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 1

HDV mono-infection of HH and the consequential induction of antiviral response.

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HDV mono-infection of HH and the consequential induction of antiviral re...
(A and B) HLCM-HH mono-infected with HDV (5,000 GEq/cell) for the indicated duration were subjected to the quantification of intracellular HDV RNA via RT-qPCR (A) or immunofluorescence microscopic analysis (IFA) for the detection of HDAg (B). Green, HDAg; blue, DAPI. Scale bar: 50 μm. The percentage shown in the image indicates the median HDAg-positive foci/total number of cells. Results are shown as mean ± SD of triplicate samples (A). GEq, genome equivalents; RT-qPCR, quantitative reverse transcription PCR; dpi, days postinfection. (C–H) HLCM-HH mono-infected with HDV (5,000 GEq/cell) for the indicated duration were subjected to comparative measurement of protein expression (C) or mRNA (E and F) or ELISA (G) for the detection or quantification of indicated molecules. RT-qPCR results represent the relative fold index to the average of the baseline (day 0) normalized by the value of GAPDH. (D) HLCM-HH mono-infected with HDV (5,000 GEq/cell) for 7 days followed by immunostaining with indicated molecules. Nuclei were visualized by staining the cells with DAPI (blue). Scale bar: 50 μm. (H) Encephalomyocarditis virus (EMCV) cytopathic effect assay. Huh7 cells were first incubated for 24 hours with the culture supernatant of HLCM-HH mono-infected with HDV (5,000 GEq/cell) for 0–21 days, followed by the inoculation with increasing titers of EMCV at 0, 1 × 102, 5 × 102, 1 × 103, 5 × 103, and 1 × 104 PFU/mL for 48 hours prior to crystal violet staining. Displayed data represent one of the biological triplicate experiments (A–H).