Host Factors Required for Dengue and Yellow Fever Virus Amplification

项目总结： 登革热和黄热病病毒是导致出血的重要人类病原体。 发烧和死亡。目前，还没有批准的抗病毒药物来治疗这些病毒。这个 RNA病毒的抗病毒药物的开发已被证明是特别困难的，因为 抗药性病毒的迅速出现。这主要是因为容易出错 聚合酶的性质，导致病毒在选择性的作用下快速进化 压力。针对病毒不具有任何基因控制的宿主因子 Over应该减少或阻止抗药性突变体的发展，因为 病毒在没有宿主因素的情况下无法发挥作用，或者因为需要更多的突变来 进行抵抗。为了实现这一目标，我们开发了一种可靠的方法来识别 在细胞培养中病毒扩增过程中与病毒RNA结合的宿主因子。我们 将使用这种方法来识别与登革热病毒和黄色病毒结合的宿主因素 发热病毒核糖核酸。我们将确定哪些宿主因素将是很好的发展目标 抗病毒靶标。此外，我们还将确定宿主在病毒生命周期中的步骤 因子参与以及蛋白质-蛋白质和蛋白质-病毒RNA的相互作用 病毒感染过程中的宿主因素。这些研究将解决宿主的机制 病毒扩增中的因子，并使高通量检测的发展成为可能 寄主因子的抑制因子。

PROJECT SUMMARY: Dengue and yellow fever virus are significant human pathogens that cause hemorrhagic fever and fatalities. Currently, there are no approved antivirals for these viruses. The development of antivirals for RNA viruses has proven to be particularly difficult due to the rapid emergence of drug resistant viruses. This is primarily due to the error prone nature of the polymerase, which results in rapid evolution of the virus under selective pressure. Targeting a host factor for which the virus does not have any genetic control over should decrease or prevent development of resistant mutants either because the virus cannot function without the host factor or because more mutations are required to confer resistance. Towards this goal we have developed a robust method to identify host factors that are bound to the viral RNA during viral amplification in cell culture. We will use this method to identify host factors that are bound to the dengue virus and yellow fever virus RNA. We will identify which host factors will be good targets to develop antiviral targets. In addition, we will also determine the step in the viral life cycle the host factors participate in and the protein-protein and protein-viral RNA interactions for that host factor during viral infection. These studies will address the mechanism of the host factor in viral amplification and enable development of a high-throughput assay fro inhibitors of the host factor.