ICTV Virus Taxonomy Profile: Hepeviridae 2022.

The family Hepeviridae includes enterically transmitted small quasi-enveloped or non-enveloped positive-sense single-stranded RNA viruses infecting mammals and birds (subfamily Orthohepevirinae) or fish (Parahepevirinae). Hepatitis E virus (genus Paslahepevirus) is responsible for self-limiting acute hepatitis in humans; the infection may become chronic in immunocompromised individuals and extrahepatic manifestations have been described. Avian hepatitis E virus (genus Avihepevirus) causes hepatitis-splenomegaly syndrome in chickens. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Hepeviridae, which is available at www.ictv.global/report/hepeviridae.

Co-Circulation of Different Hepatitis E Virus Genotype 3 Subtypes in Pigs and Wild Boar in North-East Germany, 2019.

Hepatitis E is a major cause of acute liver disease in humans worldwide. The infection is caused by hepatitis E virus (HEV) which is transmitted in Europe to humans primarily through zoonotic foodborne transmission from domestic pigs, wild boar, rabbits, and deer. HEV belongs to the family Hepeviridae, and possesses a positive-sense, single stranded RNA genome. This agent usually causes an acute self-limited infection in humans, but in people with low immunity, e.g., immunosuppressive therapy or underlying liver diseases, the infection can evolve to chronicity and is able to induce a variety of extrahepatic manifestations. Pig and wild boar have been identified as the primary animal reservoir in Europe, and consumption of raw and undercooked pork is known to pose a potential risk of foodborne HEV infection. In this study, we analysed pig and wild boar liver, faeces, and muscle samples collected in 2019 in Mecklenburg-Western Pomerania, north-east Germany. A total of 393 animals of both species were investigated using quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR), conventional nested RT-PCR and sequence analysis of amplification products. In 33 animals, HEV RNA was detected in liver and/or faeces. In one individual, viral RNA was detected in muscle tissue. Sequence analysis of a partial open reading frame 1 region demonstrated a broad variety of genotype 3 (HEV-3) subtypes. In conclusion, the study demonstrates a high, but varying prevalence of HEV RNA in swine populations in Mecklenburg-Western Pomerania. The associated risk of foodborne HEV infection needs the establishment of sustainable surveillance and treatment strategies at the interface between humans, animals, and the environment within a One Health framework.

Serological Evidence of Hepatitis E Virus Infection in Semi-Domesticated Eurasian Tundra Reindeer (Rangifer tarandus tarandus) in Norway.

Hepatitis E virus (HEV) is a common cause of viral hepatitis in humans. In developing countries, HEV-infections seem to be mainly associated with pigs, but other animal species may be involved in viral transmission. Recently, anti-HEV antibodies were detected in Norwegian wild reindeer. Here, we investigated anti-HEV seroprevalence in Norwegian semi-domesticated reindeer, animals in closer contact with humans than their wild counterparts. Blood samples (n = 516) were obtained from eight reindeer herds during the period 2013-2017 and analysed with a commercial enzyme-linked immunosorbent assay designed for detecting anti-HEV antibodies in livestock. Antibodies were found in all herds and for all sampling seasons. The overall seroprevalence was 15.7% (81/516), with adults showing a slightly higher seroprevalence (18.0%, 46/256) than calves (13.5%, 35/260, p = 0.11). The seroprevalence was not influenced by gender or latitude, and there was no temporal trend (p > 0.15). A positive association between the presence of anti-HEV antibodies and antibodies against alphaherpesvirus and pestivirus, detected in a previous screening, was found (p < 0.05). We conclude that Norwegian semi-domesticated reindeer are exposed to HEV or an antigenically similar virus. Whether the virus is affecting reindeer health or infects humans and poses a threat for human health remains unknown and warrants further investigations.

Distribution and Genetic Diversity of Hepatitis E Virus in Wild and Domestic Rabbits in Australia.

