scholarly journals Hepatitis E Virus Replication

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 719 ◽  
Author(s):  
Robert LeDesma ◽  
Ila Nimgaonkar ◽  
Alexander Ploss
Keyword(s):  
Hepatitis E Virus ◽  
Rna Virus ◽  
Hypervariable Region ◽  
Hepatitis E ◽  
Open Reading Frames ◽  
Health Concern ◽  
Viral Gene ◽  
Genome Replication ◽  
Replication Strategy ◽  
Viral Gene Product

Hepatitis E virus (HEV) is a small quasi-enveloped, (+)-sense, single-stranded RNA virus belonging to the Hepeviridae family. There are at least 20 million HEV infections annually and 60,000 HEV-related deaths worldwide. HEV can cause up to 30% mortality in pregnant women and progress to liver cirrhosis in immunocompromised individuals and is, therefore, a greatly underestimated public health concern. Although a prophylactic vaccine for HEV has been developed, it is only licensed in China, and there is currently no effective, non-teratogenic treatment. HEV encodes three open reading frames (ORFs). ORF1 is the largest viral gene product, encoding the replicative machinery of the virus including a methyltransferase, RNA helicase, and an RNA-dependent RNA polymerase. ORF1 additionally contains a number of poorly understood domains including a hypervariable region, a putative protease, and the so-called ‘X’ and ‘Y’ domains. ORF2 is the viral capsid essential for formation of infectious particles and ORF3 is a small protein essential for viral release. In this review, we focus on the domains encoded by ORF1, which collectively mediate the virus’ asymmetric genome replication strategy. We summarize what is known, unknown, and hotly debated regarding the coding and non-coding regions of HEV ORF1, and present a model of how HEV replicates its genome.

scholarly journals Characterization of the hepatitis E virus replicase

2021 ◽  
Author(s):  
Karoline Metzger ◽  
Cyrine Bentaleb ◽  
Kévin Hervouet ◽  
Virginie Alexandre ◽  
Claire Montpellier ◽  
...  
Keyword(s):  
Hepatitis E Virus ◽  
Rna Virus ◽  
Simultaneous Detection ◽  
Hypervariable Region ◽  
Hepatitis E ◽  
Full Length ◽  
Open Reading Frames ◽  
Subgenomic Rna ◽  
Genomic Rnas ◽  
Molecular Weights

AbstractHepatitis E virus (HEV) is the major cause of acute hepatitis worldwide. HEV is a positive-sense RNA virus expressing 3 open reading frames (ORFs). ORF1 encodes the ORF1 non– structural polyprotein, the viral replicase which transcribes the full-length genome and a subgenomic RNA that encodes the structural ORF2 and ORF3 proteins. The present study is focused on the replication step with the aim to determine whether the ORF1 polyprotein is processed during the HEV lifecycle and to identify where the replication takes place inside the host cell. As no commercial antibody recognizes ORF1 in HEV-replicating cells, we aimed at inserting epitope tags within the ORF1 protein without impacting the virus replication efficacy. Two insertion sites located in the hypervariable region were thus selected to tolerate the V5 epitope while preserving HEV replication efficacy. Once integrated into the infectious full-length Kernow C-1 p6 strain, the V5 epitopes did neither impact the replication of genomic nor the production of subgenomic RNA. Also, the V5-tagged viral particles remained as infectious as the wildtype particles to Huh-7.5 cells. Next, the expression pattern of the V5-tagged ORF1 was compared in heterologous expression and replicative HEV systems. A high molecular weight protein (180 kDa) that was expressed in all 3 systems and that likely corresponds to the unprocessed form of ORF1 was detected up to 25 days after electroporation in the p6 cell culture system. Additionally, less abundant products of lower molecular weights were detected in both in cytoplasmic and nuclear compartments. Concurrently, the V5-tagged ORF1 was localized by confocal microscopy inside the cell nucleus but also as compact perinuclear substructures in which ORF2 and ORF3 proteins were detected. Importantly, using in situ hybridization (RNAScope®), positive and negative-strand HEV RNAs were localized in the perinuclear substructures of HEV-producing cells. Finally, by simultaneous detection of HEV genomic RNAs and viral proteins in these substructures, we identified candidate HEV factories.

