HIV-1 Preintegration Trafficking and Nuclear Localization

HIV-1 融入社会前贩运和核定位

• 批准号: 8431330
• 负责人: Alan N. Engelman
• 金额: $ 41.13万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431330
• 关键词: AIDS/HIV problem; Affect; Antiviral Agents; Applications Grants; Biochemical Genetics; CCR5 gene; Capsid; Cell Nucleus; Cells; Chemokine (C-C Motif) Receptor 5; Chromosomes; Complex; Conflict (Psychology); Cytoplasm; DNA Integration; Data; Dependency; Development; Drug Targeting; Drug resistance; Enzymes; Feline Immunodeficiency Virus; Filament; Future; Genetic; Glycoproteins; Grant; HIV; HIV Envelope Protein gp120; HIV-1; Highly Active Antiretroviral Therapy; Housing; Infection; Integrase; Integration Host Factors; Interphase Cell; Intervention; Karyopherins; Licensing; Link; Molecular; NUP98 gene; Nuclear; Nuclear Envelope; Nuclear Import; Nuclear Inner Membrane; Nuclear Outer Membrane; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Peptide Hydrolases; Pharmaceutical Preparations; Play; Polyadenylation; Process; Proteins; RNA Interference; RNA-Directed DNA Polymerase; Research; Resistance; Role; Series; Source; Structure; Subfamily lentivirinae; Surface; Testing; Time; Toxic effect; Transcript; Viral; Viral Physiology; Viral Proteins; Virus; Virus-Cell Membrane Interaction; Work; cofactor; compliance behavior; drug development; follow-up; genome-wide; inhibitor/antagonist; mutant; novel; nucleocytoplasmic transport; success; trafficking; viral DNA; virology; virus genetics

DESCRIPTION (provided by applicant): Infection of a cell by HIV-1 proceeds through a series of steps, each of which defines a potential target for antiviral drug intervention. Current drugs target key viral activities catalyzed by the protease, reverse transcriptase, and integrase enzymes, but emergence of drug resistance calls for continual development of new drugs with novel modes of action. HIV-1 depends on interactions with numerous cellular proteins as it replicates and maraviroc, a drug that disrupts the interaction between the viral envelope glycoprotein and cellular surface CCR5 receptor, is an approved inhibitor of a virus-cell interaction that blocks the ability of the virus to enter the cell. Also crucial to HIV-1 replicatin is the ability for the preintegration complex intermediate that houses the integrase and reverse transcript to access the chromosomes inside the cell nucleus, where viral DNA integration takes place. Lentiviruses like HIV-1 use an energy-dependent process to transport their preintegration complexes through nuclear pore complexes that riddle the biphasic nuclear envelope, though the molecular mechanisms underlying HIV-1 nuclear transport are poorly understood. Work supported by this renewal grant application identified numerous cellular proteins as potential critical cofactors of HIV-1 replication and a significant number of these, including transportin-3, nucleoporin 153, and nucleoporin 358 were accordingly implicated in preintegration complex nuclear import due to their known functions within the cell. Subsequent work indeed confirmed this contention, though it remains unclear how these and other cellular and viral proteins precisely dictate HIV-1 preintegration complex nuclear import. Using numerous virology, biochemical, and genetic approaches, the work proposed herein will determine the mechanisms of HIV-1 nuclear import, focusing on novel protein interactions between the virus and host cellular components that are essential for the process. Such discoveries will define new targets for the development of inhibitors that block critical HIV-host interactions, which would be expected to increase the breadth of future antiviral armaments in the ongoing battle to control the spread of HIV/AIDS.

描述（由申请人提供）：HIV-1对细胞的感染通过一系列步骤进行，每个步骤都定义了抗病毒药物干预的潜在靶点。目前的药物靶向由蛋白酶、逆转录酶和整合酶催化的关键病毒活性，但耐药性的出现要求不断开发具有新作用模式的新药。HIV-1在复制时依赖于与许多细胞蛋白的相互作用，而马拉韦罗是一种破坏病毒包膜糖蛋白与细胞表面CCR 5受体之间相互作用的药物，是一种获批的病毒-细胞相互作用抑制剂，可阻断病毒进入细胞的能力。对于HIV-1复制同样重要是整合前复合物中间体的能力，该中间体容纳整合酶和逆转录物进入细胞核内的染色体，病毒DNA整合发生在细胞核内。慢病毒如HIV-1使用能量依赖性过程来通过核孔复合物运输其整合前复合物，所述核孔复合物使双相核被膜难以理解，尽管HIV-1核运输的分子机制知之甚少。这项更新资助申请支持的工作确定了许多细胞蛋白质作为HIV-1复制的潜在关键辅因子，其中大量蛋白质，包括转运蛋白-3， 因此，核孔蛋白153和核孔蛋白358由于其在细胞内的已知功能而与前整合复合物核输入有关。随后的工作确实证实了这一论点，但仍不清楚这些和其他细胞和病毒蛋白质如何精确地决定HIV-1整合前复合物的核输入。使用许多病毒学，生物化学和遗传学方法，本文提出的工作将确定HIV-1核输入的机制，重点是病毒和宿主细胞成分之间的新蛋白质相互作用，这是该过程所必需的。这些发现将为开发阻断关键的艾滋病毒-宿主相互作用的抑制剂确定新的靶点，这将有望在控制艾滋病毒/艾滋病传播的持续战斗中增加未来抗病毒武器的广度。