic HEV infections can have extrahepatic manifestations. No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection, and no HEV vaccine has been approved by the (United States) Food and Drug Administration. This review focuses on the molecular virology (HEV life cycle, genotypes, model systems, zoonosis), pathogenesis, clinical manifestation, and treatment of chronic HEV infection, especially in immunocompromised patients, to provide clinicians a better understanding of the global distribution of these infections and the significant effect they can have on immunocompromised patients. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment)
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Graphical abstract

Other

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8 pages, 761 KiB  
Brief Report
High Hepatitis E Virus (HEV) Seroprevalence and No Evidence of HEV Viraemia in Vietnamese Blood Donors
by Le Chi Cao, Vanessa Martin, Le Thi Kieu Linh, Tran Thi Giang, Ngo Thi Minh Chau, Ton Nu Phuong Anh, Vu Xuan Nghia, Nguyen Trong The, Truong Nhat My, Bui Tien Sy, Nguyen Linh Toan, Le Huu Song, C.-Thomas Bock and Thirumalaisamy P. Velavan
Viruses 2023, 15(10), 2075; https://doi.org/10.3390/v15102075 - 11 Oct 2023
Cited by 1 | Viewed by 1286
Abstract
The prevalence of hepatitis E virus (HEV) in the Vietnamese population remains underestimated. The aim of the present study was to investigate the seroprevalence of HEV IgG/IgM antibodies and the presence of HEV RNA in blood donors as a part of epidemiological surveillance [...] Read more.
The prevalence of hepatitis E virus (HEV) in the Vietnamese population remains underestimated. The aim of the present study was to investigate the seroprevalence of HEV IgG/IgM antibodies and the presence of HEV RNA in blood donors as a part of epidemiological surveillance for transfusion-transmitted viruses. Serum samples from blood donors (n = 553) were analysed for markers of past (anti-HEV IgG) and recent/ongoing (anti-HEV IgM) HEV infections. In addition, all serum samples were subsequently tested for HEV RNA positivity. The overall prevalence of anti-HEV IgG was 26.8% (n = 148/553), while the seroprevalence of anti-HEV IgM was 0.5% (n = 3/553). Anti-HEV IgG seroprevalence in male and female donors was similar (27.1% and 25.5%, respectively). A higher risk of hepatitis E exposure was observed with increasing age. None of the blood donors were HEV RNA positive, and there was no evidence of HEV viraemia. Although the absence of HEV viraemia in blood donors from Northern Vietnam is encouraging, further epidemiological surveillance in other geographical regions is warranted to rule out transfusion-transmitted HEV. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment)
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