Racial Differences in IFN Transcriptional Response

描述（由申请人提供）：慢性丙型肝炎病毒（HCV）是美国最常见的肝脏疾病之一。它与进行性肝纤维化、肝硬化和肝细胞癌风险增加有关。大约240万美国人患有慢性丙型肝炎感染，非洲裔美国人的感染率（3.2%）高于白种人（1.5%）。令人沮丧的是，丙型肝炎相关肝硬化的死亡率和丙型肝炎引起的肝细胞癌的发病率似乎在增加，而且这些增加预计会不成比例地影响非裔美国人。与白种人、墨西哥裔美国人和亚裔患者相比，非洲裔美国患者对基于干扰素（IFN）的治疗的反应率较低，这一事实放大了这种威胁。非裔美国人对抗病毒治疗相对缺乏反应的原因尚不清楚。用干扰素-(IFN-)治疗与血浆或血清中存在的病毒数量的两期下降有关。最初的下降（阶段1）的特点是在最初的24小时内血清HCV RNA水平迅速下降，随后在48小时内逐渐下降（阶段2）。通过数学模型的分析表明，IFN-（）的急性作用是由于其抗病毒活性阻止病毒粒子的产生或从肝脏释放，而较慢、较晚的下降是由于肝脏内受感染细胞的免疫清除。然而，IFN-(的实际“抗病毒”机制仍然不确定，并且由于IFN-（的免疫调节作用，不能排除IFN-）在增强病毒从血清中清除方面的重要作用。本提案旨在了解种族和宿主遗传因素在HCV感染中决定干扰素反应的作用。简单地说，我们的假设是：(1)与白种人相比，非裔美国人使用IFN-（干扰素）后血清和肝脏中HCV的下降速度较慢；(2)这种病毒动力学的差异反映了白种人和非裔美国人使用IFN-（干扰素）诱导的肝内和/或淋巴细胞基因表达的差异；(3)分析早期病毒学应答者和无应答者对IFN-转录反应的差异（以及特异性干扰素刺激基因（ISGs）在复制子系统中对HCV RNA复制的体外评估），将有助于更好地理解参与抑制丙型肝炎病毒复制和诱导持续病毒学应答治疗的宿主途径

DESCRIPTION (provided by the applicant): Chronic hepatitis C virus (HCV) is one of the most prevalent diseases of the liver in the United States. It is associated with progressive hepatic fibrosis, cirrhosis and increased risk of hepatocellular carcinoma. Approximately 2.4 million Americans have chronic hepatitis C infection and the rate is higher among the African Americans (3.2%) than among the Caucasian population (1.5%). Distressingly, the mortality rates for hepatitis C-related cirrhosis and the incidence of hepatocellular carcinoma due to HCV appear to be increasing, and these increases are expected to disproportionably affect African Americans. This threat is magnified by the fact that African American patients have a lower rate of response to alpha interferon (IFN() based therapy compared to Caucasian, Mexican American and Asian patients. The reasons for the relative lack of response to antiviral therapy among African Americans are not clear. Therapy with IFN-( is associated with a Diphasic decline in the quantity of virus present in plasma or serum. The initial decline (phase 1) is characterized by a rapid decrease in serum HCV RNA levels in the first 24 hours and it is followed by a much more gradual decline by 48 hours onward (phase 2). Analysis by a mathematical model suggests that the acute effect of IFN-( is due to an antiviral activity that blocks virion production or release from the liver, while the slower, later decline is due to the immune removal of infected cells within the liver. However, the actual "antiviral" mechanisms of IFN-( remain uncertain and an important role for enhanced clearance of virus from the serum due to the immunomodulatory actions of IFN-( cannot be excluded. This proposal seeks to understand the role of racial and host genetic factors in determining interferon response in HCV infection. Briefly stated, our hypotheses are: (1) that the rates of the HCV decline in serum and liver after IFN-( will be slower among African Americans compared to Caucasians, (2) that this difference in viral kinetics reflects differences in IFN-( induced intrahepatic and/or lymphocytic gene expression among Caucasians and African Americans, and (3) that an analysis of differences in the transcriptional responses to IFN-( and the in vitro evaluation of specific Interferon stimulated genes (ISGs) on HCV RNA replication in the replicon system between early virological responders and non-responders will lead to a better understanding of host pathways involved in the suppression of hepatitis C virus replication and the induction of a sustained virological response to therapy