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Hepatitis E virus (HEV) (family Hepeviridae) is one of the most common human pathogens, causing acute hepatitis and an increasingly recognized etiological agent in chronic hepatitis and extrahepatic manifestations. Recent studies reported that not only are the classical members of the species Orthohepevirus A (HEV-A) pathogenic to humans but a genetically highly divergent rat origin hepevirus (HEV-C1) in species Orthohepevirus C (HEV-C) is also able to cause zoonotic infection and symptomatic disease (hepatitis) in humans. This review summarizes the current knowledge of hepeviruses in rodents with special focus of rat origin HEV-C1. Cross-species transmission and genetic diversity of HEV-C1 and confirmation of HEV-C1 infections and symptomatic disease in humans re-opened the long-lasting and full of surprises story of HEV in human. This novel knowledge has a consequence to the epidemiology, clinical aspects, laboratory diagnosis, and prevention of HEV infection in humans.

Rat hepatitis E virus (rat HEV) was first identified in wild rats and was classified as the species Orthohepevirus C in the genera Orthohepevirus, which is genetically different from the genotypes HEV-1 to HEV-8, which are classified as the species Orthohepevirus A. Although recent reports suggest that rat HEV transmits to humans and causes hepatitis, the infectivity of rat HEV to non-human primates such as cynomolgus and rhesus monkeys remains controversial. To investigate whether rat HEV infects non-human primates, we inoculated one cynomolgus monkey and five rhesus monkeys with a V-105 strain of rat HEV via an intravenous injection. Although no significant elevation of alanine aminotransferase (ALT) was observed, rat HEV RNA was detected in fecal specimens, and seroconversion was observed in all six monkeys. The partial nucleotide sequences of the rat HEV recovered from the rat HEV-infected monkeys were identical to those of the V-105 strain, indicating that the infection was caused by the rat HEV. The rat HEV recovered from the cynomolgus and rhesus monkeys successfully infected both nude and Sprague-Dawley rats. The entire rat HEV genome recovered from nude rats was identical to that of the V-105 strain, suggesting that the rat HEV replicates in monkeys and infectious viruses were released into the fecal specimens. These results demonstrated that cynomolgus and rhesus monkeys are susceptible to rat HEV, and they indicate the possibility of a zoonotic infection of rat HEV. Cynomolgus and rhesus monkeys might be useful as animal models for vaccine development.

Hepatitis E virus (HEV) is an emerging zoonotic pathogen that has received an increasing amount of attention from virologists, clinicians, veterinarians, and epidemiologists over the past decade. The host range and animal reservoirs of HEV are rapidly expanding and a plethora of emerging HEV variants have been recently identified, some of which have the potential for interspecies infection. In this review, the detection of genetically diverse HEV variants, classified into and presumably associated with the species Orthohepevirus C, currently comprising HEV genotypes C1 and C2, by either serological or molecular approach is summarized. The distribution, genomic variability, and evolution of Orthohepevirus C are analyzed. Moreover, the potential risk of cross-species infection and zoonotic transmission of Orthohepevirus C are discussed.

Hepatitis E virus (HEV) was discovered during the Soviet occupation of Afghanistan in the 1980s, after an outbreak of unexplained hepatitis at a military camp. A pooled faecal extract from affected soldiers was ingested by a member of the research team. He became sick, and the new virus (named HEV), was detected in his stool by electron microscopy. Subsequently, endemic HEV has been identified in many resource-poor countries. Globally, HEV is the most common cause of acute viral hepatitis. The virus was not initially thought to occur in developed countries, but recent reports have shown this notion to be mistaken. The aim of this Seminar is to describe recent discoveries regarding HEV, and how they have changed our understanding of its effect on human health worldwide.

Orthohepevirus C1, also known as rat hepatitis E virus (HEV), has been shown to sporadically cause disease in immunocompromised and immunocompetent adults. While routine serological assays vary in reactivity, rat HEV is not detected in routine HEV RT-PCR. Thus, such infections could be either missed or misclassified as conventional HEV (Orthohepevirus A) infections. We conducted a retrospective screening study among serum and plasma samples from patients suspected of having HEV infection, which were archived at the national consultant laboratory for HAV and HEV between 2000 and 2020. We randomly selected n = 200 samples, which were initially tested reactive (positive or borderline) for HEV-IgM and negative for HEV RNA and re-examined them using a highly sensitive Orthohepevirus C genotype 1-specific in-house RT-qPCR (LoD 95: 6.73 copies per reaction) and a nested RT-PCR broadly reactive for Orthohepevirus A and C. Conventional sanger sequencing was conducted for resulting PCR products. No atypical HEV strains were detected (0 of 200 [0.0%; 95% confidence interval: 0.0%–1.89%], indicating that Orthohepevirus C infections in the investigated population (persons with clinical suspicion of hepatitis E and positive HEV-IgM) are very rare.

