CONTRIBUTION OF CELLULAR FACTOR TO HIV-1 ASSEMBLY

细胞因子对 HIV-1 组装的贡献

• 批准号: 8357136
• 负责人: Xinhong Dong
• 金额: $ 13.48万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357136
• 关键词: AIDS/HIV problem; Actin-Binding Protein; Actins; African American; Anti-HIV Agents; Anti-HIV Therapy; Binding; Biological; CD4 Positive T Lymphocytes; Cell membrane; Cells; Cytoskeleton; Epidemic; Filament; Funding; Gagging; Goals; Grant; HIV; HIV Infections; HIV-1; High Prevalence; Human; Intervention; Knowledge; Medical; Molecular; National Center for Research Resources; Pharmaceutical Preparations; Pilot Projects; Play; Principal Investigator; Process; Proteins; Recording of previous events; Research; Research Infrastructure; Research Priority; Resistance; Resources; Retroviridae; Role; Screening procedure; Series; Signal Transduction; Source; Staging; United States National Institutes of Health; Woman; Women' s Health; Yeasts; base; cDNA Library; cost; crosslink; filamin; gag Gene Products; health disparity; inhibitor/antagonist; macrophage; novel; particle; programs; protein transport; research study; scaffold; three dimensional structure; trafficking; transmission process; yeast two hybrid system

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A. Specific Aims The global HIV epidemic continues to expand exceeding previous predictions and has become one of the deadliest epidemics in human history. The high prevalence of HIV infection in the African-American women points to the need to develop the new medical interventions toward eliminating women's health disparities in HIV/AIDS. The emergence and transmission of HIV-1 isolates resistant to currently approved drugs makes the discovery of novel anti-HIV drugs with new mechanisms and targets a high research priority. HIV-1 Gag protein directs the highly ordered process of particle assembly and release. Distinct steps involved in these late stages of the HIV-1 replication cycle are being defined, yet significant gaps still need to be filled in our knowledge. Recently, by yeast two-hybrid screening of a human cDNA library, we identified a novel Gag-binding partner, filamin A. Filamin A (FLNa) is a non-muscle actin binding protein that plays an important role in cross-linking cortical filaments into a dynamic three-dimensional structure. FLNa interacts with different cellular proteins, and serves as a versatile scaffold required for protein trafficking, signaling transduction, and cell-cell and/or cell-matrix connections. The discovery of the FLNa-Gag interaction in a productive manner in HIV-1 particle assembly and release suggests that FLNa facilitates HIV-1 Gag trafficking to the plasma membrane by regulating the actin cytoskeleton remodeling. The overall goal of this RCMI pilot project is to define the molecular basis of the FLNa-Gag interaction and its biological significance. Our studies will provide important new information regarding retrovirus-host interactions, and will impact anti-HIV therapy by discovering and developing novel assembly inhibitors. This proposal will be accomplished in a series of experiments organized within three integrated specific aims. Specific Aim 1: To define the molecular basis of the FLNa-Gag interaction. Specific Aim 2: To define the mechanism of FLNa-regulated HIV-1 Gag trafficking. Specific Aim 3: To define the role of FLNa in human primary CD4+ T cells and macrophages.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 A.具体目标 全球艾滋病毒流行病继续扩大，超过先前的预测，已成为人类历史上最致命的流行病之一。非洲裔美国妇女艾滋病感染率高，需要制定新的医疗干预措施，以消除妇女在艾滋病毒/艾滋病的健康差距。对目前批准的药物具有耐药性的HIV-1分离株的出现和传播使得发现具有新机制和靶点的新型抗HIV药物成为高度优先的研究事项。HIV-1 Gag蛋白指导颗粒组装和释放的高度有序过程。在HIV-1复制周期的这些后期阶段所涉及的不同步骤正在被确定，但我们的知识中仍然需要填补重大空白。最近，通过酵母双杂交筛选人cDNA文库，我们鉴定了一种新的GAG结合伴侣细丝蛋白A。细丝蛋白A（FLNa）是一种非肌肉肌动蛋白结合蛋白，在将皮质细丝交联成动态三维结构方面发挥着重要作用。FLNa与不同的细胞蛋白相互作用，并作为蛋白运输、信号转导和细胞-细胞和/或细胞-基质连接所需的多功能支架。FLNa-Gag相互作用在HIV-1颗粒组装和释放中以有效方式的发现表明，FLNa通过调节肌动蛋白细胞骨架重塑促进HIV-1 Gag向质膜的运输。该RCMI试点项目的总体目标是确定FLNa-Gag相互作用的分子基础及其生物学意义。我们的研究将提供关于逆转录病毒-宿主相互作用的重要新信息，并将通过发现和开发新的组装抑制剂来影响抗HIV治疗。这一建议将在三个综合具体目标内组织的一系列实验中完成。 具体目标1：确定FLNa-Gag相互作用的分子基础。 具体目标2：确定FLNa调节HIV-1 Gag运输的机制。 具体目的3：确定FLNa在人原代CD 4 + T细胞和巨噬细胞中的作用。