Cytoplasmic-Nuclear Trafficking of HIV-1

HIV-1 的细胞质核贩运

• 批准号: 8349023
• 负责人: vineet n kewalramani
• 金额: $ 61.9万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349023
• 关键词: Animal Model; Antiviral Agents; Antiviral Therapy; Biology; Capsid; Capsid Proteins; Cell Culture Techniques; Cells; Complex; Drug Delivery Systems; Ectopic Expression; Elements; Genes; HIV; HIV Drug Resistance Program; HIV Infections; HIV-1; HIV-2; Human; Infection; Modeling; Molecular; Mus; Mutation; Nuclear; Protein Family; Proteins; Reporting; Research Personnel; Resistance; SIV; Screening procedure; Site Visit; Viral; Virus; Virus Replication; Work; improved; interest; macrophage; mutant; trafficking; transmission process

We have identified a truncated SR-family protein that has potent antiviral activity against HIV-1, HIV-2, and SIV, but no activity against MLV. Ectopic expression of the truncated SR-protein in human or mouse cells restricts the nuclear entry of HIV pre-integration complexes. Selection of HIV resistant to this factor leads to mutation in the virus capsid protein. Notably, these HIV mutants lose the ability to infect nondividing cells, and one mutation in particular interferes with HIV infection of terminally differentiated macrophages. We believe this to be a significant advance. In the era of molecular HIV studies, the discrete elements within HIV that are required for the infection of nondividing cells has proven to be a vexing question despite the sustained interest of gene therapists and HIV researchers. We are currently seeking cellular proteins targeted by the antiviral factor to better understand the machinery HIV interacts with in the infection of nondividing cells. We are also studying how the capsid mutations alter the biology of early HIV replication. In related work, we have also discovered dominant restrictions in human cells that interfere with HIV after entry but can be overcome by mutation of the viral core. These studies may provide new drug targets for antiviral therapy. Identification of HIV host cell factors will also enable the improvement of cell culture and animal models to study HIV transmission and replication. [Corresponds to KewalRamani Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]

我们已经鉴定出一种截短的SR-家庭蛋白，该蛋白具有对HIV-1，HIV-2和SIV的有效抗病毒活性，但没有针对MLV的活性。人或小鼠细胞中截短的SR蛋白的异位表达限制了HIV前整合复合物的核进入。对该因子的抗HIV的选择会导致病毒衣壳蛋白突变。值得注意的是，这些艾滋病毒突变体失去了感染非分散细胞的能力，而一个突变特别干扰了终末分化的巨噬细胞的HIV感染。我们认为这是一个重大进步。在分子HIV研究的时代，尽管基因治疗师和艾滋病毒研究人员持续了持续的兴趣，但事实证明，艾滋病毒感染所需的艾滋病毒中的离散元素已被证明是一个令人沮丧的问题。我们目前正在寻找由抗病毒因子靶向的细胞蛋白，以更好地了解与非分散细胞感染中的机械HIV相互作用。我们还研究了衣壳突变如何改变早期HIV复制的生物学。 在相关工作中，我们还发现了人类细胞中的主要限制，这些限制在进入后干扰HIV，但可以通过病毒核心突变来克服。这些研究可能为抗病毒治疗提供新的药物靶标。 HIV宿主细胞因子的鉴定还将使细胞培养和动物模型的改善以研究HIV传播和复制。 [在2007年4月的艾滋病毒抗药性计划的现场访问报告中，对应于Kewalramani项目1]