Abstract
Exposure to hepatitis E virus (HEV) bears a high risk of developing chronic infection in immunocompromised patients, including organ transplant recipients and cancer patients. We aim to identify effective anti-HEV therapies through screening and repurposing safe-in-human broad-spectrum antiviral agents. In this study, a safe-in-human broad-spectrum antiviral drug library comprising of 94 agents was used. Upon screening, we identified gemcitabine, a widely used anti-cancer drug, as a potent inhibitor of HEV replication. The antiviral effect was confirmed in a range of cell culture models with genotype 1 and 3 HEV strains. As a cytidine analog, exogenous supplementation of pyrimidine nucleosides effectively reversed the antiviral activity of gemcitabine, but the level of pyrimidine nucleosides per se does not affect HEV replication. Surprisingly, similar to interferon-alpha (IFNα) treatment, gemcitabine activates STAT1 phosphorylation. This subsequently triggers activation of interferon-sensitive response element (ISRE) and transcription of interferon-stimulated genes (ISGs). Cytidine or uridine effectively inhibits gemcitabine-induced activation of ISRE and ISGs. As expected, JAK inhibitor 1 blocked IFNα, but not gemcitabine-induced STAT1 phosphorylation, ISRE/ISG activation, and anti-HEV activity. These effects of gemcitabine were completely lost in STAT1 knockout cells. In summary, gemcitabine potently inhibits HEV replication by triggering interferon-like response through STAT1 phosphorylation but independent of Janus kinases. This represents a non-canonical antiviral mechanism, which utilizes the innate defense machinery that is distinct from the classical interferon response. These results support repurposing gemcitabine for treating hepatitis E, especially for HEV-infected cancer patients, leading to dual anti-cancer and antiviral effects.
Highlights
Hepatitis E virus (HEV), a single-stranded positive-sense RNA virus, is the most common cause of acute viral hepatitis worldwide
To identify potential anti-HEV candidates, we screened a library of 94 known safe-in-human broad-spectrum antiviral agents
To minimize off-target effects, 23 candidates with over 50% inhibition on HEV luciferase activity but less than 50% cytotoxicity were selected for subsequent validation (Fig. 1A; Supplementary Table 1)
Summary
Hepatitis E virus (HEV), a single-stranded positive-sense RNA virus, is the most common cause of acute viral hepatitis worldwide. Infection with ge notype 3 and occasionally genotype 4 HEV in immunocompromised patients is prone to develop chronic hepatitis E. This has been well-recognized in organ transplant recipients, as they universally receive immunosuppressive medication (Kamar et al, 2008; Wang et al, 2018; Zhou et al, 2013). Cancer patients, especially those undergoing chemotherapy or radiotherapy, have a compromised immune sys tem, and have been reported to develop chronic HEV infection (Fuse et al, 2015; Protin et al, 2019; Tavitian et al, 2010; von Felden et al, 2019). There is a clinical need for further developing new antiviral therapies against HEV
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