African American response to therapy for HCV

据估计，美国有400万人感染丙型肝炎（HCV），非洲裔美国人（AA）的患病率估计高达3%。最近，在干扰素和利巴韦林治疗的应答率上存在显著的种族差异，只有5%的AA患者应答，而非AA患者应答率约为40%。目前建议的总体目标是确定这种反应率的种族差异的病因。我们假设，病毒、干扰素反应或基因决定因素（如免疫反应或受体）的差异是造成这种反应率的种族差异的原因。目前的建议旨在回答4个具体问题：1)HCV准种异质性或选择在基线或治疗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)HCV免疫反应是否存在遗传决定的差异？ 4)CD81是否存在等位基因差异？ CD81是HCV的一种拟议受体（以及相关蛋白，推定的共受体）。我们将通过回顾性和前瞻性定义准物种异质性来回答这些问题，并将其与高加索人群进行比较。我们将在这两个队列中确定干扰素敏感性在干扰素受体相互作用、信号转导和干扰素诱导基因表达水平上的差异。将通过检查辅助T细胞对hcv特异性和非特异性刺激反应的强度和表型差异以及HLA和IL10基因型的等位基因差异来评估队列之间的免疫学差异。最后，我们将分析我们的队列中CD81的基因组DNA并寻找等位基因差异。我们期望看到这些因素中的任何一个或所有的差异。在队列之间检测到的差异将导致对病毒慢性性的更好理解，并将用于开发改进的治疗方法。

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.