MECHANISMS OF GENOMIC RNA PACKAGING IN INFLUENZA VIRUS

流感病毒基因组RNA包装机制

• 批准号: 7143590
• 负责人: TRISTRAM G. PARSLOW
• 金额: $ 34.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143590
• 关键词: RNA; influenza; proteins; virion

DESCRIPTION (provided by applicant): The influenza virus is humanity's most prolific viral assassin, killing tens of thousands of Americans in a typical year and as many as 20-100 million people worldwide when new a pandemic strain emerges. In order to be infectious, an individual virion must incorporate (package) at least one copy of each of the eight linear RNA segments that make up its genome. Pandemics are thought to arise when an existing strain packages one or more segments from another strain in a dually-infected host, yielding a genetic reassortant with novel immunologic and pathogenic properties. Understanding influenza RNA packaging is therefore critical for understanding and, perhaps, controlling, this lethal re-emerging virus. To date, however, the cis-acting determinants required for packaging (i.e., the packaging signals) have not been fully elucidated for any segment, and the trans-acting factors involved are unknown. Our laboratory has extensive experience in defining the requirements for RNA packaging by HIV. In recent studies, we have localized the signals required for efficient packaging to within discrete 45- to 200-base regions at one or both ends of three influenza RNA segments. We now propose to map the active regions in detail and to determine which specific features of RNA sequence and/or secondary structure are required for packaging of these and the other five segments. We will also pursue our surprising observation that 3' or 5' packaging regions are not simply interchangeable among segments, which implies that as-yet-unknown combinatorial rules govern their interactions in packaging. In addition, we have obtained compelling evidence implicating the influenza PA protein (a component of the trimeric viral RNA polymerase) as a trans-acting factor required for packaging all eight viral RNA segments. We will now investigate the molecular pathway by which PA and other viral proteins recognize the packaging signals in viral RNA segments and directing their incorporation into virions. The studies we propose will help elucidate the linkage between packaging and virion assembly, will extend our understanding of influenza genetics and reassortment, and may reveal vulnerable new targets for antiviral drug development.

描述（由申请人提供）：流感病毒是人类最多产的病毒杀手，每年都会导致数以万计的美国人死亡，当新的大流行毒株出现时，全世界会导致多达 20-1 亿人死亡。为了具有感染性，单个病毒体必须整合（包装）构成其基因组的八个线性 RNA 片段中每一个的至少一个副本。人们认为，当一种现有菌株在双重感染的宿主中包装来自另一种菌株的一个或多个片段，产生具有新的免疫学和致病特性的遗传重配时，就会出现大流行。因此，了解流感 RNA 包装对于了解甚至控制这种致命的重新出现的病毒至关重要。然而，迄今为止，包装所需的顺式作用决定因素（即包装信号）尚未完全阐明任何片段，并且所涉及的反式作用因素尚不清楚。我们的实验室在定义 HIV RNA 包装要求方面拥有丰富的经验。在最近的研究中，我们将有效包装所需的信号定位在三个流感 RNA 片段一端或两端的离散 45 至 200 个碱基区域内。我们现在建议详细绘制活性区域图，并确定包装这些和其他五个片段所需的 RNA 序列和/或二级结构的哪些特定特征。我们还将继续我们令人惊讶的观察，即 3' 或 5' 包装区域在片段之间不能简单地互换，这意味着尚未知的组合规则控制着它们在包装中的相互作用。此外，我们还获得了令人信服的证据，表明流感 PA 蛋白（三聚体病毒 RNA 聚合酶的一个组成部分）是包装所有八个病毒 RNA 片段所需的反式作用因子。我们现在将研究 PA 和其他病毒蛋白识别病毒 RNA 片段中的包装信号并指导它们掺入病毒颗粒的分子途径。我们提出的研究将有助于阐明包装和病毒粒子组装之间的联系，将扩展我们对流感遗传学和重配的理解，并可能揭示抗病毒药物开发的脆弱新靶点。