Innate Immunity and Hepatitis C Virus Infection

描述（由申请人提供）：丙型肝炎病毒（HCV）经常引起慢性感染，影响全球2亿多人。慢性HCV感染与肝纤维化、肝硬化和肝细胞癌（HCC）相关。HCV感染的批准治疗是聚乙二醇干扰素-1（IFN- 1）联合利巴韦林，根据感染病毒的基因型，其获益有限。然而，治疗失败的分子机制仍然未知。我们的长期目标是了解HCV如何在分子水平上引起持续感染，这将有助于开发有效的治疗方法。由于HCV在细胞培养中的生长受限，以及缺乏方便的病毒感染和疾病进展的动物模型，因此对HCV的研究具有挑战性。我们最近发现，HCV感染细胞培养激活干扰素β（IFN-2）的表达和诱导自噬。然而，我们并不完全了解HCV如何减弱先天免疫反应并建立慢性感染。我们假设HCV与细胞蛋白相互作用并干扰它们的功能以建立持续感染。三个互补的方法将被用来测试我们的假设：目的1将确定HCV调节细胞内IFN信号通路的分子过程。目的2将确定HCV是否通过诱导自噬损害先天免疫。最后，目标3将检查HCV感染患者的肝内先天免疫应答与治疗结果的相关性。我们的研究结果将提供病毒持续存在的分子机制，并将有助于制定未来治疗慢性HCV感染的治疗策略。公共卫生相关性：HCV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，这可能会导致新的治疗策略，治疗慢性HCV感染。

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.