In 2020, Hepatitis E virus (HEV) was detected for the first time in Australian rabbits. To improve our understanding of the genetic diversity and distribution of the virus, 1635 rabbit liver samples from locations across Australia were screened via RT-qPCR for HEV. HEV genomes were amplified and sequenced from 48 positive samples. Furthermore, we tested 380 serum samples from 11 locations across Australia for antibodies against HEV. HEV was detected in rabbits from all states and territories, except the Northern Territory. Seroprevalence varied between locations (from 0% to 22%), demonstrating that HEV is widely distributed in rabbit populations across Australia. Phylogenetic analyses showed that Australian HEV sequences are genetically diverse and that HEV was likely introduced into Australia independently on several occasions. In summary, this study broadens our understanding of the genetic diversity of rabbit HEV globally and shows that the virus is endemic in both domestic and wild rabbit populations in Australia.

Distribution and Pathogenicity of Two Cutthroat Trout Virus (CTV) Genotypes in Canada.

The sole member of the Piscihepevirus genus (family Hepeviridae) is cutthroat trout virus (CTV) but recent metatranscriptomic studies have identified numerous fish hepevirus sequences including CTV-2. In the current study, viruses with sequences resembling both CTV and CTV-2 were isolated from salmonids in eastern and western Canada. Phylogenetic analysis of eight full genomes delineated the Canadian CTV isolates into two genotypes (CTV-1 and CTV-2) within the Piscihepevirus genus. Hepevirus genomes typically have three open reading frames but an ORF3 counterpart was not predicted in the Canadian CTV isolates. In vitro replication of a CTV-2 isolate produced cytopathic effects in the CHSE-214 cell line with similar amplification efficiency as CTV. Likewise, the morphology of the CTV-2 isolate resembled CTV, yet viral replication caused dilation of the endoplasmic reticulum lumen which was not previously observed. Controlled laboratory studies exposing sockeye (Oncorhynchus nerka), pink (O. gorbuscha), and chinook salmon (O. tshawytscha) to CTV-2 resulted in persistent infections without disease and mortality. Infected Atlantic salmon (Salmo salar) and chinook salmon served as hosts and potential reservoirs of CTV-2. The data presented herein provides the first in vitro and in vivo characterization of CTV-2 and reveals greater diversity of piscihepeviruses extending the known host range and geographic distribution of CTV viruses.

A surveillance study of hepatitis E virus infection in household cats.

Hepatitis E virus (HEV) typically causes self-limiting acute viral hepatitis, however chronic infection and extrahepatic manifestations have increasingly become a significant health problem. Domestic pigs and wild boars are the main reservoirs of HEV genotype 3 and genotype 4 for human infections in industrialized countries, although molecular and serological evidence suggest that several additional animal species may act as HEV hosts. In this study, by assessing serologically and molecularly the sera of 324 household cats from Apulia region (Italy), HEV antibodies were detected with an overall prevalence of 3.1%. Viral RNA was not detected in the sera of the animals using both HEV-specific assays and a pan-hepevirus broadly reactive set of primers for Hepeviridae. These findings document a low seroprevalence to HEV in cats in the investigated geographical setting. The exact nature of the HEV-like strains circulating in feline population remains to be established.

Identification of Hepatitis E Virus in the Feces of Red Foxes (Vulpes vulpes).

Orthohepeviruses (HEV) can infect a wide range of animals, showing a relatively strict host specificity; however, its zoonotic potential, natural transmission in the wildlife are less known. Several new HEV-like viruses have been identified in various animal species, including carnivores; however, the phylogenetic relationship among these viruses is poorly resolved, since some of them were known as rodent-related so far. The red fox, the most widespread carnivore worldwide, is a known reservoir of several viruses that transmit from wildlife to humans or domestic animals; they might have a defined role in the circulation of rodent-borne HEV. In this study, we performed a HEV survey by heminested RT-PCR (Reverse Transcription PCR) on red fox fecal samples to investigate the presence of HEV in red foxes living in natural conditions, and to explore the origin of the virus via phylogenetic analysis. Out of the 26 investigated samples, HEV RNA was identified in one sample. Following Sanger sequencing, the novel sequence displayed 91% identity on the nucleotide level with recently published European common vole-HEV derived from Microtus arvalis. In contrast, it shared 85% nucleotide similarity with HEV strains described previously in red foxes. Our results strongly support "the dietary-origin" of unclassified HEV-like strains described from predators that usually prey on rodents.

