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。大约有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%）高于白人（1.5%）。令人沮丧的是，丙型肝炎相关肝硬化的死亡率和HCV引起的肝细胞癌的发病率似乎正在增加，预计这些增加将不可避免地影响非洲裔美国人。与白人、墨西哥裔美国人和亚洲患者相比，非洲裔美国人患者对α干扰素（IFN）治疗的应答率较低，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IFN-α治疗与血浆或血清中存在的病毒量的双相下降有关。最初的下降（第1阶段）的特征是在前24小时内血清HCV RNA水平迅速下降，然后在48小时内逐渐下降（第2阶段）。通过数学模型的分析表明，IFN-γ的急性效应是由于阻断病毒体产生或从肝脏释放的抗病毒活性，而较慢的、较晚的下降是由于肝脏内感染细胞的免疫清除。然而，IFN-α的实际“抗病毒”机制仍然不确定，并且不能排除IFN-α的免疫调节作用对增强病毒从血清中清除的重要作用。该建议旨在了解种族和宿主遗传因素在决定HCV感染中干扰素应答中的作用。简而言之，我们的假设是：（1）IFN-γ治疗后，血清和肝脏中HCV的下降率明显高于对照组，（与高加索人相比，非洲裔美国人的速度较慢，（2）病毒动力学的这种差异反映了IFN-γ的差异。（在高加索人和非裔美国人中诱导肝内和/或淋巴细胞基因表达，和（3）对IFN-γ转录反应差异的分析（以及在早期病毒学应答者和非应答者之间的复制子系统中特异性干扰素刺激基因（ISG）对HCV RNA复制的体外评价。应答者将导致更好地了解参与抑制丙型肝炎病毒复制和诱导对治疗的持续病毒学应答的宿主途径

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