SEQUENCE SELECTION AND PERSISTENCE OF HEPATITIS C

丙型肝炎的序列选择和持续性

• 批准号: 6650151
• 负责人: STUART C RAY
• 金额: $ 34.34万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650151
• 关键词: acute disease /disorder; clinical research; epidemiology; genetic polymorphism; genetic strain; hepatitis C; hepatitis C virus; human subject; immunogenetics; longitudinal human study; nucleic acid sequence; virus cytopathogenic effect; virus envelope; virus genetics; virus load; virus protein

DESCRIPTION (adapted from the application) The mechanisms of persistence of hepatitis C virus (HCV) infection are poorly understood, but the highly mutable viral genome offers a window on the natural history of this process. Whereas inadequate in vitro and animal models have hampered efforts to observe the virus more directly, sequence analysis has identified strains with higher pathogenic potential and resistance to pharmacologic treatment. It is not surprising that HCV sequences reveal clues to pathogenesis, because HCV exists in each infected host as a quasispecies. (a swarm of distinct but related variants), which is subject to Darwinian selection by the host's immune system. We have developed a method to identify distinct variants in each infected individual, allowing us to acquire an accurate nucleotide sequence sample of the quasispecies at greatly reduced cost. We also have access to specimens from ALIVE, a large cohort of injecting drug users, with clearly defined clinical and virologic outcomes. Our preliminary studies of acute infection suggest that self-limited viremia is associated with a less complex swarm of HCV variants, greater host selective pressure on more conserved regions (based on the ratio of within-quasispecies non-synonymous to synonymous diversity), and higher positive charge at the highly variable N-terminus of the envelope protein E2. Our central hypothesis is that an immune response directed against more conserved epitopes is associated with clearance of HCV viremia following acute infection. By testing this hypotheses in a well-characterized cohort with years of clinical and virologic data, we anticipate success in achieving greater understanding of antigenic variation as it relates to quasispecies diversity, and of the mechanisms of HCV persistence. Greater understanding of these aspects of HCV pathogenesis would have a significant impact on vaccine development and rational drug design. By combining our epidemiologic and molecular resources with novel tools, we aim to confirm and extend our preliminary observations by (1) studying a validation cohort, (2) collecting longitudinal sequence data, and (3) expanding the scope of the analysis to include more conserved regions of the HCV genome. This application is efficient and has a high likelihood of success because it makes use of a well-characterized cohort, for which years of clinical and virologic data have already been assembled.

描述（改编自应用程序） 丙型肝炎病毒（HCV）感染持续存在的机制尚不清楚 理解，但高度可变的病毒基因组提供了一个窗口，自然 这个过程的历史。尽管体外和动物模型不足， 阻碍了更直接地观察病毒的努力，序列分析 确定了具有较高致病潜力和耐药性的菌株， 药物治疗HCV序列揭示线索并不奇怪 发病机制，因为HCV存在于每个感染的主机作为准种。（一个 一群不同但相关的变种），这是受达尔文 宿主免疫系统的选择 我们已经开发出一种方法来识别每个感染者的不同变体， 个体，使我们能够获得准确的核苷酸序列样本， 准物种的成本大大降低。我们还可以从 ALIVE，一个大型的注射毒品使用者队列，具有明确的临床 和病毒学结果。 我们对急性感染的初步研究表明，自限性病毒血症是 与不太复杂的HCV变异群相关， 对更保守区域的压力（基于准种内的比例 非同义词到同义词多样性），以及 高度可变的包膜蛋白E2的N-末端。我们的核心假设 针对更保守的表位的免疫应答 与急性感染后HCV病毒血症的清除相关。通过测试 这一假设在一个具有多年临床和 病毒学数据，我们预计成功地实现更深入的了解 抗原变异，因为它涉及准种多样性，和 HCV持久性的机制。更好地了解HCV的这些方面 发病机理将对疫苗开发产生重大影响， 合理的药物设计 通过将我们的流行病学和分子资源与新工具相结合，我们的目标是 为了证实和扩展我们的初步观察，（1）研究验证 队列，（2）收集纵向序列数据，（3）扩大范围 包括HCV基因组中更保守的区域。这 应用程序是高效的，并且有很高的成功可能性，因为它使 使用一个特征良好的队列，多年的临床和病毒学研究 数据已经收集好了。