Update: proposed reference sequences for subtypes of hepatitis E virus (species Orthohepevirus A).

In this recommendation, we update our 2016 table of reference sequences of subtypes of hepatitis E virus (HEV; species Orthohepevirus A, family Hepeviridae) for which complete genome sequences are available (Smith et al., 2016). This takes into account subsequent publications describing novel viruses and additional proposals for subtype names; there are now eight genotypes and 36 subtypes. Although it remains difficult to define strict criteria for distinguishing between virus subtypes, and is not within the remit of the International Committee on Taxonomy of Viruses (ICTV), the use of agreed reference sequences will bring clarity and stability to researchers, epidemiologists and clinicians working with HEV.

A Novel Hepe-Like Virus from Farmed Giant Freshwater Prawn Macrobrachium rosenbergii.

The family Hepeviridae includes several positive-stranded RNA viruses, which infect a wide range of mammalian species, chicken, and trout. However, few hepatitis E viruses (HEVs) have been characterized from invertebrates. In this study, a hepevirus, tentatively named Crustacea hepe-like virus 1 (CHEV1), from the economically important crustacean, the giant freshwater prawn Macrobrachium rosenbergii, was characterized. The complete genome consisted of 7750 nucleotides and had a similar structure to known hepatitis E virus genomes. Phylogenetic analyses suggested it might be a novel hepe-like virus within the family Hepeviridae. To our knowledge, this is the first hepe-like virus characterized from crustaceans.

Rat Hepatitis E Virus Linked to Severe Acute Hepatitis in an Immunocompetent Patient.

Hepatitis E virus (HEV) is a major public health concern in developing countries where the primary transmission is via contaminated water. Zoonotic HEV cases have been increasingly described in Europe, Japan, and the United States, with pigs representing the main animal reservoir of infection. We report an unusual acute hepatitis infection in a previously healthy man caused by a rat HEV with a considerably divergent genomic sequence compared with other rat HEV strains. It is possible that rat HEV is an underrecognized cause of hepatitis infection, and further studies are necessary to elucidate its potential risk and mode of transmission.

Novel orthohepeviruses in wild rodents from São Paulo State, Brazil.

The Hepeviridae comprise single-stranded positive-sense RNA viruses classified into two genera, Orthohepevirus and Piscihepevirus. Orthohepeviruses have a wide host range that includes rodents, but previous studies had been restricted to rodents of the Muridae family. In this study, we applied a high-throughput sequencing approach to examine the presence of orthohepeviruses in rodents from São Paulo State, Brazil. We also used RT-PCR to determine the frequency of orthohepeviruses in our sampled population. We identified novel orthohepeviruses in blood samples derived from Necromys lasiurus (1.19%) and Calomys tener (3.66%). Therefore, our results expand the host range and viral diversity of the Hepeviridae family.

Sogatella furcifera hepe-like virus: First member of a novel Hepeviridae clade identified in an insect.

A novel virus was identified in the white-backed planthopper (Sogatella furcifera, Hemiptera: Delphacidae) and tentatively named Sogatella furcifera hepe-like virus (SfHeV). Its genome is a linear, single-stranded monopartite RNA, 7,312 nucleotides (nt) long with a 66-nt 5' UTR, 54-nt 3' UTR, and 28-nt polyA, showing typical genomic features of viruses in the family Hepeviridae, but highly divergent from known members in the family, with amino acid sequence identities of only 18.9-23% (ORF1), 13.1-18.8% (ORF2) and 1.9-11% (ORF3). Phylogenetic analysis revealed that SfHeV was closer to cutthroat trout virus (CTV), but did not cluster with any members of the family. SfHeV is the first hepe-like virus identified in a hemipteran insect and was detected in all developmental stages suggesting the presence of some level of vertical transmission. On the basis of these data, we propose that SfHeV represents a novel clade in the family Hepeviridae and tentatively name the genus Insecthepevirus.

Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis.

