Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells
Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived Cells
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DOI：
10.1128/jvi.01998-10
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发表时间：
2011-01-01
影响因子：
5.4
通讯作者：
Guo, Haitao
中科院分区：
文献类型：
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作者：
Mao, Richeng;Zhang, Jiming;Guo, Haitao
α干扰素 (IFN-α) 是一种批准用于治疗慢性乙型肝炎的药物。γ 干扰素 (IFN-γ) 是宿主体内针对乙型肝炎病毒 (HBV) 感染的先天性和适应性抗病毒免疫的关键介质。为了阐明这些细胞因子的抗病毒机制，我们测试了 37 个在肝细胞中高度诱导的 IFN 刺激基因 (ISG) 在人肝癌细胞中过度表达后抑制 HBV 复制的能力。 ISG 候选物吲哚胺 2,3-双加氧酶 (IDO) 是一种 IFN-γ 诱导的催化色氨酸降解的酶，可有效降低细胞内 HBV DNA 的水平，而不改变病毒 RNA 的稳态水平。此外，酶失活的 IDO 突变体的表达不会抑制 HBV 复制，并且培养物中色氨酸的补充完全恢复了 IDO 表达细胞中的 HBV 复制，表明 IDO 引发的抗病毒作用是由色氨酸剥夺介导的。有趣的是，IDO 介导的色氨酸剥夺优先抑制病毒蛋白翻译和基因组复制，但没有显着改变整体细胞蛋白合成。最后，补充色氨酸能够完全恢复 IFN-γ 处理的细胞中的 HBV 复制，但不能完全恢复 IFN-α 处理的细胞中的复制，这有力地证明了 IDO 是 IFN-γ 引发的人肝细胞衍生细胞中针对 HBV 的抗病毒反应的主要介质。
Alpha interferon (IFN-alpha) is an approved medication for chronic hepatitis B. Gamma interferon (IFN-gamma) is a key mediator of host innate and adaptive antiviral immunity against hepatitis B virus (HBV) infection in vivo. In an effort to elucidate the antiviral mechanism of these cytokines, 37 IFN-stimulated genes (ISGs), which are highly inducible in hepatocytes, were tested for their ability to inhibit HBV replication upon overexpression in human hepatoma cells. One ISG candidate, indoleamine 2,3-dioxygenase (IDO), an IFN-gamma-induced enzyme catalyzing tryptophan degradation, efficiently reduced the level of intracellular HBV DNA without altering the steady-state level of viral RNA. Furthermore, expression of an enzymatically inactive IDO mutant did not inhibit HBV replication, and tryptophan supplementation in culture completely restored HBV replication in IDO-expressing cells, indicating that the antiviral effect elicited by IDO is mediated by tryptophan deprivation. Interestingly, IDO-mediated tryptophan deprivation preferentially inhibited viral protein translation and genome replication but did not significantly alter global cellular protein synthesis. Finally, tryptophan supplementation was able to completely restore HBV replication in IFN-gamma- but not IFN-alpha-treated cells, which strongly argues that IDO is the primary mediator of IFN-gamma-elicited antiviral response against HBV in human hepatocyte-derived cells.