Diverse Functions of HIV-1 Capsid During Postentry Events

HIV-1衣壳在进入后事件期间的多种功能

• 批准号: 9979730
• 负责人: Masahiro Yamashita
• 金额: $ 44.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979730
• 关键词: AIDS/HIV problem; Address; Affect; Affinity; Antiviral Agents; Basic Science; Binding; Binding Proteins; Biological; Biological Assay; Biological Metamorphosis; Biology; Capsid; Capsid Proteins; Cells; Cellular Assay; Communicable Diseases; Complex; DNA; Data; Development; Drug Design; Drug resistance; Enzymes; Event; Future; Genes; Goals; Growth; HIV-1; Immune Evasion; Impairment; Infection; Innate Immune Response; Innate Immune System; Integration Host Factors; Interphase Cell; Laboratories; Life Cycle Stages; Link; Maps; Mediating; Modeling; Mutagenesis; Nuclear; Nuclear Accidents; Nuclear Import; Nucleic Acids; Pattern; Pharmacology; Play; Process; Property; Proteins; Proviruses; Resolution; Reverse Transcription; Role; Shapes; Structure; Techniques; Testing; Therapeutic; Variant; Viral; Virus; Virus Replication; Virus Shedding; antiretroviral therapy; base; chromosomal location; cofactor; combat; drug development; experimental study; fight against; fitness; innate immune sensing; insight; integration site; mutant; novel; novel therapeutics; spatiotemporal; tool; viral RNA; viral fitness; virus host interaction

Project Summary The HIV-1 capsid, which encloses viral and host components essential for establishing infection, influences every post-entry step, including reverse transcription, nuclear entry and integration targeting. These capsid- mediated events are governed by HIV-1 uncoating, a process in which the conical core sheds viral capsid proteins (CA) and transforms into reverse transcription complexes and then pre-integration complexes. Uncoating of the viral capsid is regulated by both core stability and capsid-binding host cofactors. Much remains to be learned about how the uncoating process is coordinated to facilitate viral propagation. Temporal deviations from the normal course of capsid disassembly (delayed or accelerated uncoating) by antiviral factors or pharmacological manipulation can severely impair viral infectivity. However, it still remains unclear precisely how intrinsic core stability affects capsid disassembly and downstream events. Our preliminary studies have identified a natural HIV-1 strain that appears to alter core stability without compromising viral fitness. In Aim 1, we will characterize a broad range of biological properties of this unique variant and also exploit core-destabilizing activity of capsid-targeting antivirals as a tool to study capsid stability. Current models posit that core disassembly impacts innate sensing of HIV-1 DNA but mechanistic details have yet to be elucidated. In Aim 2, we propose to examine how perturbation of uncoating by manipulating core stability and capsid interactions with host proteins affects innate immune responses. Capsid uncoating also plays roles in nuclear events, such as nuclear import and integration targeting. In Aim 3, we will address how these events are functionally linked and contribute to optimal viral growth by using various experimental approaches, including novel high-throughput single-cell assays.

项目摘要 HIV-1衣壳包裹着确定感染所必需的病毒和宿主成分，影响 进入后的每一步，包括反转录、核进入和整合靶向。这些衣壳- 介导的事件受HIV-1去涂层的控制，在这个过程中，锥形核心脱落病毒衣壳 蛋白质(CA)转化为反转录复合体，然后转化为预整合复合体。 病毒衣壳的脱壳受核心稳定性和衣壳结合宿主辅因子的调节。大有可为 关于如何协调去涂层过程以促进病毒传播，仍有待了解。时态 偏离抗病毒药物正常的衣壳拆解过程(延迟或加速脱壳) 因素或药物操纵会严重削弱病毒的感染力。然而，目前仍不清楚 究竟内在的核心稳定性如何影响衣壳拆解和下游事件。我们的预赛 研究已经确定了一种天然的HIV-1毒株，它似乎在不损害病毒的情况下改变了核心稳定性 健身。在目标1中，我们将描述这种独特变体的广泛生物学特性，并 利用衣壳靶向抗病毒药物的核心不稳定活性作为研究衣壳稳定性的工具。当前型号 假设核心解体影响对HIV-1DNA的先天感知，但机制细节尚未确定 已澄清。在目标2中，我们建议检查通过操纵核心稳定性和 衣壳与宿主蛋白的相互作用影响先天免疫反应。衣壳去涂层也在 核事件，如核进口和整合目标。在目标3中，我们将讨论这些事件是如何 通过使用各种实验方法在功能上联系在一起并有助于病毒的最佳生长， 包括新的高通量单细胞分析。