INF System in Differential Response to HCV Therapy

聚乙二醇化干扰素α（IFN α）与抗病毒药物利巴韦林的组合是目前治疗丙型肝炎（Hep C）的首选。然而，IFN α与利巴韦林的组合引起持续的病毒学应答的机制是未知的，所述持续的病毒学应答通过仅在一部分患者群体中的Hep C的清除来确定。此外，几项研究已经确定了对这些治疗方案反应相对较低的特定患者队列。例如，我们在田纳西大学健康科学中心丙型肝炎合作研究中心（UT-Hep C CRC）进行的研究与其他几项研究一致，并确定非洲裔美国人的应答率显着低于非西班牙裔白人。这一发现是重大的健康问题，因为 非洲裔美国人占美国HCV感染患者的约22%。因此，这些重要的问题将在本提案中得到解决：无应答者（和非洲裔美国人）对联合治疗反应差的分子基础是什么，利巴韦林增强IFN在丙型肝炎中的抗病毒作用的分子基础是什么。为了解决这些问题，我们已经建立了皮肤成纤维细胞系和爱泼斯坦巴尔病毒（EBV）永生化B细胞系，这些细胞系来自感染丙型肝炎基因型-1的患者，这些患者参加了在UT-丙型肝炎CRC进行的聚乙二醇干扰素与利巴韦林的临床试验。这些人类细胞系 来自应答者（R）和无应答者（NR），代表参加IFN-利巴韦林试验的白人（C）和非洲裔美国人（AA）患者。这些细胞系代表了解决本提案目标的关键试剂，即应答者与无应答者之间以及高加索人（C）与非洲裔美国人（AA）患者之间IFN系统的差异是否构成对IFN-利巴韦林治疗的差异应答的基础。在特定目标1中，我们将确定无反应者和有反应者以及高加索人和非裔美国患者在受体相互作用、信号转导或IFN诱导的基因表达水平上的IFN敏感性是否存在差异。在具体目标2中，我们将确定 利巴韦林通过调节IFN信号转导、IFN诱导的基因表达或IFN诱导的抗病毒活性来增强IFN在Hep C中的临床功效。

The combination of pegylated interferon-alpha (IFNalpha) with the antiviral drug, ribavirin, is the current treatment of choice for hepatitis C (Hep C). However, the mechanism whereby the combination of IFNalpha with ribavirin causes a sustained virological response as determined by the clearance of Hep C in only a fraction of the patient population is unknown. Moreover, several studies have identified specific cohorts of patients that have a relatively low response to these therapeutic regimens. For example, our study performed at the Hepatitis C Cooperative Research Center at the University of Tennessee Health Science Center (UT-Hep C CRC) is consistent with several other studies and has established that the response rate of African-Americans is significantly lower than non-Hispanic whites. This finding is of major health concern since African-Americans account for approximately 22% of HCV-infected patients in the US. Therefore, these important issues will be addressed in this proposal: what is the molecular basis for the poor response of nonresponders (and African-Americans) to combination therapy, and what is the molecular basis for the ability of ribavirin to potentiate IFN's antiviral action in Hep C. To address these questions we have established skin fibroblast cell lines and Epstein Barr Virus (EBV)-immortalized B cell lines from patients infected with Hep C genotype-1 enrolled in the clinical trial of pegylated IFN with ribavirin at the UT-Hep C CRC. These human cell lines were derived from responders (R) and nonresponders (NR), and represent Caucasian (C) and African-American (AA) patients enrolled in the IFN-ribavirin trial. These cell lines represent key reagents to address the goal of this proposal, whether differences in the IFN system between responders versus nonresponders, and Caucasian (C) versus African-American (AA) patients, underlie the differential response to IFN-ribavirin therapy. In Specific Aim 1 we will determine whether there is a difference between non-responders and responders, and Caucasian and African-American patients, in IFN sensitivity at the levels of receptor interaction, signal transduction or IFN-induced gene expression. In Specific Aim 2 we will determine whether ribavirin enhances the clinical efficacy of IFN in Hep C by modulating IFN signal transduction, IFN-induced gene expression or induction of antiviral activity by IFN.