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Viruses
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Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition
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Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition

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

Deadline for manuscript submissions: 31 August 2025 | Viewed by 7234

Special Issue Editor

Prof. Dr. Hiroaki Okamoto

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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 Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatitis E virus (HEV), the causative agent of hepatitis E, is the 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 off-label treatments. 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 that 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

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Keywords

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

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Related Special Issue

Published Papers (7 papers)

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11 pages, 6760 KiB  
Article
The Epidemiology of Hepatitis E in Israel and Potential Risk Factors: A Cross-Sectional Population-Based Serological Survey of Hepatitis E Virus in Northern Israel
by Rasha Daniel, Shira Zelber-Sagi, Mira Barak and Eli Zuckerman
Viruses 2025, 17(4), 536; https://doi.org/10.3390/v17040536 - 7 Apr 2025
Viewed by 304
Abstract
Hepatitis E Virus (HEV) has gained public health attention as one of the causative agents of viral hepatitis. Our study aimed to provide data about HEV seropositivity in the Israeli general population, including its seroprevalence geographical distribution, and to identify variables as possible [...] Read more.
Hepatitis E Virus (HEV) has gained public health attention as one of the causative agents of viral hepatitis. Our study aimed to provide data about HEV seropositivity in the Israeli general population, including its seroprevalence geographical distribution, and to identify variables as possible risk factors for HEV exposure. A seroprevalence cross-sectional study was conducted: HEV serological status was determined in 716 blood samples collected from the routine check-up blood samples. Demographic information was available for all samples. The overall prevalence of HEV IgG in an apparently healthy population in the north of Israel was 10.5%, with no evidence of positive HEV IgM. There was a significant association between HEV seropositivity and elderly age and low socioeconomic status (SES). The age-adjusted seroprevalence was significantly lower among Jews compared to Arabs with a rate ratio of 2.02. We identified clusters (hot spots) of HEV infection in three regions under study. Our results confirmed a high prevalence of anti-HEV in the country where clinical hepatitis E is not endemic. For the first time, this study showed that a hot spot analysis was able to provide new knowledge about actual exposure zones. As HEV infection is not a notifiable disease, it is probably underdiagnosed. Thus, better awareness among physicians is warranted. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition)
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12 pages, 1061 KiB  
Communication
Recent Hepatitis E Virus Infection in Wild Boars and Other Ungulates in Japan
by Milagros Virhuez-Mendoza, Keita Ishijima, Kango Tatemoto, Yudai Kuroda, Yusuke Inoue, Ayano Nishino, Tsukasa Yamamoto, Akihiko Uda, Akitoyo Hotta, Hidenori Kabeya, Hiroshi Shimoda, Kazuo Suzuki, Tomoyoshi Komiya, Junji Seto, Yuki Iwashina, Daisuke Hirano, Mikio Sawada, Sayuri Yamaguchi, Fusayo Hosaka and Ken Maeda
Viruses 2025, 17(4), 524; https://doi.org/10.3390/v17040524 - 4 Apr 2025
Viewed by 467
Abstract
Hepatitis E virus (HEV) is a zoonotic pathogen with multiple hosts, posing significant public health risks, especially in regions like Japan where game meat consumption is prevalent. This study investigated HEV infection and viral shedding in wild boars, sika deer, and Japanese serows [...] Read more.
