How a positive-strand RNA virus such as HCV can subvert autophagy?

HCV感染引起一系列疾病，从无症状携带者到终末期肝病，包括肝硬化和肝细胞癌。全世界超过2%的人口被感染，仅在美国，HCV相关死亡的人数估计为每年10000人。自噬是所有真核细胞中高度进化保守的过程。它包括将胞质溶胶的某些区域隔离在双膜囊泡内，并将内容物输送到溶酶体进行降解和物质的再循环。自噬在抗病毒宿主防御中也发挥着重要作用。然而，尽管其具有抗病毒特性，但几种正链RNA病毒已经进化为利用自噬或自噬相关蛋白来促进自身复制。目前，这些过程的基本机制在很大程度上是完全未知的。在这项研究计划中，我们有兴趣继续我们正在进行的研究，在丙型肝炎病毒复制周期中的自噬蛋白的先决条件。我们已经证明了自噬延伸复合物的蛋白质定位于HCV复制位点，并且是病毒复制所需的。因此，我们的目标是确定这种复合物如何在病毒诱导的膜网形成中发挥作用。第二个目标是了解HCV如何阻止自噬体的成熟以避免其降解。虽然每种病毒都具有几个独特的特征，使它们彼此区分开来，但我们认为，对拟议目标的解决应该揭示几种病毒所使用的一般机制，这些病毒已知需要自噬以某种方式进行复制。尽管近年来对自噬的研究已经取得了巨大的进展，但据我所知，我的实验室仍然是加拿大唯一一个从事这一特定主题的实验室。由于这项创新性研究处于决定病毒消除或病毒传播的前沿，加拿大研究人员留在这一新兴领域是很重要的。

HCV infection causes a spectrum of diseases ranging from asymptomatic carrier to end-stage liver disease, which includes cirrhosis and hepatocellular carcinoma. With more than 2% of the worldwide population infected, the number of HCV- related death is estimated at 10 000 per year in the USA alone. Autophagy is a highly evolutionarily conserved process of all eukaryotic cells. It involves the sequestration of regions of cytosol within double-membrane vesicles and delivery of the contents to lysosome for degradation and the recycling of the material. Recent advance on autophagy has demonstrated that it also plays an important role in antiviral host defence. However, despite its antiviral properties, several positive-strand RNA viruses have evolved to utilize autophagy or autophagy-related proteins to promote their own replication. At the moment, the mechanisms underlying those processes are, for the most part, completely unknown. In this research proposal, we are interested in pursuing our ongoing research on the prerequisite of autophagy proteins in the replication cycle of HCV. We already demonstrated that proteins of the Autophagy-Elongation-Complex are localized at the HCV replication site and are required for viral replication. Therefore our goal is to determine how this complex plays a role in the formation of the membranous-web that is induced by the virus. The second objective is to understand how HCV can block the maturation of autophagosome to avoid its degradation. Although each virus possesses several unique features that set them apart from each other, we believe that resolution of the proposed goal should reveal general mechanisms used by several viruses that are known to need autophagy somehow for their replication. Even-though research on autophagy has expended tremendously in recent years, to my knowledge, my laboratory is still the only one working on this particular subject in Canada. Because this innovative research is at the frontier between what determine virus elimination or viral propagation, it is important that Canadian researchers remain in this emergent field.