RACIAL DIFFERENCE IN HCV/HOST INTERACTIONS

HCV/宿主相互作用中的种族差异

• 批准号: 6751213
• 负责人: JAQUELYN F FLECKENSTEIN
• 金额: $ 80.96万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751213
• 关键词: African American; caucasian American; cooperative study; hepatitis C; hepatitis C virus; racial /ethnic difference

The University of Tennessee, Memphis Hepatitis C Cooperative Research Center will use studies of HCV/host interactions to determine why African American patients with HCV respond poorly to standard therapy (interferon and ribavirin). Hepatitis C is common, 1.8% of all Americans, but is even more common among African Americans, and in persons living in poverty. In Memphis, 55% of the population is African American, 34% of whom live below the poverty line. In a previous study, we documented a response rate of only 5% in this population, contrasted with 40% in whites. We propose to systematically characterize the differences between African Americans and whites by allelic variations in cellular ligands/receptors for HCV (Project 1). In Project 2, we will continue to develop an in vitro system for studying HCV, a chimeric VSV virus with the hepatitis C E1 and E2 envelope proteins expressed on its surface. We will use this model to characterize virus/cell interactions, testing antibodies to specific dominant quasispecies, contrasting our African American patients with whites. We will further characterize the putative receptor for HCV, CD81, to define its associated proteins, possible co-receptors (Project 3). These data will interface back to our patients as we search for allelic variations between African Americans and whites to explain the differences in response to therapy. Using the surrogate virus model, we will also screen libraries of small molecules to search for compounds that can block E2/CD81 binding (Project # African American population responds so poorly. Understanding this phenomenon will provide insights into why present day therapy is still only moderately successful in all populations, will allow us to predict who is more likely to respond, and will pave the way to developing better therapy for this emerging health problem.

田纳西大学孟菲斯分校丙型肝炎合作研究中心将利用对丙型肝炎病毒/宿主相互作用的研究，确定感染丙型肝炎病毒的非裔美国患者对标准治疗(干扰素和利巴韦林)反应差的原因。丙型肝炎很常见，占所有美国人的1.8%，但在非裔美国人和生活贫困的人中更常见。在孟菲斯，55%的人口是非洲裔美国人，其中34%的人生活在贫困线以下。在之前的一项研究中，我们记录了这一人群的应答率仅为5%，而白人的应答率为40%。我们建议通过丙型肝炎病毒细胞配体/受体的等位基因变化来系统地描述非裔美国人和白人之间的差异(项目1)。在项目2中，我们将继续开发用于研究丙型肝炎病毒的体外系统，丙型肝炎病毒是一种嵌合的VSV病毒，其表面表达丙型肝炎病毒包膜蛋白。我们将使用这个模型来表征病毒/细胞的相互作用，测试针对特定优势准种的抗体，将我们的非裔美国人患者与白人进行对比。我们将进一步确定假定的丙型肝炎病毒受体CD81，以确定其相关蛋白，可能的辅助受体(项目3)。当我们寻找非裔美国人和白人之间的等位基因变异以解释治疗反应的差异时，这些数据将反馈给我们的患者。使用代理病毒模型，我们还将筛选小分子文库，以寻找可以阻止E2/CD81结合的化合物(项目#非洲裔美国人群体反应如此之差。了解这一现象将为我们提供洞察，了解为什么目前的治疗在所有人群中仍然只取得适度的成功，将使我们能够预测谁更有可能做出反应，并将为开发更好的治疗这一新出现的健康问题铺平道路。

项目成果

Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.

• DOI: 10.1002/hep.22549
• 发表时间: 2008-12
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Kuntzen, Thomas;Timm, Joerg;Berical, Andrew;Lennon, Niall;Berlin, Aaron M.;Young, Sarah K.;Lee, Bongshin;Heckerman, David;Carlson, Jonathan;Reyor, Laura L.;Kleyman, Marianna;McMahon, Cory M.;Birch, Christopher;Wiesch, Julian Schulze zur;Ledlie, Timothy;Koehrsen, Michael;Kodira, Chinnappa;Roberts, Andrew D.;Lauer, Georg M.;Rosen, Hugo R.;Bihl, Florian;Cerny, Andreas;Spengler, Ulrich;Liu, Zhimin;Kim, Arthr Y.;Xing, Yanming;Schneidewind, Arne;Madey, Margaret A.;Fleckenstein, Jaquelyn F.;Park, Vicki M.;Galagan, James E.;Nusbaum, Chad;Walker, Bruce D.;Lake-Bakaar, Gerond V.;Daar, Eric S.;Jacobson, Ira M.;Gomperts, Edivard D.;Edlin, Brian R.;Donfield, Sharyne M.;Chung, Raymond T.;Talal, Andrew H.;Marion, Tony;Birren, Bruce W.;Henn, Mattliew R.;Allen, Todd M.
• 通讯作者: Allen, Todd M.