scholarly journals First molecular detection of hepatitis E virus genome in camel and pig faecal samples in Ethiopia

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fufa Dawo Bari ◽  
Haimanot Belete Wodaje ◽  
Umer Said ◽  
Hika Waktole ◽  
Melaku Sombo ◽  
...  
Keyword(s):  
Public Health ◽  
Hepatitis E Virus ◽  
Addis Ababa ◽  
Hepatitis E ◽  
Human Infection ◽  
Health Concern ◽  
Universal Primers ◽  
Viral Gene ◽  
Public Health Importance ◽  
Faecal Samples

Abstract Background Hepatitis E is an enteric and zoonotic disease caused by hepatitis E virus (HEV) that is mainly transmitted via the faecal-oral route through contaminated food or the environment. The virus is an emerging infectious agent causing acute human infection worldwide. A high seroprevalence of the disease was reported in pregnant women in Addis Ababa, Ethiopia, raising significant public health concern. The presence of HEV specific antibodies were also reported in dromedary camels in the country; however, the infectious virus and/or the viral genome have not been demonstrated to date in animal samples. Methods To address this gap, a total of 95 faecal samples collected from both apparently healthy pigs of uncharacterised types (50 samples) in Burayu and Addis Ababa areas and camels (Camelus dromedarius, 45 samples) in west Hararghe were screened for the presence of HEV genome using universal primers in a fully nested reverse transcription polymerase chain reaction (nRT-PCR). The protocol is capable of detecting HEV in faecal samples from both pigs and camels. Results The nRT-PCR detected HEV genes in six (12%) pig faecal samples and one camel sample (2.2%). Therefore, the results indicate that HEV is circulating in both pigs and camels in Ethiopia and these animals and their products could serve as a potential source of infection for humans. Conclusion The detection of HEV in both animals could raise another concern regarding its public health importance as both animals’ meat and camel milk are consumed in the country. Further studies to determine the prevalence and distribution of the virus in different animals and their products, water bodies, food chain, and vegetables are warranted, along with viral gene sequencing for detailed genetic characterisation of the isolates circulating in the country. This information is critically important to design and institute appropriate control and/or preventive measures.

Hepatitis E virus

2011 ◽  
Author(s):  
X. J. Meng
Keyword(s):  
Hepatitis E Virus ◽  
Animal Species ◽  
Rna Virus ◽  
Hepatitis E ◽  
Open Reading Frames ◽  
Industrialized Countries ◽  
Efficient Cell Culture System ◽  
The Family ◽  
Avian Hev ◽  
Animal Strains

Hepatitis E virus (HEV) is a small, non-enveloped, single-strand, positive-sense RNA virus of approximately 7.2 kb in size. HEV is classified in the family Hepeviridae consisting of four recognized major genotypes that infect humans and other animals. Genotypes 1 and 2 HEV are restricted to humans and often associated with large outbreaks and epidemics in developing countries with poor sanitation conditions, whereas genotypes 3 and 4 HEV infect humans, pigs and other animal species and are responsible for sporadic cases of hepatitis E in both developing and industrialized countries. The avian HEV associated with Hepatitis-Splenomegaly syndrome in chickens is genetically and antigenically related to mammalian HEV, and likely represents a new genus in the family. There exist three open reading frames in HEV genome: ORF1 encodes non-structural proteins, ORF2 encodes the capsid protein, and the ORF3 encodes a small phosphoprotein. ORF2 and ORF3 are translated from a single bicistronic mRNA, and overlap each other but neither overlaps ORF1. Due to the lack of an efficient cell culture system and a practical animal model for HEV, the mechanisms of HEV replication and pathogenesis are poorly understood. The recent identification and characterization of animal strains of HEV from pigs and chickens and the demonstrated ability of cross-species infection by these animal strains raise potential public health concerns for zoonotic HEV transmission. It has been shown that the genotypes 3 and 4 HEV strains from pigs can infect humans, and vice versa. Accumulating evidence indicated that hepatitis E is a zoonotic disease, and swine and perhaps other animal species are reservoirs for HEV. A vaccine against HEV is not yet available.

scholarly journals Classification, structure and molecular diagnostics of avian hepatitis E virus

