Aspirin improves both reactivity and durability of type-I interferon signaling to achieve functional cure of chronic hepatitis B
Miao, Y.; Yuan, Y.; Chen, Y.; Liu, J.; Huang, F.; Zhang, T.; Zhang, R.; Zhao, Q.; Cui, Q.; Tian, W.; He, W.; Zuo, Y.; Zheng, Z.; Zhao, Z.; Li, M.; Qian, F.; Zhu, L.; Zhu, C.; Zheng, H.
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Type-I interferon (IFN-I) is currently the only drug for achieving a functional cure of chronic hepatitis B-virus (HBV) infection that is defined as HBsAg loss. However, the IFN-I-mediated functional cure rate is extremely low thus far. Previous studies demonstrated that IFN-I-induced degradation of IFN-I receptor-1 (IFNAR1) restricts the reactivity of IFN-I signaling. Here, we further reveal that IRF9 de-phosphorylation inhibits the durability of IFN-I signaling. We found that IRF9-Tyr112 phosphorylation is critical for IRF9 binding to the promoters of interferon-stimulated genes (ISGs), while PTP1B induces IRF9 de-phosphorylation and therefore attenuates IFN-I signaling durability and ISGs expression. Interestingly, we found that Aspirin can both rescue IRF9 phosphorylation and inhibit IFNAR1 degradation, thus remolding IFN-I signaling. Importantly, the functional cure rate after the IFN-I and Aspirin combination (IA) therapy reached over 86% (13/15). This study reveals the IA therapy as an effective therapeutic way for achieving a chronic HBV functional cure.
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