Hepatitis E virus (HEV) is a zoonotic pathogen with multiple hosts, posing significant public health risks, especially in regions like Japan where game meat consumption is prevalent. This study investigated HEV infection and viral shedding in wild boars, sika deer, and Japanese serows across Japan. A total of 1896 serum samples were tested for anti-HEV antibodies, 1034 for HEV RNA, and 473 fecal samples for viral shedding. Anti-HEV antibodies were detected in wild boars from all seven prefectures studied, while HEV RNA was detected in wild boars from Fukuoka, Oita, and Miyazaki in southern Japan, as well as Yamaguchi prefecture. Genetic analysis revealed subtypes 3b, 4a, and 4g, with 3b being the most prevalent. Subtype 3b exhibited distinct geographical clustering, whereas 4g persisted exclusively in Yamaguchi for over 12 years. Infectious HEV particles were confirmed in wild boar feces, highlighting the risk of environmental contamination and zoonotic transmission. Sika deer showed no evidence of HEV infection, and only one Japanese serow tested positive for antibodies without detectable RNA. These findings underscore the importance of ongoing surveillance to assess the zoonotic risks from game meat consumption and prevention of HEV transmission to humans. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition)
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16 pages, 2588 KiB  
Article
The Prevalence, Risk Factors, and Outcomes of Hepatitis E Virus Infection in Solid Organ Transplant Recipients in a Highly Endemic Area of Italy
by Barbara Binda, Giovanna Picchi, Roberto Bruni, Alessandro Di Gasbarro, Elisabetta Madonna, Umbertina Villano, Giulio Pisani, Alberto Carocci, Cinzia Marcantonio, Filippo Montali, Alessandra Panarese, Francesco Pisani, Anna Rita Ciccaglione and Enea Spada
Viruses 2025, 17(4), 502; https://doi.org/10.3390/v17040502 - 31 Mar 2025
Viewed by 323
Abstract
Hepatitis E virus (HEV) infection can become chronic in immunocompromised patients, like solid organ transplant recipients (SOTRs). We evaluated HEV prevalence, risk factors, and outcomes among SOTRs in a hyperendemic HEV area. Three hundred SOTRs were enrolled from April to July 2019 and [...] Read more.
Hepatitis E virus (HEV) infection can become chronic in immunocompromised patients, like solid organ transplant recipients (SOTRs). We evaluated HEV prevalence, risk factors, and outcomes among SOTRs in a hyperendemic HEV area. Three hundred SOTRs were enrolled from April to July 2019 and tested for anti-HEV IgM and IgG and HEV RNA. Sixty-three recipients (21%) were positive for any HEV marker. HEV infection was independently associated with older age and pork liver sausage consumption. Three viremic recipients harbored genotype 3e and 3f according to HEV RNA sequencing and phylogenetic analysis. Overall, 10 recipients had markers of active/recent infection (HEV RNA and/or anti-HEV IgM) and were followed up prospectively. Five of them spontaneously resolved their HEV infection. In two recipients, HEV clearance was achieved only through immunosuppression reduction, while three needed ribavirin therapy to achieve virologic resolution. We observed a chronic course in 30% of SOTRs with active/recent HEV infection. No association was found between tacrolimus assumption and chronicization. In conclusion, we found a high prevalence of infection among SOTRs attending a transplant center in a hyperendemic Italian HEV region. Systematic screening for all HEV markers and dietary education for infection control are needed for transplant recipients. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition)
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17 pages, 2448 KiB  
Article
Genetic Diversity and Molecular Evolution of Hepatitis E Virus Within the Genus Chirohepevirus in Bats
by Bo Wang, Peter Cronin, Marcus G. Mah, Xing-Lou Yang and Yvonne C. F. Su
Viruses 2025, 17(3), 339; https://doi.org/10.3390/v17030339 - 28 Feb 2025
Viewed by 498
Abstract
Hepatitis E virus (HEV) is a major zoonotic pathogen causing hepatitis E, with strains identified in various animal species, including pigs, wild boar, rabbits, deer, camels, and rats. These variants are capable of crossing species barriers and infecting humans. HEV belongs to the [...] Read more.
