Innate Immunity and Hepatitis C Virus Infection

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)经常导致慢性感染，影响全球超过2亿人。慢性丙型肝炎病毒感染与肝纤维化、肝硬变和肝细胞癌有关。已批准的治疗丙型肝炎病毒感染的方法是聚乙二醇化干扰素-1(干扰素-1)与利巴韦林联合使用，根据感染病毒的基因型别，其疗效有限。然而，治疗失败的分子机制仍不清楚。我们的长期目标是在分子水平上了解丙型肝炎病毒如何导致持续感染，这将有助于开发有效的治疗方法。由于丙型肝炎病毒在细胞培养中的生长有限，而且缺乏方便的病毒感染和疾病进展的动物模型，因此对丙型肝炎病毒的研究具有挑战性。我们最近发现，在细胞培养中，丙型肝炎病毒感染会激活干扰素-2的表达，并诱导自噬。然而，我们并不完全了解丙型肝炎病毒是如何钝化先天免疫反应和建立慢性感染的。我们推测，丙型肝炎病毒与细胞蛋白相互作用，扰乱它们的功能，以建立持续感染。我们将使用三种互补的方法来验证我们的假设：Aim 1将确定丙型肝炎病毒调节细胞内干扰素信号通路的分子过程。目的2确定丙型肝炎病毒是否通过诱导自噬而损害先天免疫。最后，AIM 3将检查丙型肝炎病毒感染患者的肝内天然免疫反应，以与治疗结果相关。我们提出的研究结果将提供病毒持续存在的分子机制，并将有助于设计未来治疗慢性丙型肝炎病毒感染的治疗策略。公共卫生相关性：丙型肝炎病毒感染影响全球2亿多人。我们的研究将揭示病毒持续存在的分子机制，这可能导致治疗慢性丙型肝炎病毒感染的新的治疗策略。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) often causes chronic infection that affects over 200 million people worldwide. Chronic HCV infection is associated with fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The approved therapy for HCV infection is pegylated interferon-1 (IFN- 1) in combination with ribavirin that offers limited benefit depending on the genotype of the infecting virus. However, the molecular mechanisms underlying treatment failure remain unknown. Our long-term goal is to understand how HCV causes persistent infection at the molecular level, which will help in developing effective therapeutic modalities. Studies on HCV is challenging because of its limited growth in cell culture, and lack of a convenient animal model for virus infection and disease progression. We have recently shown that HCV infection in cell culture activates interferon beta (IFN-2) expression and induces autophagy. However, we do not fully understand how HCV blunts innate immune response and establishes chronic infection. We hypothesize that HCV interacts with cellular proteins and perturb their functions for establishment of persistent infection. Three complementary approaches will be used to test our hypothesis: Aim 1 will determine molecular processes by which HCV modulates intracellular IFN signaling pathway. Aim 2 will determine whether HCV impairs innate immunity by induction of autophagy. Finally, Aim 3 will examine intrahepatic innate immune response in HCV infected patients to correlate with treatment outcome. The results from our proposed studies will provide molecular mechanisms for viral persistence, and will aid in devising future therapeutic strategies for treatment of chronic HCV infection. PUBLIC HEALTH RELEVANCE: HCV infection affects over 200 million people worldwide. Our study will reveal the molecular mechanisms of viral persistence, which may lead to new therapeutic strategies for treatment of chronic HCV infection.