Ｃ型肝炎病毒蛋白對細胞內甲型干擾素反應可能之影響

Abstract

C型肝炎病毒（HCV）的感染已經成為公共衛生以及傳染病學界的重要課題之一。根據世界衛生組織的統計，全世界約有百分之三的人為HCV的帶原者，其中高達百分之八十的人在二十到三十年之後會發生肝硬化，甚至最後死於HCV所引起的肝癌。目前僅有長效型的甲型干擾素（IFN-α）合併抗病毒藥物Ribavirin可治療HCV的感染，但是成效最多只有百分之五十至六十，而且隨著病毒基因型的不同也會有所差異。本研究主要從兩方面來探討造成HCV無法被IFN-α清除的分子機制。首先，我們確認HCV的NS3/4A、NS4B和NS5A蛋白質具有抑制IFN-α對下游JAK-STAT signaling活化的能力。在檢驗每個活化過程的步驟之後，發現NS4B可以阻止ISGF3 complex和DNA的結合，因而導致ISRE主導的基因轉錄無法被啟動。另一方面，我們也重新檢視core在ISRE活化過程當中的影響。在七個從病人血清裡分離出來、分屬基因型1b和2a的core clone當中，每個clone對於ISRE的活化和下游ISG的表現都有不同程度的影響。於是我們比對這七個core的胺基酸序列，並推測某些胺基酸的改變是造成此現象的原因。根據以上的結果，我們認為更多關於NS4B對抗IFN-α訊息傳遞所使用機制的研究，將有助於開發對抗HCV感染的新方法；同時我們也要指出，研究core胺基酸序列的改變與其如何影響JAK-STAT signaling的關係，將有助於釐清core在HCV對抗IFN-α時所扮演的角色。

Hepatitis C virus (HCV) infection is one of the major problems of public health worldwide. Approximate 3% of the world’s population are chronically infected and may gradually develop chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma (HCC) in the subsequent 20 to 30 years. IFN-alpha is one of the cytokines produced by most animal cells to resist viral replication and is by far the most standard therapy for HCV infection. However, the overall achievement of eliminating HCV only reaches 50-60% and is significantly altered by the virus genotypes. Here we investigated the underlying mechanisms from two aspects. First, we investigate the mechanisms that NS3/4A, NS4B, or NS5A used to inhibit the IFN-alpha-induced responses. The signaling of ISRE activation was examined step by step. It was found that NS4B significantly reduced the DNA binding ability of ISGF3. Second, we examined the effects of core on the ISRE activity using seven clones derived from patient sera infected by HCV genotype 1b or 2a. Distinct properties on ISRE activity and expression of ISGs were demonstrated clone by clone, and some putative amino acid changes were proposed to be responsible for these obscure results. We thus suggested that HCV NS4B deserved more attention for the development of new anti-HCV strategies and when attempting on unraveling the character of core, one should beware of the influence caused by every single amino acid substitutions.