Impact of CTL Escape Mutations on HCV Replicative Fitness

针对丙型肝炎病毒和艾滋病毒等高度可变病原体的疫苗开发仍然是主要的 由于这些病原体能够迅速变异以逃避关键的免疫反应，因此面临挑战。 不幸的是，开发这些疫苗的努力收效甚微，部分原因是无法 确定有效免疫的确切相关因素。CD8+T细胞(CTL)似乎对许多 高度可变的病原体，包括丙型肝炎病毒，这是由特定的人类白细胞抗原I类的协会支持的 控制艾滋病毒、疟疾和丙型肝炎的等位基因。艾滋病毒和丙型肝炎病毒的最新数据现在开始表明， 控制与特定CD8+T细胞对病毒靶区的反应能力有关 由于逃逸突变对病毒复制的影响，逃逸受到损害。这项提议的目标是 利用病毒序列进化识别那些能够发挥最大作用的CD8+T细胞反应 丙型肝炎病毒选择性压力作为CD8+T细胞疗效的替代标志物。我们计划全面 检查整个丙型肝炎病毒中CTL逃逸突变的频率和位置以确定CDS反应 (已定义的和新的)施加选择压力，确定影响外部宿主和病毒因素 CTL逃逸，并测量突变对病毒复制的影响。应用全面的病毒 对这些问题的测序和功能免疫学将有助于阐明特定CDS的影响 对控制丙型肝炎病毒的反应和逃逸突变提供了独特的洞察力和特异性和 CDS应答的功能对丙型肝炎病毒的控制至关重要。因此，这些努力将有助于确定 对控制丙型肝炎病毒至关重要的免疫反应，作为其他高度可变病原体的模型，以便 指导针对这些难以控制的病原体设计有效的疫苗。

The development of vaccines against highly variable pathogens such as HCV and HIV remains a major challenge due to the ability of these pathogens to rapidly mutate to evade critical immune responses. Unfortunately, efforts to develop these vaccines have met with little success, in part due to the inability to identify the precise correlates of effective immunity. CD8+ T cells (CTL) appear critical to the control of many highly variable pathogens including HCV, which is supported by the association of particular HLA class I alleles with control of HIV, malaria, and HCV. Recent data in HIV and HCV now begin to suggest that this control is associated with the ability of particular CD8+ T cell responses to target regions in which viral escape is impaired due to the impact of escape mutations on viral replication. The goal of this proposal is to utilize viral sequence evolution to identify those CD8+ T cell responses capable of exerting the greatest selective pressure upon HCV as a surrogate marker of CD8+ T cell efficacy. We plan to comprehensively examine the frequency and location of CTL escape mutations across HCV to identify CDS responses (defined and novel) exerting selective pressure, determine the extrinsic host and viral factors that influence CTL escape, and measure the impact of mutations on viral replication. Applying comprehensive viral sequencing and functional immunology to these questions will help elucidate the impact of particular CDS responses and escape mutations on control of HCV and provide unique insight into the specificity and function of CDS responses most critical to the control of HCV. Therefore, these efforts will help identify immune responses critical to the control of HCV, as a model for other highly variable pathogens, in order to guide the design of effective vaccines against these difficult to control pathogens.