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Host Factors Required for Dengue and Yellow Fever Virus Amplification

登革热和黄热病病毒扩增所需的宿主因素

基本信息

批准号：
8889884
负责人：
Sunnie R Thompson
金额：
$ 39.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8889884
关键词：
Address Adenoviruses Affect Antiviral Agents Binding Binding Sites Biochemical Biological Assay Cell Culture Techniques Cells Complex Cytolysis Data Defect Dengue Dengue Virus Development Drug resistance Evolution Genetic Goals Growth Herpesvirus 1 Human Human poliovirus In Vitro Infection Infection Control Integration Host Factors Knowledge Label Life Life Cycle Stages Maps Mass Spectrum Analysis Metabolic Methods Mutation Nature Pathway Analysis Pathway interactions Phase Polioviruses Polymerase Process Protein Binding Proteins Proteomics RNA RNA Sequences RNA Viruses Reporter Resistance Resistance development Reverse Transcriptase Polymerase Chain Reaction Role Specificity Sucrose Therapeutic Thiouracil Time Toxic effect Translations Viral Viral Hemorrhagic Fevers Viral Pathogenesis Viral Proteins Virus Virus Diseases Yellow Fever Yellow Fever Virus Infection Yellow fever virus base comparative crosslink density drug resistant virus high throughput screening inhibitor/antagonist link protein mutant pathogen pressure prevent protein protein interaction response stable isotope viral RNA virus host interaction

项目摘要

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.

项目概要：登革热和黄热病病毒是引起出血性疾病的重要人类病原体，发烧和死亡。目前，还没有针对这些病毒的批准的抗病毒药物。的 RNA病毒的抗病毒药物的开发已被证明是特别困难的，抗药性病毒的迅速出现。这主要是由于容易出错聚合酶的性质，这导致病毒在选择性条件下快速进化，压力针对病毒没有任何遗传控制的宿主因子应该减少或防止抗性突变体的发展，没有宿主因子，病毒就不能发挥功能，或者因为需要更多的突变，赋予抵抗力。为了实现这一目标，我们开发了一种强大的方法来识别在细胞培养物中病毒扩增期间与病毒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子，发热病毒RNA。我们将确定哪些主机因素将是开发的良好目标抗病毒靶点此外，我们还将确定病毒生命周期中的宿主步骤蛋白质-蛋白质和蛋白质-病毒RNA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在病毒扩增的因素，并使高通量检测的发展，宿主因子的抑制剂。