2019 ◽  
Vol 75 (02) ◽  
pp. 6228-2019
Author(s):  
JOANNA NERC ◽  
PIOTR SZELESZCZUK
Keyword(s):  
Hepatitis E Virus ◽  
Rna Virus ◽  
Genetic Material ◽  
Hepatitis E ◽  
Open Reading Frames ◽  
Aetiological Factor ◽  
Base Pairs ◽  
Avian Hepatitis E Virus ◽  
And Function ◽  
Overlapping Open Reading Frames

Pathological syndromes caused by avian hepatitis E virus have been described as big liver and spleen disease; necrotic haemorrhagic hepatitis-splenomegaly syndrome; necrotic, haemorrhagic, hepatomegalic hepatitis; or hepatitis-liver haemorrhage syndrome. The aetiological factor of this syndrome belongs to the Hepeviridae family. Avian hepatitis E virus is a single-strand RNA virus whose genome consists of approx. 7,200 base pairs and contains a short non-coding 5’ terminus (27-35 nucleotides) followed by three partially overlapping open reading frames: ORF1, ORF3 and ORF2. Since the avian strains of hepatitis viruses do not replicate in cell cultures, molecular biology techniques are used in the diagnosis of infections. This article discusses in detail the structure and function of each ORF of avian hepatitis E virus, as well as methods for the identification of the genetic material of this pathogen.

scholarly journals Comprehensive analysis of genetic and evolutionary features of the hepatitis E virus

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sarra Baha ◽  
Nouredine Behloul ◽  
Zhenzhen Liu ◽  
Wenjuan Wei ◽  
Ruihua Shi ◽  
...  
Keyword(s):  
Natural Selection ◽  
Codon Usage ◽  
Hepatitis E Virus ◽  
Hepatitis E ◽  
Open Reading Frames ◽  
Health Concern ◽  
Global Public Health ◽  
Genotype 1 ◽  
Mutation Pressure ◽  
Evolutionary Features

Abstract Background The hepatitis E virus (HEV) is the causative pathogen of hepatitis E, a global public health concern. HEV comprises 8 genotypes with a wide host range and geographic distribution. This study aims to determine the genetic factors influencing the molecular adaptive changes of HEV open reading frames (ORFs) and estimate the HEV origin and evolutionary history. Results Sequences of HEV strains isolated between 1982 and 2017 were retrieved and multiple analyses were performed to determine overall codon usage patterns, effects of natural selection and/or mutation pressure and host influence on the evolution of HEV ORFs. Besides, Bayesian Coalescent Markov Chain Monte Carlo (MCMC) Analysis was performed to estimate the spatial-temporal evolution of HEV. The results indicated an A/C nucleotide bias and ORF-dependent codon usage bias affected mainly by natural selection. The adaptation of HEV ORFs to their hosts was also ORF-dependent, with ORF1 and ORF2 sharing an almost similar adaptation profile to the different hosts. The discriminant analysis based on the adaptation index suggested that ORF1 and ORF3 could play a pivotal role in viral host tropism. Conclusion In this study, we estimate that the common ancestor of the modern HEV strains emerged ~ 6000 years ago, in the period following the domestication of pigs. Then, natural selection played the major role in the evolution of the codon usage of HEV ORFs. The significant adaptation of ORF1 of genotype 1 to humans, makes ORF1 an evolutionary indicator of HEV host speciation, and could explain the epidemic character of genotype 1 strains in humans.

scholarly journals Epidemiology and genotype 3 subtype dynamics of hepatitis E virus in Belgium, 2010 to 2017

2019 ◽  
Vol 24 (10) ◽  
Author(s):  
Vanessa Suin ◽  
Sofieke E Klamer ◽  
Veronik Hutse ◽  
Magali Wautier ◽  
Marjorie Jacques ◽  
...  
Keyword(s):  
Hepatitis E Virus ◽  
Rna Virus ◽  
Hepatitis E ◽  
Health Concern ◽  
Genotype 3 ◽  
Serum Samples ◽  
Genotype 4 ◽  
Reference Centre ◽  
Surveillance Report ◽  
Epidemiological Trends

