Interferon System Underlie Differential Response to Therapy for Hepatitis C Virus

干扰素系统是丙型肝炎病毒治疗差异反应的基础

• 批准号: 7475231
• 负责人: LAWRENCE MARC PFEFFER
• 金额: $ 21.73万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475231
• 关键词: Accounting; Address; African American; Antiviral Agents; B-Lymphocytes; Caucasians; Caucasoid Race; Cell Line; Clinical Trials; Combined Modality Therapy; Enrollment; Fibroblasts; Gene Expression; Genotype; Goals; Health; Health Sciences; Hepatitis C; Hepatitis C virus; Human Cell Line; Human Herpesvirus 4; Immune response; Interferon-alpha; Interferons; Molecular; Not Hispanic or Latino; Nuclear; Pathway interactions; Patients; Pegylated Interferon Alfa; Play; Population; Protein Family; RNA; Range; Rate; Reagent; Research; Research Personnel; Ribavirin; Role; STAT protein; STAT1 gene; STAT2 gene; STAT3 gene; Signal Pathway; Signal Transduction; Signal Transduction Induction; Signal Transduction Pathway; Skin; Study Section; System; Tennessee; Therapeutic; Treatment Protocols; United States; Universities; Virus; base; clinical efficacy; cohort; cytokine; member; nucleoside analog; receptor; response; transcription factor

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.

当前对丙型肝炎（HEP C）的选择治疗方法是，丙酸酯 - α（IFNALPHA）与抗病毒药物Ribavirin的结合。但是，IFNALPHA与利巴韦林组合的机制会导致持续的病毒学反应，这是仅在一小部分患者人群中清除HEP C确定的机制，尚不清楚。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患者的特定人群。例如，我们在田纳西大学健康科学中心（UT-HEP C CRC）的丙型肝炎合作研究中心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。这一发现引起了重大健康关注 在美国，非裔美国人约占HCV感染患者的22％。因此，这些重要问题将在本提案中解决：非反应者（以及非裔美国人）对联合治疗的反应不佳的分子基础是什么，以及利巴韦林在HEP中增强IFN IFN在HEP中的抗病毒作用的能力的分子基础是什么。 HEP C C基因型1在UT-HEP C CRC的Pegypated IFN的临床试验中纳入了临床试验。这些人类细胞系 源自响应者（R）和非反应者（NR），代表参加IFN-Ribavirin试验的高加索（C）和非裔美国人（AA）患者。这些细胞系代表着关键试剂，以解决该提案的目标，无论反应者与非反应者之间的IFN系统差异，以及高加索（C）与非裔美国人（AA）患者的差异，这是对IFN- ribavirin治疗的差异反应。在特定目标1中，我们将确定在受体相互作用，信号转导或IFN诱导的基因表达的水平上，非反应者和反应者和高加索和非裔美国人患者之间是否存在差异。在特定目标2中，我们将确定是否 利巴韦林通过调节IFN信号转导，IFN诱导的基因表达或IFN诱导抗病毒活性来增强HEP C中IFN的临床疗效。