-
Emerging Microbes & Infections Feb 2018Hepatitis E virus (HEV, genus Orthohepevirus) is a common cause of hepatitis worldwide. Human-infecting HEV strains (Orthohepevirus A) include human-restricted and...
Hepatitis E virus (HEV, genus Orthohepevirus) is a common cause of hepatitis worldwide. Human-infecting HEV strains (Orthohepevirus A) include human-restricted and enzootic genotypes. Viruses in the Orthohepevirus A species also infect rabbits (HEV-3ra), camels, and swine. Using a selection-informed method, we dated the origin of the Orthohepevirus genus at least 21 million years ago, whereas the Orthohepevirus A species originated in Asia, most likely from a human-infecting ancestor that existed ~4500 to 6800 years ago. In this period, the appearance of large human settlements probably facilitated HEV emergence and spread. The earliest events in Orthohepevirus A evolutionary history involved the separation of the enzootic and human-restricted genotypes, as well as the split of the camel-infecting genotypes, which occurred during the time-frame of camel domestication. The place and timing of HEV-3ra divergence also correspond to the circumstances of rabbit domestication. This study clarifies the origin and historical events underlying HEV dispersal.
Topics: Animals; Asia; Genetic Variation; Genotype; Hepatitis E; Hepatitis E virus; History, Ancient; Humans; Rabbits; Swine
PubMed: 29410449
DOI: 10.1038/s41426-017-0009-6 -
Viruses Jan 2020Hepatitis E virus (HEV) is a major concern in public health worldwide. Infections with HEV genotypes 3, 4, or 7 can lead to chronic hepatitis while genotype 1 infections...
Hepatitis E virus (HEV) is a major concern in public health worldwide. Infections with HEV genotypes 3, 4, or 7 can lead to chronic hepatitis while genotype 1 infections can trigger severe hepatitis in pregnant women. Infections with all genotypes can worsen chronic liver diseases. As virions are lipid-associated in blood and naked in feces, efficient methods of propagating HEV clinical strains in vitro and evaluating the infectivity of both HEV forms are needed. We evaluated the spread of clinical strains of HEV genotypes 1 (HEV1) and 3 (HEV3) by quantifying viral RNA in culture supernatants and cell lysates. Infectivity was determined by endpoint dilution and calculation of the tissue culture infectious dose 50 (TCID50). An enhanced HEV production could be obtained varying the composition of the medium, including fetal bovine serum (FBS) and dimethylsulfoxide (DMSO) content. This increased TCID50 from 10 to 100-fold and allowed us to quantify HEV1 infectivity. These optimized methods for propagating and measuring HEV infectivity could be applied to health safety processes and will be useful for testing new antiviral drugs.
Topics: Culture Media; Genotype; Hep G2 Cells; Hepatitis E virus; Humans; RNA, Viral; Virus Cultivation
PubMed: 31991673
DOI: 10.3390/v12020139 -
Cold Spring Harbor Perspectives in... Aug 2019The recognition of hepatitis E as a discreet disease entity in the late 1970s followed the development of serological tests for hepatitis A and the discovery that large... (Review)
Review
The recognition of hepatitis E as a discreet disease entity in the late 1970s followed the development of serological tests for hepatitis A and the discovery that large waterborne outbreaks of hepatitis in India were not caused by hepatitis A virus (HAV). These "enterically transmitted non-A, non-B hepatitis" outbreaks had distinctive epidemiologic features, including the highest attack rates among young adults, little secondary household transmission of infection, and severe disease in pregnant women. The responsible agent, hepatitis E virus (HEV), was identified several years later in extracts of feces from a self-inoculated virologist. Multiple genetically related HEV genotypes are now known to exist, two of which are common in domestic swine herds and the cause of sporadic cases of acute hepatitis in economically well-developed countries. HEV genotypes possess impressive genetic and biologic diversity, and present many unanswered questions concerning their natural host range, potential for zoonotic transmission, and disease pathogenesis.
Topics: Animals; Developing Countries; Hepatitis E; Hepatitis E virus; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Zoonoses
PubMed: 29735576
DOI: 10.1101/cshperspect.a033449 -
Virology Journal May 2023Hepatitis E virus (HEV) circulation in humans and swine has been extensively studied in South America over the last two decades. Nevertheless, only 2.1% of reported HEV...
Hepatitis E virus (HEV) circulation in humans and swine has been extensively studied in South America over the last two decades. Nevertheless, only 2.1% of reported HEV strains are available as complete genome sequences. Therefore, many clinical, epidemiological, and evolutionary aspects of circulating HEV in the continent still need to be clarified. Here, we conducted a retrospective evolutionary analysis of one human case and six swine HEV strains previously reported in northeastern, southern, and southeastern Brazil. We obtained two complete and four nearly complete genomic sequences. Evolutionary analysis comparing the whole genomic and capsid gene sequences revealed high genetic variability. This included the circulation of at least one unrecognized unique South American subtype. Our results corroborate that sequencing the whole capsid gene could be used as an alternative for HEV subtype assignment in the absence of complete genomic sequences. Moreover, our results substantiate the evidence for zoonotic transmission by comparing a larger genomic fragment recovered from the sample of the autochthonous human hepatitis E case. Further studies should continuously investigate HEV genetic diversity and zoonotic transmission of HEV in South America.