The hepatitis E virus (HEV) is a widespread human infection that causes mainly acute infection and can evolve to a chronic manifestation in immunocompromised individuals. In addition to the common strains of hepatitis E virus (HEV-A), known as Paslahepevirus balayani, pathogenic to humans, a genetically highly divergent rat origin hepevirus (RHEV) can cause hepatitis possessing a potential risk of cross-species infection and zoonotic transmission. Rocahepevirus ratti, formerly known as Orthohepevirus C, is a single-stranded RNA virus, recently reassigned to Rocahepevirus genus in the Hepeviridae family, including genotypes C1 and C2. RHEV primarily infects rats but has been identified as a rodent zoonotic virus capable of infecting humans through the consumption of contaminated food or water, causing both acute and chronic hepatitis cases in both animals and humans. This review compiles data concluding that 60% (295/489) of RHEV infections are found in Asia, being the continent with the highest zoonotic and transmission potential. Asia not only has the most animal cases but also 16 out of 21 human infections worldwide. Europe follows with 26% (128/489) of RHEV infections in animals, resulting in four human cases out of twenty-one globally. Phylogenetic analysis and genomic sequencing will be employed to gather global data, determine epidemiology, and assess geographical distribution. This information will enhance diagnostic accuracy, pathogenesis understanding, and help prevent cross-species transmission, particularly to humans.

Hepatitis E virus (HEV) infection has a global distribution with diverse hosts, including mammals and avians. In this study, an avian Hepatitis E virus (aHEV) strain with a high mortality rate of about 30%, designated as SDXT20, was obtained from the liver of 30-week-old Hubbard chickens with severe hepatosplenomegaly in 2020 in Eastern China and HEV was proved to be the only pathogen by next-generation sequencing. Its complete genome, which encodes three open reading frames (ORFs), is 6649 nt in length. ORF1-3 encodes three proteins with lengths of 1532 aa, 606 aa, and 82 aa, respectively, and ORF2 and ORF3 overlap with each other. BLAST-based similarity analysis of the complete viral genome demonstrated that SDXT20 had merely 80.5–92.2% similarity with avian Avihepevirus magniiecur strains and 50.4%–54.8% lower similarity with Paslahepevirus balayani, Rocahepevirus ratti, and Chirohepevirus eptesici species. Further genetic evolution analysis of the complete genome and ORF2 revealed that the isolate was genetically distinct from known aHEVs, and it belonged to a novel genetically distinct aHEV. This study provides data for further analysis of the multi-host and cross-host genetic evolution of HEVs.

Rodents host different orthohepeviruses, namely orthohepevirus C genotype HEV-C1 (rat hepatitis E virus, HEV) and the additional putative genotypes HEV-C3 and HEV-C4. Here, we screened 2,961 rodents from Central Europe by reverse transcription polymerase chain reaction (RT-PCR) and identified HEV RNA in 13 common voles (Microtus arvalis) and one bank vole (Myodes glareolus) with detection rates of 2% (95% confidence interval [CI]: 1-3.4) and 0.08% (95% CI: 0.002-0.46), respectively. Sequencing of a 279-nucleotide RT-PCR amplicon corresponding to a region within open reading frame (ORF) 1 showed a high degree of similarity to recently described common vole-associated HEV (cvHEV) sequences from Hungary. Five novel complete cvHEV genome sequences from Central Europe showed the typical HEV genome organization with ORF1, ORF2 and ORF3 and RNA secondary structure. Uncommon features included a noncanonical start codon in ORF3, multiple insertions and deletions within ORF1 and ORF2/ORF3, and the absence of a putative ORF4. Phylogenetic analysis showed all of the novel cvHEV sequences to be monophyletic, clustering most closely with an unassigned bird-derived sequence and other sequences of the species Orthohepevirus C. The nucleotide and amino acid sequence divergence of the common vole-derived sequences was significantly correlated with the spatial distance between the trapping sites, indicating mostly local evolutionary processes. Detection of closely related HEV sequences in common voles in multiple localities over a distance of 800 kilometers suggested that common voles are infected by cvHEV across broad geographic distances. The common vole-associated HEV strain is clearly divergent from HEV sequences recently found in narrow-headed voles (Microtus gregalis) and other cricetid rodents.

Hepatitis E virus (HEV) causes self-limiting acute hepatitis in humans that can eventually result in acute liver failures or progress to chronic infections. While in tropical and sub-tropical areas, HEV infections are associated with important waterborne epidemics, in Northern countries, HEV infections are autochthonous with a zoonotic origin. In the past decade, it has become clear that certain HEV genotypes are zoonotic and that swine, and more generally Suidae, are the main reservoir. Zoonotic transmissions of the virus may occur via direct contact with infected pigs, wild boars or consumption of contaminated meat. This review describes the current knowledge on domestic and wild Suidae as reservoirs of HEV and the evidence of the different routes of HEV transmission between these animals and humans.

The adverse relationship between viral hepatitis and pregnancy in developing countries had been interpreted as a reflection of retrospectively biased hospital-based data collection by the West. However, the discovery of hepatitis E virus (HEV) as the etiological agent of an epidemic of non-A, non-B hepatitis in Kashmir, and the documenting of the increased incidence and severity of hepatitis E in pregnancy via a house-to-house survey, unmasked this unholy alliance. In the Hepeviridae family, HEV-genotype (gt)1 from genus Orthohepevirus A has a unique open reading frame (ORF)4-encoded protein which enhances viral polymerase activity and viral replication. The epidemics caused by HEV-gt1, but not any other Orthohepevirus A genotype, show an adverse relationship with pregnancy in humans. The pathogenesis of the association is complex and at present not well understood. Possibly multiple factors play a role in causing severe liver disease in the pregnant women including infection and damage to the maternal-fetal interface by HEV-gt1; vertical transmission of HEV to fetus causing severe fetal/neonatal hepatitis; and combined viral and hormone related immune dysfunction of diverse nature in the pregnant women, promoting viral replication. Management is multidisciplinary and needs a close watch for the development and management of acute liver failure. (ALF). Preliminary data suggest beneficial maternal outcomes by early termination of pregnancy in patients with lower grades of encephalopathy.