Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes

Testoni, Barbara; Durantel, David; Lebossé, Fanny; Fresquet, Judith; Helle, François; Negro, Francesco; Donato, Maria Francesca; Levrero, Massimo; Zoulim, Fabien

doi:10.1136/gutjnl-2014-309011

Cited by 16 publications

(12 citation statements)

References 52 publications

(52 reference statements)

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“…By comparing mocktreated and RBV-treated PHH, both HEV inoculated or not, we show that RBV leads to a repression of specific genes. In the case of HCV, similar observations have been made, where RBV downregulates abnormally preactivated ISGs following HCV infection of PHH, which then restored IFN-responsiveness in the hepatic environment (39).…”

Section: Discussionsupporting

confidence: 57%

Robust hepatitis E virus infection and transcriptional response in human hepatocytes

Todt

Friesland

Moeller

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and the leading cause for acute viral hepatitis worldwide. The virus is classified as a member of the genus Orthohepevirus A within the Hepeviridae family. Due to the absence of a robust cell culture model for HEV infection, the analysis of the viral life cycle, the development of effective antivirals and a vaccine is severely limited. In this study, we established a protocol based on the HEV genotype 3 p6 (Kernow C-1) and the human hepatoma cell lines HepG2 and HepG2/C3A with different media conditions to produce intracellular HEV cell culture-derived particles (HEVcc) with viral titers between 105 and 106 FFU/mL. Viral titers could be further enhanced by an HEV variant harboring a mutation in the RNA-dependent RNA polymerase. These HEVcc particles were characterized in density gradients and allowed the trans-complementation of subgenomic reporter HEV replicons. In addition, in vitro produced intracellular-derived particles were infectious in liver-humanized mice with high RNA copy numbers detectable in serum and feces. Efficient infection of primary human and swine hepatocytes using the developed protocol could be observed and was inhibited by ribavirin. Finally, RNA sequencing studies of HEV-infected primary human hepatocytes demonstrated a temporally structured transcriptional defense response. In conclusion, this robust cell culture model of HEV infection provides a powerful tool for studying viral–host interactions that should facilitate the discovery of antiviral drugs for this important zoonotic pathogen.

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Section: Discussionsupporting

confidence: 57%

Robust hepatitis E virus infection and transcriptional response in human hepatocytes

Todt

Friesland

Moeller

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…However, this process is independent of the classical JAK-STAT cascade, suggesting a non-canonical mechanism that is independent of IFNs [104]. Ribavirin, an inhibitor of the IMPDH enzyme, was shown to reset a subset of ISG promoters to a 'ready to be activated' state, thus potentiating ISG activation [105]. However, crosstalk between nucleotide synthesis and the innate immune response remains to be further elucidated.…”

Section: Nucleotide Synthesis Inhibitormentioning

confidence: 99%

Transcriptional Regulation of Antiviral Interferon-Stimulated Genes

Wang

et al. 2017

Trends in Microbiology

161

123

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Interferon-stimulated genes (ISGs) are a group of gene products that coordinately combat pathogen invasions, in particular viral infections. Transcription of ISGs occurs rapidly upon pathogen invasion, and this is classically provoked via activation of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, mainly by interferons (IFNs). However, a plethora of recent studies have reported a variety of non-canonical mechanisms regulating ISG transcription. These new studies are extremely important for understanding the quantitative and temporal differences in ISG transcription under specific circumstances. Because these canonical and non-canonical regulatory mechanisms are essential for defining the nature of host defense and associated detrimental proinflammatory effects, we comprehensively review the state of this rapidly evolving field and the clinical implications of recently acquired knowledge in this respect.

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“…We were also unable to assess the influence of RBV on hepatic immunity, as all subjects in SPARE received either low (600 mg daily) or weight‐based (1000–1200 mg daily) RBV. RBV retains an important role for multiple DAA regimens in trials and clinical practice, appears to reduce the odds of relapse in some studies , and has been shown to modulate intrahepatic immunity and increase IFN sensitivity . In the current study, we hypothesized that cirrhosis and the use of RBV‐free DAA regimens might impact changes in innate immunity during IFN‐free HCV treatment.…”

mentioning

confidence: 94%

Achieving sustained virologic response after interferon‐free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis

Meissner

Kohli

Virtaneva

et al. 2016

Journal of Viral Hepatitis

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SummaryChronic hepatitis C virus (HCV) infection can now be treated with oral directly acting antiviral agents, either with or without ribavirin (RBV). Virologic relapse after treatment can occur, and in some studies was more common in cirrhotic subjects. We previously observed changes in hepatic immunity during interferon (IFN)‐free therapy that correlated with favourable outcome in subjects with early liver disease. Here, we compared changes in endogenous IFN pathways during IFN‐free, RBV‐free therapy between cirrhotic and noncirrhotic subjects. mRNA and microRNA (miRNA) expression analyses were performed on paired pre‐ and post‐treatment liver biopsies from genotype‐1 HCV subjects treated with sofosbuvir/ledipasvir (SOF/LDV) for 12 weeks (n = 4, 3 cirrhotics) or SOF/LDV combined with GS‐9669 or GS‐9451 for 6 weeks (n = 6, 0 cirrhotics). Nine of ten subjects achieved a sustained virologic response (SVR), while one noncirrhotic subject relapsed. Hepatic IFN‐stimulated gene expression decreased with treatment in the liver of all subjects, with no observable impact of cirrhosis. Hepatic gene expression of type III IFNs (IFNL1,IFNL3,IFNL4‐ΔG) similarly decreased with treatment, while IFNA2 expression, undetectable in all subjects pretreatment, was detected post‐treatment in three subjects who achieved a SVR. Only the subject who relapsed had detectable IFNL4‐ΔG expression in post‐treatment liver. Other IFNs had no change in gene expression (IFNG,IFNB1,IFNA5) or could not be detected. Although expression of multiple hepatic miRNAs changed with treatment, many miRNAs previously implicated in HCV replication and IFN signalling had unchanged expression. In conclusion, favourable treatment outcome during IFN‐free HCV therapy is associated with changes in the host IFN response regardless of cirrhosis.

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Ribavirin restores IFNα responsiveness in HCV-infected livers by epigenetic remodelling at interferon stimulated genes

Abstract: RBV-induced epigenetic changes, leading to decreased ISG expression, restore an IFN-responsive hepatic environment in patients with HCV, which may also prove useful in IFN-free regimens.

Cited by 16 publications

References 52 publications

Robust hepatitis E virus infection and transcriptional response in human hepatocytes

Robust hepatitis E virus infection and transcriptional response in human hepatocytes

Transcriptional Regulation of Antiviral Interferon-Stimulated Genes

Achieving sustained virologic response after interferon‐free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis

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