Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response
Takeshi Chida, Yuji Ishida, Sho Morioka, Go Sugahara, Christine Han, Bill Lam, Chihiro Yamasaki, Remi Sugahara, Meng Li, Yasuhito Tanaka, T. Jake Liang, Chise Tateno, Takeshi Saito
Takeshi Chida, Yuji Ishida, Sho Morioka, Go Sugahara, Christine Han, Bill Lam, Chihiro Yamasaki, Remi Sugahara, Meng Li, Yasuhito Tanaka, T. Jake Liang, Chise Tateno, Takeshi Saito
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Research Article Hepatology Virology

Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response

Abstract

Hepatitis delta virus (HDV), a satellite virus of HBV, is regarded as the most severe type of hepatitis virus because of the substantial morbidity and mortality. The IFN system is the first line of defense against viral infections and an essential element of antiviral immunity; however, the role of the hepatic IFN system in controlling HBV-HDV infection remains poorly understood. Herein, we showed that HDV infection of human hepatocytes induced a potent and persistent activation of the IFN system whereas HBV was inert in triggering hepatic antiviral response. Moreover, we demonstrated that HDV-induced constitutive activation of the hepatic IFN system resulted in a potent suppression of HBV while modestly inhibiting HDV. Thus, these pathogens are equipped with distinctive immunogenicity and varying sensitivity to the antiviral effectors of IFN, leading to the establishment of a paradoxical mode of viral interference wherein HDV, the superinfectant, outcompetes HBV, the primary pathogen. Furthermore, our study revealed that HDV-induced constitutive IFN system activation led to a state of IFN refractoriness, rendering therapeutic IFNs ineffective. The present study provides potentially novel insights into the role of the hepatic IFN system in regulating HBV-HDV infection dynamics and its therapeutic implications through elucidating the molecular basis underlying the inefficacy of IFN-based antiviral strategies against HBV-HDV infection.

Authors

Takeshi Chida, Yuji Ishida, Sho Morioka, Go Sugahara, Christine Han, Bill Lam, Chihiro Yamasaki, Remi Sugahara, Meng Li, Yasuhito Tanaka, T. Jake Liang, Chise Tateno, Takeshi Saito

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Figure 4

HDV infection induces IFN refractoriness in hepatocytes.

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HDV infection induces IFN refractoriness in hepatocytes. (A and B) HLCM-...
(A and B) HLCM-HH mono-infected with HBV, superinfected with HBV-HDV for 10 days, or mono-infected with HDV for 10 days followed by PEG–IFN-α-2a (10 ng/mL) treatment for indicated hours and the cell lysates subjected to immunoblotting analysis for detection of indicated molecules. (C) HLCM-HH mono-infected with HBV or superinfected with HBV-HDV for 10 days were treated with PEG–IFN-α-2a at indicated concentrations for 10 days, and total cell lysates were subjected to quantification of HBV pgRNA (top) and HDV RNA (bottom). Results are shown as mean ± SD of triplicate samples. ***P < 0.001 determined by unpaired 2-tailed Student’s t test. (D–F) HLCM-HH were treated with PEG–IFN-α-2a (10 ng/mL) for 5 days per cycle, up to 5 times. Total cell lysates were harvested at the indicated time points for immunoblotting analysis for detection of respective proteins (D and F) or 8 hours after each treatment for RT-qPCR array analysis of ISGs (E). Results are shown as mean ± SD of triplicate samples. Displayed data represent one of the biological triplicate experiments (A–F).