Hepatitis E virus (HEV) is a major zoonotic pathogen causing hepatitis E, with strains identified in various animal species, including pigs, wild boar, rabbits, deer, camels, and rats. These variants are capable of crossing species barriers and infecting humans. HEV belongs to the family Hepeviridae, which has recently divided into two subfamilies: Orthohepevirinae and Parahepevirinae, and five genera: Paslahepevirus, Avihepevirus, Rocahepevirus, Chirohepevirus, and Piscihepevirus. Recent advances in high-throughput sequencing, particularly of bat viromes, have revealed numerous HEV-related viruses, raising concerns about their zoonotic potential. Bat-derived HEVs have been classified into the genus Chirohepevirus, which includes three distinct species. In this study, we analyzed 64 chirohepevirus sequences from 22 bat species across six bat families collected from nine countries. Twelve sequences represent complete or nearly complete viral genomes (>6410 nucleotides) containing the characteristic three HEV open reading frames (ORFs). These strains exhibited high sequence divergence (>25%) within their respective host genera or species. Phylogenetic analyses with maximum likelihood methods identified at least seven distinct subclades within Chirohepevirus, each potentially representing an independent species. Additionally, the close phylogenetic relationship between chirohepevirus strains and their bat hosts indicates a pattern of virus–host co-speciation. Our findings expand the known diversity within the family Hepeviridae and provide new insights into the evolution of bat-associated HEV. Continued surveillance of chirohepevirus will be essential for understanding its potential for zoonotic transmission and public health risks. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition)
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13 pages, 5993 KiB  
Article
Strain- and Subtype-Specific Replication of Genotype 3 Hepatitis E Viruses in Mongolian Gerbils
by Tiancheng Li, Yusuke Sakai, Yasushi Ami, Yuriko Suzaki and Masanori Isogawa
Viruses 2024, 16(10), 1605; https://doi.org/10.3390/v16101605 - 12 Oct 2024
Cited by 1 | Viewed by 1214
Abstract
Since Mongolian gerbils are broadly susceptible to hepatitis E virus (HEV), including genotypes 1, 4, 5, and 8 (HEV-1, HEV-5, HEV-5, and HEV-8) and rat HEV, they are a useful small animal model for HEV. However, we have observed that the subtypes HEV-3k [...] Read more.
Since Mongolian gerbils are broadly susceptible to hepatitis E virus (HEV), including genotypes 1, 4, 5, and 8 (HEV-1, HEV-5, HEV-5, and HEV-8) and rat HEV, they are a useful small animal model for HEV. However, we have observed that the subtypes HEV-3k and HEV-3ra in genotype 3 HEV (HEV-3) were not infected efficiently in the gerbils. A small-animal model for HEV-3 is also needed since HEV-3 is responsible for major zoonotic HEV infections. To investigate whether gerbils can be used as animal models for other subtypes of HEV-3, we injected gerbils with five HEV-3 subtypes (HEV-3b, -3e, -3f, -3k, and -3ra) and compared the infectivity of the subtypes. We detected viral RNA in the gerbils’ feces. High titers of anti-HEV IgG antibodies in serum were induced in all HEV-3b/ch-, HEV-3f-, and HEV-3e-injected gerbils. Especially, the HEV-3e-injected animals released high levels of viruses into their feces for an extended period. The virus replication was limited in the HEV-3b/wb-injected and HEV-3k-injected groups. Although viral RNA was detected in HEV-3ra-injected gerbils, the copy numbers in fecal specimens were low; no antibodies were detected in the sera. These results indicate that although HEV-3′s infectivity in gerbils depends on the subtype and strain, Mongolian gerbils have potential as a small-animal model for HEV-3. A further comparison of HEV-3e with different genotype strains (HEV-4i and HEV-5) and different genera (rat HEV) revealed different ALT elevations among the strains, and liver damage occurred in HEV-4i- and HEV-5-infected but not HEV-3e- or rat HEV-infected gerbils, demonstrating variable pathogenicity across HEVs from different genera and genotypes in Mongolian gerbils. HEV-4i- and HEV-5-infected Mongolian gerbils might be candidate animal models to examine HEV’s pathogenicity. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition)
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21 pages, 13118 KiB  
Article
Production and Characterization of Self-Assembled Virus-like Particles Comprising Capsid Proteins from Genotypes 3 and 4 Hepatitis E Virus (HEV) and Rabbit HEV Expressed in Escherichia coli
by Tominari Kobayashi, Masaharu Takahashi, Satoshi Ohta, Yu Hoshino, Kentaro Yamada, Suljid Jirintai, Putu Prathiwi Primadharsini, Shigeo Nagashima, Kazumoto Murata and Hiroaki Okamoto
Viruses 2024, 16(9), 1400; https://doi.org/10.3390/v16091400 - 31 Aug 2024
