Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling

Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling
Title:
Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling
Other Titles:
Hepatology
Keywords:
Publication Date:
25 April 2021
Citation:
Chen, J., Li, Y., Lai, F., Wang, Y., Sutter, K., Dittmer, U., … Yuan, Z. (2021). Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling. Hepatology, 73(2), 486–502. doi:10.1002/hep.31282
Abstract:
Background and Aims: Interferon (IFN)‐α, composed of numerous subtypes, plays a crucial role in immune defense. As the most studied subtype, IFN‐α2 has been used for treating chronic hepatitis B virus (HBV) infection, with advantages of finite treatment duration and sustained virologic response, but its efficacy remains relatively low. This study aimed to screen for IFN‐α subtypes with the highest anti‐HBV potency and to characterize mechanisms of IFN‐α–mediated HBV restriction. Approach and Results: Using cell culture–based HBV infection systems and a human‐liver chimeric mouse model, IFN‐α subtype–mediated antiviral response and signaling activation were comprehensively analyzed. IFN‐α14 was identified as the most effective subtype in suppression of HBV covalently closed circular DNA transcription and HBV e antigen/HBV surface antigen production, with median inhibitory concentration values approximately 100‐fold lower than those of the conventional IFN‐α2. IFN‐α14 alone elicited IFN‐α and IFN‐γ signaling crosstalk in a manner similar to the combined use of IFN‐α2 and IFN‐γ, inducing multiple potent antiviral effectors, which synergistically restricted HBV replication. Guanylate binding protein 5, one of the most differentially expressed genes between IFN‐α14–treated and IFN‐α2–treated liver cells, was identified as an HBV restriction factor. A strong IFN‐α–IFN‐α receptor subunit 1 interaction determines the anti‐HBV activity of IFN‐α. The in vivo anti‐HBV activity of IFN‐α14 and treatment‐related transcriptional patterns were further confirmed, and few adverse effects were observed. Conclusions: A concerted IFN‐α and IFN‐γ response in liver, which could be efficiently elicited by IFN‐α subtype 14, is associated with potent HBV suppression. These data deepen the understanding of the divergent activities of IFN‐α subtypes and the mechanism underlying the synergism between IFN‐α and IFN‐γ signaling, with implications for improved IFN therapy and HBV curative strategies.
License type:
Publisher Copyright
Funding Info:
This research / project is supported by the National Science and Technology Major Project of China - -
Grant Reference no. : 2018ZX10301208, 2017ZX10202202

This research / project is supported by the National Natural Science Foundation of China - -
Grant Reference no. : 81974304, 91842309

This research / project is supported by the Research Unit of Cure of Chronic Hepatitis B Virus Infection, Chinese Academy of Medical Sciences - -
Grant Reference no. : 2019RU037

This research / project is supported by the Shanghai Municipal Education Commission - -
Grant Reference no. : 201701070007E00057

This research / project is supported by the Shanghai Municipal Health Commission - -
Grant Reference no. : 20174Y0180

This research / project is supported by the German Research Foundation - -
Grant Reference no. : SFB/Transregio TRR60

This research / project is supported by the National Medical Research Council, Singapore - Eradication of HBV TCR Program
Grant Reference no. : NMRC/TCR/014-NUHS/2015

This research / project is supported by the National Research Foundation, Singapore - National Research Foundation Fellowship Singapore
Grant Reference no. : NRF-NRFF2017-03
Description:
This is the peer reviewed version of the following article: Chen, J., Li, Y., Lai, F., Wang, Y., Sutter, K., Dittmer, U., … Yuan, Z. (2021). Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling. Hepatology, 73(2), 486–502. doi:10.1002/hep.31282, which has been published in final form at https://doi.org/10.1002/hep.31282. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
ISSN:
0270-9139
1527-3350
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