Antiviral Activities of Different Interferon Types and Subtypes against Hepatitis E Virus Replication

Todt, Daniel; François, Clément; Anggakusuma,; Behrendt, Patrick; Engelmann, Michael; Knegendorf, Leonard; Vièyres, Gabrielle; Wedemeyer, Heiner; Hartmann, Rune; Pietschmann, Thomas; Duverlie, Gilles; Steinmann, Eike

doi:10.1128/aac.02427-15

Cited by 82 publications

(92 citation statements)

References 43 publications

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“…As different studies have reported that HEV is able to counteract the IFN‐stimulated gene (ISG) response in human liver cells,34, 35 we next investigated the viral restriction of the IFN pathway by determination of ISG expression after HEV transfection in placental‐derived cells. JEG‐3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…According to McConkey and colleagues,30 two‐dimensional‐cultured JEG‐3 cells secrete only small amounts of beta‐human chorionic gonadotropin, and production of human placental lactogen was also reduced, limiting studies of endogenous hormone‐driven influences of HEV infection on the IFN response. However, the already moderate inhibition of HEV replication by IFN‐α in human liver cell lines34 was even weaker in the placental‐derived cell line selective for gt1 replication (Fig. 6), while both HEV gts were able to efficiently down‐regulate selected ISGs in the liver‐ and placental‐derived cell line (Fig.…”

Section: Discussionmentioning

confidence: 98%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Hepatitis E virus replication and interferon responses in human placental cells

Knegendorf

Drave

Thi

et al. 2018

Hepatology Communications

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“…Similar to responses to other viruses, IFN-α subtypes have different anti-hepatitis virus activities. IFN-α2a and IFN-α2b are superior to IFN-α1, IFN-α16 and IFN-α21 against HCV replication [123]. However, studies show that IFN-α8 is the most effective at suppressing intracellular HCV replication among human IFN-α1, α2, α5, α8, α10, and IFN-αcon1 [124].…”

Section: Hepatitismentioning

confidence: 99%

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

Gong

Zhao

et al. 2018

Cell Physiol Biochem

141

111

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The interferons (IFNs) are a primary defense against pathogens because of the strong antiviral activities they induce. IFNs can be classified into three groups: type I, type II and type III, according to their genetic, structural, and functional characteristics and their receptors on the cell surface. The type I IFNs are the largest group and include IFN-α, IFN-β, IFN-ε, IFN-ω, IFN-κ, IFN-δ, IFN-τ and IFN-ζ. The use of IFNs for the treatment of viral infectious diseases on their antiviral activity may become an important therapeutic option, for example, IFN-α is well known for the successful treatment of hepatitis B and C virus infections, and interest is increasing in the antiviral efficacy of other novel IFN classes and their potential applications. Therefore, in this review, we summarize the recent progress in the study of the biological activities of all the type I IFN classes and their potential applications in the treatment of infections with immunodeficiency virus, hepatitis viruses, and influenza viruses.

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“…However, natalizumab has since been used exclusively as monotherapy, and any potential beneficial effect of IFN β has therefore never been studied. As stated above, there are other type I IFNs, including IFN α , IFN κ , IFN ω , of which IFN α appears to have the most potent anti‐viral properties 15, 16, 17. Secondly, there are pharmacological limitations.…”

Section: Discussionmentioning

confidence: 99%

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Hussain

Cravens

Doelger

et al. 2018

Ann Clin Transl Neurol

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ObjectiveNatalizumab blocks α4‐integrin‐mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α4‐integrin deficiency.MethodWe generated the conditional knock out mouse strain Mx1.Cre+ α4‐integrinfl/fl, in which the α4‐integrin gene is ablated upon treatment with the TLR3 agonist poly I:C. Adoptive transfer of purified lymphocytes from poly I:C‐treated Mx1.Cre+ α4‐integrinfl/fl donors into naive recipients recapitulates immunosuppression under natalizumab. Active experimental autoimmune encephalomyelitis (EAE) in Mx1.Cre+ α4‐integrinfl/fl mice treated with poly I:C represents immune‐reconstitution.ResultsAdoptive transfer of T cells from poly I:C treated Mx1.Cre+ α4‐integrinfl/fl mice causes minimal EAE. The in vitro migratory capability of CD45+ splenocytes from these mice is reduced. In contrast, actively‐induced EAE after poly I:C treatment results in full disease susceptibility of Mx1.Cre+ α4‐integrinfl/fl mice, and the number and composition of CNS leukocytes is similar to controls. Extravasation of Evans Blue indicates a compromised blood‐brain barrier. Poly I:C treatment results in a 2‐fold increase in IFN β transcription in the spinal cord.InterpretationOur data suggest that TLR3 agonism in the setting of relative α4‐integrin deficiency can reestablish CNS immune surveillance in an experimental model. This pathway may present a feasible treatment strategy to treat and prevent PML under natalizumab therapy and should be considered for further experimental evaluation in a controlled setting.

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Antiviral Activities of Different Interferon Types and Subtypes against Hepatitis E Virus Replication

Cited by 82 publications

References 43 publications

Hepatitis E virus replication and interferon responses in human placental cells

Hepatitis E virus replication and interferon responses in human placental cells

Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

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