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：
8391158
负责人：
Ileana M. Cristea
金额：
$ 21.96万
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/8391158
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. PUBLIC HEALTH RELEVANCE: RNA viruses rapidly evolve resistant viruses to antiviral that target the viral proteins. An antivial that targets a host protein would significantly reduce or prevent drug resistance. Therefore, we will identify host factors that interact with dengue and yellow fever viral RNAs and determine their role in the viral life cycle in order to identify an effective antiviral target.

描述（由申请人提供）：登革热和黄热病病毒是引起出血热和死亡的重要人类病原体。目前，这些病毒尚无批准的抗病毒药。事实证明，由于耐药性病毒的迅速出现，RNA病毒抗病毒药的发展已被证明特别困难。这主要是由于聚合酶的误差性质，这导致选择性压力下病毒的快速演变。针对宿主因素该病毒没有任何遗传控制应减少或防止抗性突变体的发展，因为没有宿主因子就无法发挥作用，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，我们开发了一种强大的方法来识别病毒扩增I细胞培养过程中与病毒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结合的宿主因素。我们将确定哪些宿主因素将是开发抗病毒靶标的良好目标。此外，我们还将确定病毒生命周期中宿主福特参与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。这些研究将解决宿主因子扩增的机理，并能够通过宿主因子的抑制剂开发高通量测定法。公共卫生相关性： RNA病毒迅速将抗性病毒演变为靶向病毒蛋白的抗病毒。靶向宿主蛋白的抗动物会显着降低或防止耐药性。因此，我们将确定与登革热和黄热病病毒RNA相互作用的宿主因素，并确定其在病毒生命周期中的作用，以确定有效的抗病毒药靶。