Cited by 1 | Viewed by 2318
Abstract
The zoonotic transmission of hepatitis E virus (HEV) genotypes 3 (HEV-3) and 4 (HEV-4), and rabbit HEV (HEV-3ra) has been documented. Vaccination against HEV infection depends on the capsid (open reading frame 2, ORF2) protein, which is highly immunogenic and elicits effective virus-neutralizing [...] Read more.
The zoonotic transmission of hepatitis E virus (HEV) genotypes 3 (HEV-3) and 4 (HEV-4), and rabbit HEV (HEV-3ra) has been documented. Vaccination against HEV infection depends on the capsid (open reading frame 2, ORF2) protein, which is highly immunogenic and elicits effective virus-neutralizing antibodies. Escherichia coli (E. coli) is utilized as an effective system for producing HEV-like particles (VLPs). However, research on the production of ORF2 proteins from these HEV genotypes in E. coli to form VLPs has been modest. In this study, we constructed 21 recombinant plasmids expressing various N-terminally and C-terminally truncated HEV ORF2 proteins for HEV-3, HEV-3ra, and HEV-4 in E. coli. We successfully obtained nine HEV-3, two HEV-3ra, and ten HEV-4 ORF2 proteins, which were primarily localized in inclusion bodies. These proteins were solubilized in 4 M urea, filtered, and subjected to gel filtration. Results revealed that six HEV-3, one HEV-3ra, and two HEV-4 truncated proteins could assemble into VLPs. The purified VLPs displayed molecular weights ranging from 27.1 to 63.4 kDa and demonstrated high purity (74.7–95.3%), as assessed by bioanalyzer, with yields of 13.9–89.6 mg per 100 mL of TB medium. Immunoelectron microscopy confirmed the origin of these VLPs from HEV ORF2. Antigenicity testing indicated that these VLPs possess characteristic HEV antigenicity. Evaluation of immunogenicity in Balb/cAJcl mice revealed robust anti-HEV IgG responses, highlighting the potential of these VLPs as immunogens. These findings suggest that the generated HEV VLPs of different genotypes could serve as valuable tools for HEV research and vaccine development. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition)
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10 pages, 1100 KiB  
Case Report
Case of Fatal Hepatitis Related to HEV-3 Infection in Central Italy
by Monica Borghi, Alessandro Graziani, Daniele Marini, Elisabetta Madonna, Umbertina Villano, Elisabetta Suffredini, Teresa Vicenza, Elida Mataj, Roberto Bruni, Anna Rita Ciccaglione, Barbara Camilloni and Silvia Bozza
Viruses 2024, 16(12), 1869; https://doi.org/10.3390/v16121869 - 30 Nov 2024
Viewed by 1197
Abstract
Hepatitis E virus (HEV) is a global health problem, causing an estimated 20 million infections annually. Thus, the management of HEV requires special consideration. In developed countries, hepatitis E is mainly recognized as a foodborne disease (mainly transmitted via undercooked meat consumption) that [...] Read more.
Hepatitis E virus (HEV) is a global health problem, causing an estimated 20 million infections annually. Thus, the management of HEV requires special consideration. In developed countries, hepatitis E is mainly recognized as a foodborne disease (mainly transmitted via undercooked meat consumption) that is generally caused by genotype 3 and 4 circulating in various animals, including pigs and wild boars. The current absence of officially recognized protocols for the analysis of HEV in foods and the lack of awareness of this disease among healthcare workers, together with the high percentage of asymptomatic cases, make HEV infection highly underestimated. Most HEV-3 infections in immunocompetent individuals are self-limited. Nevertheless, the possibility of serious forms of liver disease, especially in patients with co-morbidities, should be considered because it can lead to a fatal outcome. Here, we report a case of fatal hepatitis related to HEV-3 infection in a 67-year-old male patient with underlying chronic liver disease (CLD) and living in a region where a high prevalence and genetic heterogeneity of HEV-3 in wild boar has been recently demonstrated. Our case report describes the interdisciplinary approach used (from the diagnosis to the virus phylogenetic characterization) in order to improve epidemiologic HEV surveillance in central Italy. Full article
(This article belongs to the Special Issue Hepatitis E: Molecular Virology, Pathogenesis, and Treatment, 2nd Edition)
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