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

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...

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Autores principales: Chida, Takeshi, Ishida, Yuji, Morioka, Sho, Sugahara, Go, Han, Christine, Lam, Bill, Yamasaki, Chihiro, Sugahara, Remi, Li, Meng, Tanaka, Yasuhito, Liang, T. Jake, Tateno, Chise, Saito, Takeshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10243812/
https://www.ncbi.nlm.nih.gov/pubmed/37154158
http://dx.doi.org/10.1172/jci.insight.162404
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author Chida, Takeshi
Ishida, Yuji
Morioka, Sho
Sugahara, Go
Han, Christine
Lam, Bill
Yamasaki, Chihiro
Sugahara, Remi
Li, Meng
Tanaka, Yasuhito
Liang, T. Jake
Tateno, Chise
Saito, Takeshi
author_facet Chida, Takeshi
Ishida, Yuji
Morioka, Sho
Sugahara, Go
Han, Christine
Lam, Bill
Yamasaki, Chihiro
Sugahara, Remi
Li, Meng
Tanaka, Yasuhito
Liang, T. Jake
Tateno, Chise
Saito, Takeshi
author_sort Chida, Takeshi
collection PubMed
description 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.
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spelling pubmed-102438122023-06-07 Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response Chida, Takeshi Ishida, Yuji Morioka, Sho Sugahara, Go Han, Christine Lam, Bill Yamasaki, Chihiro Sugahara, Remi Li, Meng Tanaka, Yasuhito Liang, T. Jake Tateno, Chise Saito, Takeshi JCI Insight Research Article 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. American Society for Clinical Investigation 2023-05-08 /pmc/articles/PMC10243812/ /pubmed/37154158 http://dx.doi.org/10.1172/jci.insight.162404 Text en © 2023 Chida et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Chida, Takeshi
Ishida, Yuji
Morioka, Sho
Sugahara, Go
Han, Christine
Lam, Bill
Yamasaki, Chihiro
Sugahara, Remi
Li, Meng
Tanaka, Yasuhito
Liang, T. Jake
Tateno, Chise
Saito, Takeshi
Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response
title Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response
title_full Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response
title_fullStr Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response
title_full_unstemmed Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response
title_short Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response
title_sort persistent hepatic ifn system activation in hbv-hdv infection determines viral replication dynamics and therapeutic response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10243812/
https://www.ncbi.nlm.nih.gov/pubmed/37154158
http://dx.doi.org/10.1172/jci.insight.162404
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