Inhibition of HCV by the serpin antithrombin III.
Inhibition of HCV by the serpin antithrombin III.
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DOI：
10.1186/1743-422x-9-226
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发表时间：
2012-10-02
期刊：
影响因子：
4.8
通讯作者：
Geiben-Lynn R
中科院分区：
文献类型：
--
作者：
Asmal M;Seaman M;Lin W;Chung RT;Letvin NL;Geiben-Lynn R
尽管最近在慢性丙型肝炎病毒感染的治疗方面取得了巨大的进展，但基于干扰素α的治疗对某些人群仍然具有挑战性，包括那些具有不利il - 28b基因型、精神合并症、HIV合并症和失代偿性肝病的人群。我们最近表明，ATIII，一种丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶），具有广泛的抗病毒特性。我们现在表明，在OR6复制子模型中，ATIII能够在微摩尔浓度下抑制HCV。在机制水平上，通过基因表达阵列，我们发现ATIII治疗下调了参与肝硬化和肝细胞癌发病的多种宿主细胞信号转导因子，包括Jun、Myc和BMP2。通过蛋白质相互作用网络分析，我们发现由ATIII引起的基因表达变化依赖于先前与HCV疾病进展或HCV复制相关的三个节点：NFκB、P38 MAPK和ERK1/2。我们的研究结果表明，ATIII刺激了一种新的先天抗病毒宿主细胞防御，不同于目前的治疗方案。
Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection, interferon-α based therapy remains challenging for certain populations, including those with unfavorable IL28B genotypes, psychiatric co-morbidity, HIV co-infection, and decompensated liver disease. We have recently shown that ATIII, a serine protease inhibitor (serpin), has broad antiviral properties. We now show that ATIII is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations. At a mechanistic level using gene-expression arrays, we found that ATIII treatment down-regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma, including Jun, Myc and BMP2. Using a protein interactive network analysis we found that changes in gene-expression caused by ATIII were dependent on three nodes previously implicated in HCV disease progression or HCV replication: NFκB, P38 MAPK, and ERK1/2. Our findings suggest that ATIII stimulates a novel innate antiviral host cell defense different from current treatment options.