Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles

Ding, Qiang; Heller, Brigitte; Capuccino, Juan M. Valdez; Song, Bokai; Nimgaonkar, Ila; Hrebikova, Gabriela; Contreras, Jorge E.; Ploß, Alexander

doi:10.1073/pnas.1614955114

Cited by 186 publications

(219 citation statements)

References 45 publications

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“…Plasmid constructs containing the full‐length HEV genome (Kernow‐C1 P6 clone) with 1634R or 1634K mutations were generated accordingly . Plasmid pLVX‐ORF2‐IRES‐zsGrenn1 was kindly provided by Alexander Ploss (Princeton University) . Plasmid pEGFP‐C1‐ORF3 was constructed in our lab.…”

Section: Methodsmentioning

confidence: 99%

The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

Wang

et al. 2018

Hepatology

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HEV infection elicits an active IFN-related antiviral response in vitro and in patients, triggered by the viral RNA and mediated by IFN regulatory factors 3 and 7 and the Janus kinase-signal transducer and activator of transcription cascade; these findings have revealed new insights into HEV-host interactions and provided the basis for understanding the pathogenesis and outcome of HEV infection. (Hepatology 2018;67:2096-2112).

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Section: Methodsmentioning

confidence: 99%

The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

Wang

et al. 2018

Hepatology

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“…Its genome contains a positive‐oriented single‐stranded RNA with three open reading frames (ORF), of which ORF1 encodes a multifunctional polyprotein involved in RNA replication, ORF2 the viral capsid protein, and ORF3 a nonstructural protein that can function as a viroporin 2, 3. HEV infections in humans are caused by five genotypes (gts) that differ in their worldwide distribution, their hosts, and their route of transmission.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis E virus replication and interferon responses in human placental cells

Knegendorf

Drave

Thi

et al. 2018

Hepatology Communications

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Hepatitis E virus (HEV) is a member of the genus Orthohepevirus in the family Hepeviridae and the causative agent of hepatitis E in humans. HEV is a major health problem in developing countries, causing mortality rates up to 25% in pregnant women. However, these cases are mainly reported for HEV genotype (gt)1, while gt3 infections are usually associated with subclinical courses of disease. The pathogenic mechanisms of adverse maternal and fetal outcome during pregnancy in HEV‐infected pregnant women remain elusive. In this study, we observed that HEV is capable of completing the full viral life cycle in placental‐derived cells (JEG‐3). Following transfection of JEG‐3 cells, HEV replication of both HEV gts could be observed. Furthermore, determination of extracellular and intracellular viral capsid levels, infectivity, and biophysical properties revealed production of HEV infectious particles with similar characteristics as in liver‐derived cells. Viral entry was analyzed by infection of target cells and detection of either viral RNA or staining for viral capsid protein by immunofluorescence. HEV gt1 and gt3 were efficiently inhibited by ribavirin in placental as well as in human hepatoma cells. In contrast, interferon‐α sensitivity was lower in the placental cells compared to liver cells for gt1 but not gt3 HEV. Simultaneous determination of interferon‐stimulated gene expression levels demonstrated an efficient HEV‐dependent restriction in JEG‐3. Conclusion: We showed differential tissue‐specific host responses to HEV genotypes, adding to our understanding of the mechanisms contributing to fatal outcomes of HEV infections during pregnancy. Using this cell‐culture system, new therapeutic options for HEV during pregnancy can be identified and evaluated. (Hepatology Communications 2018;2:173–187)

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“…At the N-terminal part of the protein two hydrophobic domains are located, D1 and D2, where D1 is important for cytoskeleton association [28]. Part of D1 and D2 act as an ion channel important for viral egress [29]. Two other regions, P1 and P2, are proline-rich domains.…”

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confidence: 99%

Hepatitis E Virus Genotype 3 Genomes from RNA-Positive but Serologically Negative Plasma Donors Have CUG as the Start Codon for ORF3

et al. 2018

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Hepatitis E virus (HEV) is a pathogen that causes hepatitis worldwide. Molecular studies have identified HEV RNA in blood products although its significance is not understood. This study was undertaken to characterize HEV genomes in asymptomatic plasma donors from Sweden and Germany lacking anti-HEV. Complete open reading frames (ORFs) were obtained from HEV strains in 5 out of 18 plasma donors who tested positive for HEV RNA. All strains had CUG as the start codon of ORF3, while 147 GenBank strains all had AUG as the start codon (p < 0.0001). This substitution was found in both interrelated and unrelated strains belonging to different phylogenetic clades. The HEV strains from the seronegative plasma donors had no other substitution in common, which may be why the CUG substitution seems to explain the seronegativity.

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Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles

Cited by 186 publications

References 45 publications

The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response

Hepatitis E virus replication and interferon responses in human placental cells

Hepatitis E Virus Genotype 3 Genomes from RNA-Positive but Serologically Negative Plasma Donors Have CUG as the Start Codon for ORF3

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