African American response to therapy for HCV

非洲裔美国人对 HCV 治疗的反应

• 批准号: 6344216
• 负责人: JAQUELYN F FLECKENSTEIN
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344216
• 关键词: African American; CD antigens; caucasian American; clinical research; cooperative study; hepatitis C; hepatitis C virus; human subject; human therapy evaluation; immunogenetics; interferons; microorganism disease chemotherapy; racial /ethnic difference; ribavirin

Hepatitis C (HCV) is estimated to infect 4 million people in the United States and the prevalence in the African American (AA) population is estimated to be as high as 3%. Recently, a significant racial disparity in the response rate to therapy with Interferon and Ribavirin has been reported with only 5% of AA responding is compared to approximately 40% in the non AA population. The overall goal of the present proposal is to determine the etiology of this racial difference in response rates. We hypothesize that some combination of difference in the virus, interferon response or genetically determined factors such as immune response or receptors is responsible for this racial difference in response rates. The present proposal is designed to answer 4 specific questions: 1) Is there a difference in HCV quasispecies heterogeneity or selection either at baseline or in response to therapy 2) Are there differences in interferon sensitivity or response between races 3) Are there genetically determined differences in immune responses to HCV and 4) Are there allelic differences in CD81, a proposed receptor for HCV (and associated proteins, putative co-receptors). We will answer these questions by retrospectively and prospectively defining quasispecies heterogeneity in a treated AA cohort and comparing this to a Caucasian cohort. We will define differences in interferon sensitivity at the levels of interferon-receptor interaction, signal transduction and interferon-induced gene expression in these two cohorts. Immunological differences between cohorts will be evaluated by examining the differences in both strength and phenotype of T helper cell responses to HCV-specific and non-specific stimulation and also allelic differences in HLA and IL10 genotypes. Finally, we will analyze the genomic DNA of our cohorts for CD81 and look for allelic differences. We expect to see differences in any or all of these factors. Differences detected between cohorts will lead to an improved understanding of viral chronicity and will be applied to the development of improved therapies.

据估计，丙型肝炎（HCV）在美国感染了400万人，非洲裔美国人（AA）人群的患病率估计高达3%。最近，据报道，干扰素和利巴韦林治疗的反应率存在显著的种族差异，AA患者中只有5%有反应，而非AA人群中约有40%有反应。本提案的总体目标是确定缓解率种族差异的病因。我们推测，病毒、干扰素反应或遗传决定因素（如免疫反应或受体）的某些差异组合是反应率的种族差异的原因。本提案旨在回答4个具体问题：1）HCV准种异质性或选择在基线或对治疗的反应中是否存在差异2）干扰素敏感性或反应在种族之间是否存在差异3）对HCV的免疫反应是否存在遗传决定的差异和4）CD 81，一种建议的HCV受体（和相关蛋白质，推定的共受体）。我们将通过回顾性和前瞻性地定义接受治疗的AA队列中的准种异质性并将其与白人队列进行比较来回答这些问题。我们将在干扰素-受体相互作用、信号转导和干扰素诱导的基因表达水平上确定这两个队列中干扰素敏感性的差异。将通过检查T辅助细胞对HCV特异性和非特异性刺激的应答强度和表型的差异以及HLA和IL 10基因型的等位基因差异来评价队列之间的免疫学差异。最后，我们将分析我们的CD 81队列的基因组DNA，并寻找等位基因差异。我们希望看到任何或所有这些因素的差异。在队列之间检测到的差异将导致对病毒慢性化的更好理解，并将应用于改进疗法的开发。