Interferon System Underlie Differential Response to Therapy for Hepatitis C Virus

聚乙二醇化干扰素- α (ifn - α)联合抗病毒药物利巴韦林是目前丙型肝炎（Hep C）的首选治疗方法。然而，ifn - α与利巴韦林联合引起持续病毒学反应的机制尚不清楚，这是由一小部分患者体内丙型肝炎病毒的清除所决定的。此外，一些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群体。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，并确定非裔美国人的反应率明显低于非西班牙裔白人。这一发现引起了人们对健康的关注

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.