Background Hepatitis E virus (HEV) is an emerging public health concern in high-income countries and can cause acute and chronic hepatitis. Reported numbers of indigenously acquired HEV infection have increased in the past decade in many European countries. Since 2010, the National Reference Centre (NRC) for Hepatitis Viruses has been testing samples of suspected hepatitis E cases in Belgium. Aim In this surveillance report, we present the epidemiological trends of symptomatic HEV infections in Belgium, from the distribution by age, sex and geography to the molecular characterisation of the viral strains. Method Serum samples of suspected cases sent to the NRC between 2010 and 2017 were analysed for the presence of HEV-specific IgM and RNA. Virus was sequenced for genotyping and phylogenetic analysis in all samples containing sufficient viral RNA. Results The NRC reported an increase in the number of samples from suspected cases (from 309 to 2,663 per year) and in the number of laboratory-confirmed hepatitis E cases (from 25 to 117 per year). Among 217 sequenced samples, 92.6% were genotype 3 (HEV-3), followed by 6.5% of genotype 1 and 0.9% of genotype 4. HEV-3 subtype viruses were mainly 3f, 3c and 3e. HEV-3f was the most common subtype until 2015, while HEV-3c became the most common subtype in 2016 and 2017. Conclusion The increasing trend of HEV diagnoses in Belgium may be largely explained by increased awareness and testing.

Detection and characterisation of hepatitis E virus in naturally infected swine in Croatia

2013 ◽  
Vol 61 (4) ◽  
pp. 517-528 ◽  
Author(s):  
Zoran Lipej ◽  
Dinko Novosel ◽  
Lea Vojta ◽  
Besi Roić ◽  
Miljenko Šimpraga ◽  
...  
Keyword(s):  
Hepatitis E Virus ◽  
Age Groups ◽  
Hepatitis E ◽  
Health Concern ◽  
Rt Pcr ◽  
Animal Reservoir ◽  
Naturally Occurring ◽  
High Prevalence ◽  
Swine Herds ◽  
Bile Samples

Hepatitis E is a viral zoonotic disease infecting swine worldwide. Since pigs represent a likely animal reservoir for the hepatitis E virus, the epidemiology of naturally occurring hepatitis E was investigated in Croatian swine herds. Nearly all tested animals were seropositive for antibodies against the hepatitis E virus (55/60, 91.7%). Active infection was detected in all age groups by RT-PCR of viral RNA in serum (8/60, 13.3%) and bile samples (3/37, 8.1%), which was further confirmed by histopathological findings of characteristic lesions in the livers of the infected animals. Three new strains of hepatitis E virus were isolated from Croatian pig herds. Phylogenetic analysis using median-joining networks clustered those Croatian strains with isolates from various parts of the world, indicating their likely origin in international trade. Similarity to human isolates implies a zoonotic potential of Croatian strains, which raises a public health concern, especially in the light of the high prevalence of hepatitis E in the herds studied.

scholarly journals Zinc Salts Block Hepatitis E Virus Replication by Inhibiting the Activity of Viral RNA-Dependent RNA Polymerase

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Nidhi Kaushik ◽  
Chandru Subramani ◽  
Saumya Anang ◽  
Rajagopalan Muthumohan ◽  
Shalimar ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Hepatitis E Virus ◽  
Zinc Supplementation ◽  
Hepatitis E ◽  
Viral Rna ◽  
Health Concern ◽  
Healthy Individuals ◽  
Genomic Rna ◽  
Rna Dependent Rna Polymerase ◽  
Zinc Salts