Topics: Swine; Humans; Animals; Hepatitis E virus; Brazil; Retrospective Studies; Sequence Analysis, DNA; Genotype; Phylogeny
PubMed: 37131237
DOI: 10.1186/s12985-023-02047-6 -
Viruses Dec 2020Hepatitis E virus (HEV) is the etiological agent behind hepatitis E infection. Domestic pigs and wild boars are the main animal reservoirs of HEV. Very few papers...
Hepatitis E virus (HEV) is the etiological agent behind hepatitis E infection. Domestic pigs and wild boars are the main animal reservoirs of HEV. Very few papers describe HEV infection in goats and sheep. As the data pertaining to the presence of HEV virus in the milk of small ruminants in Europe are lacking, the aim of this paper was to examine a representative number of milk samples from these animals. The detection of HEV genome (HEV RNA) was performed using reverse transcriptase real-time polymerase chain reaction (RT-qPCR). HEV RNA was found in 2.8% of the examined samples. Positivity ranged from 10 to 10 genome equivalents/mL (GE/mL) with a median of 9.99 × 10 GE/mL. On the basis of these results, the milk of small ruminants could represent a source of HEV infection to consumers.
Topics: Animal Diseases; Animals; Czech Republic; Goats; Hepatitis E; Hepatitis E virus; Milk; RNA, Viral; Sheep
PubMed: 33322702
DOI: 10.3390/v12121429 -
Liver International : Official Journal... Apr 2015Fulminant hepatitis is a rare outcome of infection with hepatitis E virus. Several recent reports suggest that virus variation is an important determinant of disease...
BACKGROUND & AIMS
Fulminant hepatitis is a rare outcome of infection with hepatitis E virus. Several recent reports suggest that virus variation is an important determinant of disease progression. To critically examine the evidence that virus-specific factors underlie the development of fulminant hepatitis following hepatitis E virus infection.
METHODS
Published sequence information of hepatitis E virus isolates from patients with and without fulminant hepatitis was collected and analysed using statistical tests to identify associations between virus polymorphisms and disease outcome.
RESULTS
Fulminant hepatitis has been reported following infection with all four hepatitis E virus genotypes that infect humans comprising multiple phylogenetic lineages within genotypes 1, 3 and 4. Analysis of virus sequences from individuals infected by a common source did not detect any common substitutions associated with progression to fulminant hepatitis. Re-analysis of previously reported associations between virus substitutions and fulminant hepatitis suggests that these were probably the result of sampling biases.
CONCLUSIONS
Host-specific factors rather than virus genotype, variants or specific substitutions appear to be responsible for the development of fulminant hepatitis.
Topics: Genotype; Hepatitis E; Hepatitis E virus; Host-Pathogen Interactions; Humans; Phenotype; Polymorphism, Genetic; Prognosis; Risk Factors
PubMed: 24974734
DOI: 10.1111/liv.12629 -
BioMed Research International 2018Hepatitis E virus (HEV) is a common etiology of acute viral hepatitis worldwide. Recombinant HEV vaccines have been developed, but only one is commercially available and... (Review)
Review
Hepatitis E virus (HEV) is a common etiology of acute viral hepatitis worldwide. Recombinant HEV vaccines have been developed, but only one is commercially available and licensed in China since 2011. Epidemiological studies have identified genotype 3 as the major cause of chronic infection in immunocompromised individuals. Ribavirin has been shown to be effective as a monotherapy to induce HEV clearance in chronic patients who have undergone solid organ transplant (SOT) under immunosuppressive therapy. Efforts and improvements in prevention and control have been made to reduce the instances of acute and chronic hepatitis E in endemic and nonendemic countries. However, this review shows that further studies are required to demonstrate the importance of preventive vaccination and treatment worldwide, with emphasis on hepatitis E infection in the public health system.
Topics: China; Genotype; Hepatitis E; Hepatitis E virus; Humans; Ribavirin; Vaccines, Synthetic
PubMed: 29546064
DOI: 10.1155/2018/5769201 -
The Journal of General Virology Nov 2015Infection with hepatitis E virus (HEV) can be clinically inapparent or produce symptoms and signs of hepatitis of varying severity and occasional fatality. This...
Infection with hepatitis E virus (HEV) can be clinically inapparent or produce symptoms and signs of hepatitis of varying severity and occasional fatality. This variability in clinical outcomes may reflect differences in host susceptibility or the presence of virally encoded determinants of pathogenicity. Analysis of complete genome sequences supports the division of HEV genotype 3 (HEV-3) variants into three major clades: 3ra comprising HEV isolates from rabbits, and 3efg and 3abchij comprising the corresponding named subtypes derived from humans and pigs. Using this framework, we investigated associations between viral genetic variability of HEV-3 in symptomatic and asymptomatic infections by comparing HEV-3 subgenomic sequences previously obtained from blood donors with those from patients presenting with hepatitis in the UK (54 blood donors, 148 hepatitis patients), the Netherlands (38 blood donors, 119 hepatitis patients), France (24 blood donors, 55 hepatitis patients) and Germany (14 blood donors, 36 hepatitis patients). In none of these countries was evidence found for a significant association between virus variants and patient group (P>0.05 Fisher's exact test). Furthermore, within a group of 123 patients in Scotland with clinically apparent HEV infections, we found no evidence for an association between variants of HEV-3 and disease severity or alanine aminotransferase level. The lack of detectable virally encoded determinants of disease outcomes in HEV-3 infection implies a more important role for host factors in its clinical phenotype.
