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：
8522155
负责人：
Ileana M. Cristea
金额：
$ 19.43万
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：
2012
资助国家：
美国
起止时间：
2012-08-03 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522155
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

DESCRIPTION (provided by applicant): 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 i 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 fators 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.

描述（由申请人提供）：登革热和黄热病病毒是导致出血热和死亡的重要人类病原体。目前，还没有针对这些病毒的批准的抗病毒药物。由于耐药病毒的迅速出现，RNA病毒抗病毒药物的开发已被证明特别困难。这主要是由于聚合酶容易出错的性质，导致病毒在选择压力下快速进化。针对宿主因素该病毒没有任何遗传控制，应该减少或防止抗性突变体的发展，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才能赋予抗性。为了实现这一目标，我们开发了一种可靠的方法来识别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热病病毒 RNA 结合的宿主因子。我们将确定哪些宿主因子将成为开发抗病毒靶点的良好靶点。此外，我们还将确定宿主因子参与病毒生命周期的步骤，以及病毒感染期间该宿主因子的蛋白质-蛋白质和蛋白质-病毒RNA相互作用。这些研究将解决病毒扩增中宿主因子的机制，并能够开发宿主因子抑制剂的高通量测定。