Viruses from the Coronaviridae, Togaviridae, and Hepeviridae families ​all contain genes that encode a conserved protein domain, called a macrodomain; however, the role of this domain during infection has remained enigmatic. The recent discovery that mammalian macrodomain proteins enzymatically remove ADP-ribose, a common post-translation modification, from proteins has led to an outburst of studies describing both the enzymatic activity and function of viral macrodomains. These new studies have defined these domains as de-ADP-ribosylating enzymes, which indicates that these viruses have evolved to counteract antiviral ADP-ribosylation, likely mediated by poly-ADP-ribose polymerases (PARPs). Here, we comprehensively review this rapidly expanding field, describing the structures and enzymatic activities of viral macrodomains, and discussing their roles in viral replication and pathogenesis.

ICTV Virus Taxonomy Profile: Hepeviridae.

The family Hepeviridae includes enterically transmitted small non-enveloped positive-sense RNA viruses. It includes the genera Piscihepevirus, whose members infect fish, and Orthohepevirus, whose members infect mammals and birds. Members of the genus Orthohepevirus include hepatitis E virus, which is responsible for self-limiting acute hepatitis in humans and several mammalian species; the infection may become chronic in immunocompromised individuals. Extrahepatic manifestations of Guillain-Barré syndrome, neuralgic amyotrophy, glomerulonephritis and pancreatitis have been described in humans. Avian hepatitis E virus causes hepatitis-splenomegaly syndrome in chickens. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Hepeviridae, which is available at www.ictv.global/report/hepeviridae.

Detection of rat hepatitis E virus in wild Norway rats (Rattus norvegicus) and Black rats (Rattus rattus) from 11 European countries.

Rat hepatitis E virus (HEV) is genetically only distantly related to hepeviruses found in other mammalian reservoirs and in humans. It was initially detected in Norway rats (Rattus norvegicus) from Germany, and subsequently in rats from Vietnam, the USA, Indonesia, China, Denmark and France. Here, we report on a molecular survey of Norway rats and Black rats (Rattus rattus) from 12 European countries for ratHEV and human pathogenic hepeviruses. RatHEV-specific real-time and conventional RT-PCR investigations revealed the presence of ratHEV in 63 of 508 (12.4%) rats at the majority of sites in 11 of 12 countries. In contrast, a real-time RT-PCR specific for human pathogenic HEV genotypes 1-4 and a nested broad-spectrum (NBS) RT-PCR with subsequent sequence determination did not detect any infections with these genotypes. Only in a single Norway rat from Belgium a rabbit HEV-like genotype 3 sequence was detected. Phylogenetic analysis indicated a clustering of all other novel Norway and Black rat-derived sequences with ratHEV sequences from Europe, the USA and a Black rat-derived sequence from Indonesia within the proposed ratHEV genotype 1. No difference in infection status was detected related to age, sex, rat species or density of human settlements and zoological gardens. In conclusion, our investigation shows a broad geographical distribution of ratHEV in Norway and Black rats from Europe and its presence in all settlement types investigated.

Ancient recombination events and the origins of hepatitis E virus.

BACKGROUND: Hepatitis E virus (HEV) is an enteric, single-stranded, positive sense RNA virus and a significant etiological agent of hepatitis, causing sporadic infections and outbreaks globally. Tracing the evolutionary ancestry of HEV has proved difficult since its identification in 1992, it has been reclassified several times, and confusion remains surrounding its origins and ancestry. RESULTS: To reveal close protein relatives of the Hepeviridae family, similarity searching of the GenBank database was carried out using a complete Orthohepevirus A, HEV genotype I (GI) ORF1 protein sequence and individual proteins. The closest non-Hepeviridae homologues to the HEV ORF1 encoded polyprotein were found to be those from the lepidopteran-infecting Alphatetraviridae family members. A consistent relationship to this was found using a phylogenetic approach; the Hepeviridae RdRp clustered with those of the Alphatetraviridae and Benyviridae families. This puts the Hepeviridae ORF1 region within the "Alpha-like" super-group of viruses. In marked contrast, the HEV GI capsid was found to be most closely related to the chicken astrovirus capsid, with phylogenetic trees clustering the Hepeviridae capsid together with those from the Astroviridae family, and surprisingly within the "Picorna-like" supergroup. These results indicate an ancient recombination event has occurred at the junction of the non-structural and structure encoding regions, which led to the emergence of the entire Hepeviridae family. The Astroviridae capsid is also closely related to the Tymoviridae family of monopartite, T = 3 icosahedral plant viruses, whilst its non-structural region is related to viruses of the Potyviridae; a large family of plant-infecting viruses with a flexible filamentous rod-shaped virion. Thus, we identified a separate inter-viral family recombination event, again at the non-structural/structural junction, which likely led to the creation of the Astroviridae. CONCLUSIONS: In summary, we have shown that new viral families have been created though recombination at the junction of the genome that encodes non-structural and structural proteins, and such recombination events are implicated in the genesis of important human pathogens; HEV, astrovirus and rubella virus.