ABSTRACT Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis in healthy individuals and leads to chronic disease in immunocompromised individuals. HEV infection in pregnant women results in a more severe outcome, with the mortality rate going up to 30%. Though the virus usually causes sporadic infection, epidemics have been reported in developing and resource-starved countries. No specific antiviral exists against HEV. A combination of interferon and ribavirin therapy has been used to control the disease with some success. Zinc is an essential micronutrient that plays crucial roles in multiple cellular processes. Zinc salts are known to be effective in reducing infections caused by few viruses. Here, we investigated the effect of zinc salts on HEV replication. In a human hepatoma cell (Huh7) culture model, zinc salts inhibited the replication of genotype 1 (g-1) and g-3 HEV replicons and g-1 HEV infectious genomic RNA in a dose-dependent manner. Analysis of a replication-defective mutant of g-1 HEV genomic RNA under similar conditions ruled out the possibility of zinc salts acting on replication-independent processes. An ORF4-Huh7 cell line-based infection model of g-1 HEV further confirmed the above observations. Zinc salts did not show any effect on the entry of g-1 HEV into the host cell. Furthermore, our data reveal that zinc salts directly inhibit the activity of viral RNA-dependent RNA polymerase (RdRp), leading to inhibition of viral replication. Taken together, these studies unravel the ability of zinc salts in inhibiting HEV replication, suggesting their possible therapeutic value in controlling HEV infection. IMPORTANCE Hepatitis E virus (HEV) is a public health concern in resource-starved countries due to frequent outbreaks. It is also emerging as a health concern in developed countries owing to its ability to cause acute and chronic infection in organ transplant and immunocompromised individuals. Although antivirals such as ribavirin have been used to treat HEV cases, there are known side effects and limitations of such therapy. Our discovery of the ability of zinc salts to block HEV replication by virtue of their ability to inhibit the activity of viral RdRp is important because these findings pave the way to test the efficacy of zinc supplementation therapy in HEV-infected patients. Since zinc supplementation therapy is known to be safe in healthy individuals and since high-dose zinc is used in the treatment of Wilson's disease, it may be possible to control HEV-associated health problems following a similar treatment regimen.

scholarly journals Identification of the Intragenomic Promoter Controlling Hepatitis E Virus Subgenomic RNA Transcription

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Qiang Ding ◽  
Ila Nimgaonkar ◽  
Nicholas F. Archer ◽  
Yaron Bram ◽  
Brigitte Heller ◽  
...  
Keyword(s):  
Hepatitis E Virus ◽  
Regulatory Element ◽  
Hepatitis E ◽  
Regulatory Elements ◽  
Genome Replication ◽  
Genomic Rna ◽  
Chronic Infections ◽  
Particle Assembly ◽  
Subgenomic Rna ◽  
General Importance

ABSTRACT Approximately 20 million hepatitis E virus (HEV) infections occur annually in both developing and industrialized countries. Most infections are self-limiting, but they can lead to chronic infections and cirrhosis in immunocompromised patients, and death in pregnant women. The mechanisms of HEV replication remain incompletely understood due to scarcity of adequate experimental platforms. HEV undergoes asymmetric genome replication, but it produces an additional subgenomic (SG) RNA encoding the viral capsid and a viroporin in partially overlapping open reading frames. Using a novel transcomplementation system, we mapped the intragenomic subgenomic promoter regulating SG RNA synthesis. This cis -acting element is highly conserved across all eight HEV genotypes, and when the element is mutated, it abrogates particle assembly and release. Our work defines previously unappreciated viral regulatory elements and provides the first in-depth view of the intracellular genome dynamics of this emerging human pathogen. IMPORTANCE HEV is an emerging pathogen causing severe liver disease. The genetic information of HEV is encoded in RNA. The genomic RNA is initially copied into a complementary, antigenomic RNA that is a template for synthesis of more genomic RNA and for so-called subgenomic RNA. In this study, we identified the precise region within the HEV genome at which the synthesis of the subgenomic RNA is initiated. The nucleotides within this region are conserved across genetically distinct variants of HEV, highlighting the general importance of this segment for the virus. To identify this regulatory element, we developed a new experimental system that is a powerful tool with broad utility to mechanistically dissect many other poorly understood functional elements of HEV.

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

2019 ◽  
Vol 220 (6) ◽  
pp. 951-955 ◽  
Author(s):  
Anton Andonov ◽  
Mark Robbins ◽  
Jamie Borlang ◽  
Jingxin Cao ◽  
Todd Hatchette ◽  
...  
Keyword(s):  
Acute Hepatitis ◽  
Hepatitis E Virus ◽  
Genomic Sequence ◽  
Hepatitis E ◽  
The United States ◽  
Immunocompetent Patient ◽  
Health Concern ◽  
Animal Reservoir ◽  
Hepatitis Infection ◽  
Severe Acute Hepatitis

Abstract 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.

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