SEQUENCE SELECTION AND PERSISTENCE OF HEPATITIS C

说明(改编自应用程序) 丙型肝炎病毒(丙型肝炎病毒)持续感染的机制较差 我明白，但高度变异的病毒基因组提供了一扇了解自然 这一过程的历史。而在体外和动物模型中不充分的 阻碍了更直接地观察病毒的努力，序列分析已经 鉴定出具有较高致病潜力和抗药性的菌株 药物治疗。丙型肝炎病毒序列揭示线索并不令人惊讶 致病机制，因为丙型肝炎病毒以准种的形式存在于每个感染的宿主体内。(A) 一大群不同但相关的变种)，这取决于达尔文主义 由宿主的免疫系统进行选择。 我们已经开发出一种方法来识别每个感染者的不同变异 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。我们还获得了来自 活着，一大群注射吸毒者，有明确的临床定义 以及病毒学结果。 我们对急性感染的初步研究表明，自限性病毒血症是 与不太复杂的丙型肝炎病毒变异株群相关，更具宿主选择性 对更保守区域的压力(基于准物种内的比率 与同义多样性不是同义词)，以及 包膜蛋白E2的高度可变的N-末端。我们的中心假设 是针对更保守的表位的免疫反应 与急性感染后丙型肝炎病毒血症的清除有关。通过测试 这一假说与多年的临床和临床研究结果相吻合。 病毒学数据，我们预计在获得更多了解方面取得成功 与准物种多样性有关的抗原变异，以及 丙型肝炎病毒持续存在的机制。更好地了解丙型肝炎病毒的这些方面 致病机制将对疫苗的开发和 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 通过(1)研究验证来证实和扩展我们的初步观察 队列，(2)收集纵向序列数据，(3)扩大范围 包括丙型肝炎病毒基因组中更保守的区域。这 应用程序是高效的，而且成功的可能性很高，因为它使 使用一个特征良好的队列，多年来的临床和病毒学 数据已经收集完毕。

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.