Topics: France; Genetic Variation; Germany; Hepatitis E; Hepatitis E virus; Humans; Molecular Sequence Data; Netherlands; Phylogeny; Scotland; Virulence
PubMed: 26282123
DOI: 10.1099/jgv.0.000264 -
Journal of Virology Mar 2022Hepatitis E virus (HEV) is a quasi-enveloped virus with a single-stranded positive-sense RNA genome belonging to the family . Studies of the molecular aspects of HEV and...
Hepatitis E virus (HEV) is a quasi-enveloped virus with a single-stranded positive-sense RNA genome belonging to the family . Studies of the molecular aspects of HEV and drug screening have benefited from the discovery of bioluminescent reporter genes. However, the stability of large foreign genes is difficult to maintain after insertion into the viral genome. Currently, ribavirin is used to treat HEV-infected patients who require antiviral therapy. This has several major drawbacks. Thus, the development of novel anti-HEV drugs is of great importance. We developed a system consisting of recombinant infectious HEV harboring a small luciferase gene (nanoKAZ) in the hypervariable region (HVR) of the open reading frame 1 (ORF1) (HEV-nanoKAZ). It replicated efficiently in cultured cells, was genetically stable, and had morphological characteristics similar to those of the parental virus. Both membrane-associated (eHEV-nanoKAZ) and membrane-unassociated (neHEV-nanoKAZ) particles were infectious. HEV particles circulating in the bloodstream and attaching to hepatocytes in HEV-infected patients are membrane-associated; thus, eHEV-nanoKAZ was applied in drug screening. The eHEV-nanoKAZ system covers at least the inhibitor of HEV entry and inhibitor of HEV RNA replication. Four drugs with anti-HEV activity were identified. Their effectiveness in cultured cells was confirmed in naive and HEV-producing PLC/PRF/5 cells. Two hit drugs (azithromycin and ritonavir) strongly inhibited HEV production in culture supernatants, as well as intracellular expression of ORF2 protein, and may therefore be candidate novel anti-HEV drugs. The HEV-nanoKAZ system was developed and applied in drug screening and is expected to be useful for investigating the HEV life cycle. Bioluminescent reporter viruses are essential tools in molecular virological research. They have been widely used to investigate viral life cycles and in the development of antiviral drugs. For drug screening, the use of a bioluminescent reporter virus helps shorten the time required to perform the assay. A system, consisting of recombinant infectious HEV harboring the nanoKAZ gene in the HVR of ORF1 (HEV-nanoKAZ), was developed in this study and was successfully applied to drug screening in which four hit drugs with anti-HEV activity were identified. The results of this study provide evidence supporting the use of this system in more variable HEV studies. In addition, both forms of viral particles (eHEV-nanoKAZ and neHEV-nanoKAZ) are infectious, which will enable their application in HEV studies requiring both forms of viral particles, such as in the investigation of unknown HEV receptors and the elucidation of host factors important for HEV entry.
Topics: Antiviral Agents; Drug Evaluation, Preclinical; Hepatitis E virus; Humans; Virus Internalization; Virus Replication
PubMed: 35107380
DOI: 10.1128/jvi.01906-21 -
Virology Jan 2019Hepatitis E virus (HEV) infection is widespread in the global pig population. Although clinically inapparent in pigs, HEV infection is the cause of Hepatitis E in humans...
Hepatitis E virus (HEV) infection is widespread in the global pig population. Although clinically inapparent in pigs, HEV infection is the cause of Hepatitis E in humans and transmission via the food chain has been established. Following a 2013 study that investigated prevalence of HEV infection in UK slaughter-age pigs samples indicating highest viral load were selected for further characterisation. High throughput sequencing was used to obtain the complete coding sequence from five samples. An in-frame insertion was observed within the HEV hypervariable region in two samples. To interrogate whether this mutation may be the cause of high-level viraemia and faecal shedding as observed in the sampled pigs virus isolation and culture was conducted. Based on viral growth kinetics there was no evidence that these insertions affected replication efficiency in vitro, suggesting as yet undetermined host factors may affect the course of infection and consequently the risk of foodborne transmission.
Topics: Animals; Feces; Food Microbiology; Genome, Viral; Hepatitis E; Hepatitis E virus; Mutagenesis, Insertional; Open Reading Frames; Phylogeny; Prevalence; RNA, Viral; Sequence Analysis, RNA; Sus scrofa; Swine; United Kingdom; Viremia
PubMed: 30496912
DOI: 10.1016/j.virol.2018.10.018