Chen Junbo, Xu Wei, Chen Yanni, Xie Xueping, Zhang Yecheng, Ma Chunqiang, Yang Qingyu, Han Yang, Zhu Chengliang, Xiong Ying, Wu Kailang, Liu Fang, Liu Yingle, Wu Jianguo
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China
J Virol. 2017 Mar 29;91(8). doi: 10.1128/JVI.01824-16. Print 2017 Apr 15.
Hepatitis B virus (HBV) infection may cause acute hepatitis B, chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma (HCC). However, the mechanisms by which HBV evades host immunity and maintains chronic infection are largely unknown. Here, we revealed that matrix metalloproteinase 9 (MMP-9) is activated in peripheral blood mononuclear cells (PBMCs) of HBV-infected patients, and HBV stimulates MMP-9 expression in macrophages and PBMCs isolated from healthy individuals. MMP-9 plays important roles in the breakdown of the extracellular matrix and in the facilitation of tumor progression, invasion, metastasis, and angiogenesis. MMP-9 also regulates respiratory syncytial virus (RSV) replication, but the mechanism underlying such regulation is unknown. We further demonstrated that MMP-9 facilitates HBV replication by repressing the interferon (IFN)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, IFN action, STAT1/2 phosphorylation, and IFN-stimulated gene (ISG) expression. Moreover, MMP-9 binds to type I IFN receptor 1 (IFNAR1) and facilitates IFNAR1 phosphorylation, ubiquitination, subcellular distribution, and degradation to interfere with the binding of IFANR1 to IFN-α. Thus, we identified a novel positive-feedback regulation loop between HBV replication and MMP-9 production. On one hand, HBV activates MMP-9 in infected patients and leukocytes. On the other hand, MMP-9 facilitates HBV replication through repressing IFN/JAK/STAT signaling, IFNAR1 function, and IFN-α action. Therefore, HBV may take the advantage of MMP-9 function to establish or maintain chronic infection. Hepatitis B virus (HBV) infection may cause chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). However, the mechanisms by which HBV maintains chronic infection are largely unknown. Matrix metalloproteinase 9 (MMP-9) plays important roles in the facilitation of tumor progression, invasion, metastasis, and angiogenesis. However, the effects of MMP-9 on HBV replication and pathogenesis are not known. This study reveals that MMP-9 expression is activated in patients with CHB, and HBV stimulates MMP-9 production in PBMCs and macrophages. More interestingly, MMP-9 in turn promotes HBV replication through suppressing IFN-α action. Moreover, MMP-9 interacts with type I interferon receptor 1 (IFNAR1) to disturb the binding of IFN-α to IFNAR1 and facilitate the phosphorylation, ubiquitination, subcellular distribution, and degradation of IFNAR1. Therefore, these results discover a novel role of MMP-9 in viral replication and reveal a new mechanism by which HBV evades host immunity to maintain persistent infection.
乙型肝炎病毒（HBV）感染可导致急性乙型肝炎、慢性乙型肝炎（CHB）、肝硬化和肝细胞癌（HCC）。然而，HBV逃避宿主免疫并维持慢性感染的机制在很大程度上尚不清楚。在此，我们发现基质金属蛋白酶9（MMP-9）在HBV感染患者的外周血单核细胞（PBMC）中被激活，并且HBV刺激从健康个体分离的巨噬细胞和PBMC中MMP-9的表达。MMP-9在细胞外基质的降解以及促进肿瘤进展、侵袭、转移和血管生成中起重要作用。MMP-9还调节呼吸道合胞病毒（RSV）复制，但其调节机制尚不清楚。我们进一步证明，MMP-9通过抑制干扰素（IFN）/Janus激酶（JAK）/信号转导和转录激活因子（STAT）途径、IFN作用、STAT1/2磷酸化以及IFN刺激基因（ISG）表达来促进HBV复制。此外，MMP-9与I型干扰素受体1（IFNAR1）结合，并促进IFNAR1的磷酸化、泛素化、亚细胞分布和降解，从而干扰IFANR1与IFN-α的结合。因此，我们确定了HBV复制与MMP-9产生之间的一种新型正反馈调节环。一方面，HBV在感染患者和白细胞中激活MMP-9。另一方面，MMP-9通过抑制IFN/JAK/STAT信号传导、IFNAR1功能和IFN-α作用来促进HBV复制。因此，HBV可能利用MMP-9的功能来建立或维持慢性感染。乙型肝炎病毒（HBV）感染可导致慢性乙型肝炎（CHB）和肝细胞癌（HCC）。然而，HBV维持慢性感染的机制在很大程度上尚不清楚。基质金属蛋白酶9（MMP-9）在促进肿瘤进展、侵袭、转移和血管生成中起重要作用。然而，MMP-9对HBV复制和发病机制的影响尚不清楚。本研究表明，CHB患者中MMP-9表达被激活，并且HBV刺激PBMC和巨噬细胞中MMP-9的产生。更有趣的是，MMP-9反过来通过抑制IFN-α作用促进HBV复制。此外，MMP-9与I型干扰素受体1（IFNAR1）相互作用，干扰IFN-α与IFNAR1的结合，并促进IFNAR1的磷酸化、泛素化、亚细胞分布和降解。因此，这些结果发现了MMP-9在病毒复制中的新作用，并揭示了HBV逃避宿主免疫以维持持续感染的新机制。
