Functional Variation of Rev and RRE Activity During HIV Infection

HIV 感染期间 Rev 和 RRE 活性的功能变化

• 批准号: 8858647
• 负责人: MARIE-LOUISE HAMMARSKJOLD
• 金额: $ 29.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8858647
• 关键词: Address; Affect; Binding; Binding Sites; Cell Culture Techniques; Cells; Clinical; Complex; Data; Elements; Equilibrium; Funding; Grant; HIV; HIV Infections; HIV therapy; Health; Immune; Immune system; Individual; Infection; Laboratories; Manuscripts; Modeling; Pathway interactions; Patients; Play; Proteins; Publications; RNA; Role; Staging; Structure; Time; Variant; Viral; Viral Genome; Viral Proteins; Viral Structural Proteins; Virus; base; design; genome sequencing; insight; novel; research study; rev Genes; stem; virus pathogenesis

DESCRIPTION (provided by applicant): This proposal explores the basis for the different Rev/RRE activities that evolve in patients during infection, and also addresses how the structure of the RRE regulates Rev function. It also examines if the modulation of Rev/RRE function plays a role in two different clinical scenarios. Recent data, obtained by single genome sequencing, show that both Rev and RRE activity in an infected individual vary as HIV evolves, and that this variation arises from only a few changes in either Rev or RRE sequence. This change in Rev/RRE activity can profoundly affect rates of viral replication. The data also show that the pairing of any particular Rev sequence with different RREs leads to significant changes in overall Rev/RRE activity levels. This emphasizes the importance of analyzing Rev and RRE as a cognate pair derived from the same viral genome. At the present time, there is no mechanistic understanding of how small changes in sequence of either Rev or RRE modulate their combined activity. One of the aims of this proposal addresses this issue. We have also recently obtained data that demonstrate that the RRE is a dynamic RNA structure. In particular, stem loop regions III and IV can exist either as a single stem loop or as two separate ones, and the two structures probably are in equilibrium. Our data suggest that the formation of the structure with the individual stem loop IV is critical for Rev and RRE function. Another aim will examine the mechanistic basis for this. In the last aim, we will also further explore the hypothesis that good immune control selects for viruses with lower Rev/RRE activity. In addition we will also examine if viruses with lower Rev/RRE activity are favored in establishment of latently infected cells. The specific aims are: Specific Aim #1: What is the functional significance of the stem loop III/IV RRE sequence rearrangement? Specific Aim #2: What is the basis for the differences in activity that are observed with selected Rev- RRE pairs derived from infected patients? Specific Aim #3: Analysis of Rev-RRE activity in two different clinical scenarios.

描述（由申请人提供）：该提案探讨了感染期间患者体内演变的不同 Rev/RRE 活动的基础，并探讨了 RRE 的结构如何调节 Rev 功能。它还检查 Rev/RRE 功能的调节是否在两种不同的临床情况中发挥作用。 通过单基因组测序获得的最新数据表明，受感染个体的 Rev 和 RRE 活性随着 HIV 的进化而变化，并且这种变化仅由 Rev 或 RRE 序列的少数变化引起。 Rev/RRE 活性的这种变化可以深刻影响病毒复制速率。数据还表明，任何特定 Rev 序列与不同 RRE 的配对都会导致总体 Rev/RRE 活性水平发生显着变化。这强调了将 Rev 和 RRE 作为源自同一病毒基因组的同源对进行分析的重要性。目前，对于 Rev 或 RRE 序列的微小变化如何调节它们的组合活性还没有机制上的理解。该提案的目的之一就是解决这个问题。 我们最近还获得了数据证明 RRE 是一种动态 RNA 结构。特别是，茎环区域III和IV可以作为单个茎环存在，也可以作为两个单独的茎环存在，并且这两种结构可能处于平衡状态。我们的数据表明，单个茎环 IV 结构的形成对于 Rev 和 RRE 功能至关重要。另一个目标是研究其机制基础。 在最后一个目标中，我们还将进一步探索这样的假设：良好的免疫控制会选择 Rev/RRE 活性较低的病毒。此外，我们还将检查 Rev/RRE 活性较低的病毒是否有利于建立潜伏感染细胞。 具体目标是： 具体目标#1：茎环 III/IV RRE 序列重排的功能意义是什么？ 具体目标#2：从感染患者中选择的 Rev-RRE 对中观察到的活性差异的基础是什么？ 具体目标#3：分析两种不同临床情况下的 Rev-RRE 活性。