Pan-Genotype Hepatitis E Virus Replication in Stem Cell–Derived Hepatocellular Systems

Wu, Xianfang; Thi, Viet Loan Dao; Liu, Peng; Takacs, Constantin N.; Xiang, Kuanhui; Andrus, Linda; Gouttenoire, Jérôme; Moradpour, Darius; Rice, Charles M.

doi:10.1053/j.gastro.2017.10.041

Cited by 50 publications

(77 citation statements)

References 46 publications

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“…Therapeutic alternatives have been evaluated in vitro and in vivo. Sofosbuvir (SOF), a drug targeting the HCV NS5B polymerase, has shown to have an inhibitory effect on HEV replication [60]. Furthermore, the combination of SOF and RBV have demonstrated a cumulative effect for inhibiting HEV viral replication, suggesting a potential alternative approach.…”

Section: Discussionmentioning

confidence: 99%

Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients

et al. 2019

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The hepatitis E virus (HEV) is the major cause of acute hepatitis of viral origin worldwide. Despite its usual course as an asymptomatic self-limited hepatitis, there are highly susceptible populations, such as those with underlying immunosuppression, which could develop chronic hepatitis. In this situation, implementation of therapy is mandatory in the sense to facilitate viral clearance. Currently, there are no specific drugs approved for HEV infection, but ribavirin (RBV), the drug of choice, is used for off-label treatment. Here, we present two cases of chronic HEV infection in transplant patients, reviewing and discussing the therapeutic approach available in the literature. The use of RBV for the treatment of an HEV infection in organ transplant patients seems to be effective. The recommendation of 12 weeks of therapy is adequate in terms of efficacy. Nevertheless, there are important issues that urgently need to be assessed, such as optimal duration of therapy and drug dosage.

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Section: Discussionmentioning

confidence: 99%

Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients

et al. 2019

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“…2). HLCs offer an improved, physiologically relevant traceable system for studying the replication and antiviral response of primary HEV isolates (Wu et al, 2018). Previously, silvestrol has been mainly characterized in antitumor models such as chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma and also hepatocellular carcinoma (Cencic et al, 2009;Lucas et al, 2009;Alinari et al, 2012;Kogure et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Next, we evaluated the antiviral effect of silvestrol in HEV infection experiments using cell culture-derived infectious HEV (HEV CC ) based on the p6 isolate (Dao Thi et al, 2016) in HepG2/C3A cells and patientderived HEV of gts 1-4 in pluripotent stem cell-derived hepatocyte-like cells (HLCs) (Wu et al, 2018). At first, we evaluated the antiviral activity of silvestrol with the HEVp6 replicon in the HepG2/C3A cell line and observed a shift of the dose-response curves in comparison to Huh7.5 (suppl.…”

Section: Inhibition Of Cell Culture-and Patient-derived Hev Infectionmentioning

confidence: 99%

The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo

et al. 2018

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Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients and type I interferon (IFN) has been evaluated in a few infected transplantation patients in vivo. However, no effective and specific treatments against HEV infections are currently available. In this study, we evaluated the natural compound silvestrol, isolated from the plant Aglaia foveolata, and known for its specific inhibition of the DEAD-box RNA helicase eIF4A in state-of-the-art HEV experimental model systems. Silvestrol blocked HEV replication of different subgenomic replicons in a dose-dependent manner at low nanomolar concentrations and acted additive to ribavirin (RBV). In addition, HEV p6-based full length replication and production of infectious particles was reduced in the presence of silvestrol. A pangenotypic effect of the compound was further demonstrated with primary isolates from four different human genotypes in HEV infection experiments of hepatocyte-like cells derived from human embryonic and induced pluripotent stem cells. In vivo, HEV RNA levels rapidly declined in the feces of treated mice while no effect was observed in the vehicle treated control animals. In conclusion, silvestrol could be identified as pangenotypic HEV replication inhibitor in vitro with additive effect to RBV and further demonstrated high potency in vivo. The compound therefore may be considered in future treatment strategies of chronic hepatitis E in immunocompromised patients.

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“…Wu et al reported that human iPS-Heps are permissive for non-cell culture-adopted HEV in contrast to hepatoma cells. HEV replication induces an antiviral innate immune response in iPS-Heps [49]. These reports indicate that human iPS-Heps can be used as an experimental model to develop antiviral agents against HCV and HEV.…”

Section: Disease Models Of Hepatitis C Virus (Hcv) and Hepatitis E Vimentioning

confidence: 90%

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

Kakinuma

Watanabe

2019

Immunological Medicine

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Results of recent studies have shown that disease models using human induced pluripotent stem (iPS) cells have recapitulated the pathophysiology of genetic liver diseases, viral hepatitis and hepatic fibrosis. The utilization of human iPS cells as a model of liver diseases has several substantial advantages compared with primary hepatocytes and cancer cell lines, such as the potential for unlimited expansion and similarity of biological characteristics to normal liver cells. In this review, we have focused on modeling liver diseases using human iPS cells and discussed the experimental evidence that supports the utility of such disease models, including that in our recent studies. Genetically modified or patient-derived human iPS cells can mimic congenital liver disease phenotypes. Human iPS-derived hepatic cells can be infected with the hepatitis viruses. The co-culture of human iPS-derived hepatocytes and mesenchyme partially mimics the process of liver fibrosis. Human iPS cell-derived hepatic cells and the co-culture system of such cells will contribute to the progress of studies on the pathophysiology of genetic and non-genetic liver diseases and development of novel therapeutic strategies for treating liver diseases.

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Pan-Genotype Hepatitis E Virus Replication in Stem Cell–Derived Hepatocellular Systems

Cited by 50 publications

References 46 publications

Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients

Ribavirin as a First Treatment Approach for Hepatitis E Virus Infection in Transplant Recipient Patients

The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo

Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells

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