La pluralité de l'hépatite E : des formes cliniques aux souches animales.

The concept of zoonotic viral hepatitis E has emerged a few years ago in countries where sporadic cases of hepatitis E were not associated with travel in geographical areas where the virus is endemic (tropical or subtropical regions) . Improved diagnostic methods and the awareness of clinicians helped to better assess the impact of infection by hepatitis E virus (HEV) and identify new related syndromes. Similarly, the description of chronic forms of hepatitis E in immunocompromised patients raises the question of the treatment and prevention of this disease. Recent advances in the identification of animal reservoirs of HEV have confirmed that the strains circulating in domestic and wild pigs are genetically close to strains identified in indigenous cases. Characterization of HEV infection in swine herds has identified risk factors associated to the virus spreading. In addition, the identification of HEV in the food chain or products containing pork has shown that it is a food-borne zoonosis. The arrival of recent technologies to identify new agents helped expand the family of HEV related viruses and identify potential new animal reservoirs.

In silico and in vitro interrogation of a widely used HEV RT-qPCR assay for detection of the species Orthohepevirus A.

Hepatitis E virus (HEV) infection is a public health concern worldwide, associated with waterborne outbreaks in developing countries and reported as an emerging zoonotic infection in high-income countries. A recent consensus proposal classified the isolates from human, swine, wild boar, deer, mongoose, rabbit and camel in seven genotypes within the species Orthohepevirus A. In this report a popular HEV RT-qPCR assay was assessed for the detection of the species Orthohepevirus A. In silico analysis of 189 complete genome sequences showed that the assay targets a highly conserved region in the Orthohepevirus A genome. Additionally, plasmid standards were constructed to test the effect of probe- and primer-binding site mutations in the assay performance. The assay proved robust enough to detect strains with mutations in the probe-binding site and in the 3' end primer-binding site regions. A degenerate version of the reverse primer improves the performance of the assay particularly in the detection of HEV-5 and 6. The addition and detection of MS2 RNA in each RT-qPCR reaction monitored for amplification inhibition and did not affect the performance of the assay in the detection of the HEV RNA international standard. Therefore, the RT-qPCR assay can be confidently used for the RNA detection of the seven genotypes within the species Orthohepevirus A.

Hepeviridae: an expanding family of vertebrate viruses.

The hepatitis E virus (HEV) was first identified in 1990, although hepatitis E-like diseases in humans have been recorded for a long time dating back to the 18th century. The HEV genotypes 1-4 have been subsequently detected in human hepatitis E cases with different geographical distribution and different modes of transmission. Genotypes 3 and 4 have been identified in parallel in pigs, wild boars and other animal species and their zoonotic potential has been confirmed. Until 2010, these genotypes along with avian HEV strains infecting chicken were the only known representatives of the family Hepeviridae. Thereafter, additional HEV-related viruses have been detected in wild boars, distinct HEV-like viruses were identified in rats, rabbit, ferret, mink, fox, bats and moose, and a distantly related agent was described from closely related salmonid fish. This review summarizes the characteristics of the so far known HEV-like viruses, their phylogenetic relationship, host association and proposed involvement in diseases. Based on the reviewed knowledge, a suggestion for a new taxonomic grouping scheme of the viruses within the family Hepeviridae is presented.