African American response to therapy for HCV

据估计，丙型肝炎(丙型肝炎)在美国感染了400万人，非洲裔美国人(AA)人口的流行率估计高达3%。最近，据报道，干扰素和利巴韦林治疗的应答率存在显著的种族差异，只有5%的再生障碍性贫血有效，而在非再生障碍性贫血人群中，这一比例约为40%。本提案的总体目标是确定答复率存在种族差异的原因。我们假设，病毒、干扰素反应或免疫反应或受体等遗传决定因素的某种组合导致了反应率的种族差异。目前的建议旨在回答4个具体问题：1)在基线或治疗反应中，丙型肝炎病毒准种异质性或选择是否存在差异；2)不同小种之间的干扰素敏感性或反应是否存在差异；3)对丙型肝炎病毒的免疫反应是否存在遗传决定的差异；4)丙型肝炎病毒受体CD81(及其相关蛋白，可能的辅助受体)是否存在等位基因差异。我们将通过回顾和前瞻性地定义接受治疗的AA队列中的准物种异质性，并将其与高加索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定义这两个队列中干扰素敏感性的差异。通过检测辅助性T细胞对丙型肝炎病毒特异性和非特异性刺激的反应强度和表型的差异，以及人类白细胞抗原和白介素10基因的等位基因差异，来评估队列之间的免疫学差异。最后，我们将分析我们队列中CD81的基因组DNA，并寻找等位基因差异。我们预计这些因素中的任何一个或所有因素都会有所不同。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，并将被应用于改进治疗的开发。

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.