Behavior of HIV in Viral Environments (B-HIVE)

HIV 在病毒环境中的行为 (B-HIVE)

• 批准号: 10508443
• 负责人: Stefan G Sarafianos
• 金额: $ 628.9万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10508443
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Behavior; Binding Sites; Biological; Biophysics; Capsid; Cell Communication; Cell Nucleus; Cells; Characteristics; Chemicals; Collaborations; Communication; Computational Biology; Cytoplasm; Disease; Education and Outreach; Environment; Evolution; Funding; Genetic Transcription; Genome; Goals; HIV; HIV Integrase; HIV-1; Human Resources; Infection; Infrastructure; Integration Host Factors; Joints; Leadership; Mentors; Modeling; Molecular; Nuclear; Nuclear Accidents; Nucleic Acids; Nucleosome Core Particle; Pathogenesis; Positioning Attribute; Production; Proteins; Publications; RNA; RNA-Directed DNA Polymerase; Research; Research Personnel; Role; Scientific Advances and Accomplishments; Shapes; Site; Synthesis Chemistry; Testing; Time; United States National Institutes of Health; Universities; Viral; Viral Packaging; Virus; Virus Replication; Washington; experience; gene product; inhibitor; insight; integration site; member; next generation; novel; novel therapeutic intervention; organizational structure; particle; programs; protein complex; small molecule; small molecule inhibitor; success; trafficking; viral RNA; virology

ABSTRACT, OVERVIEW The Behavior of HIV In Viral Environments (B-HIVE) Center has been formed to further the understanding of HIV-1 and HIV-1/cellular host factor macromolecular interactions within distinct cellular environments, which shape the HIV replication cycle. With the limited size of HIV’s RNA genome, it is no surprise that many of the same gene products end up performing different functions in different cellular environments at different times during replication. These various HIV-1-cell host factor interactions promote the cellular pathogenesis, and ultimately disease, characteristic of HIV-1/AIDS. All members have joined the B-HIVE Center with the common goal to collaboratively investigate the dynamic HIV-1 and HIV-1/cellular host factor macromolecular interactions within distinct cellular environments that occur during infection. The B-HIVE Center will capitalize on well- established collaborations between top HIV researchers and scientific accomplishments that provide the rationale to ask new and challenging questions and will be informed by the former HIVE Center (HIV Interaction and Viral Evolution), an organizational structure proven to be effective at not only HIV-1 research, but also by exemplary communication to training, and outreach activities. The B-HIVE team of highly collaborative investigators includes well-established experts in structural, biophysical, chemical, and computational biology, virology, and synthetic chemistry. Only as a Center do the researchers have the necessary combined expertise and critical mass to effectively study the dynamic and mechanistic implications of macromolecular interactions of HIV and cellular host factors within distinct cellular environments. The overall aims of the B-HIVE are organized around three complementary Projects that focus on specific stages of the viral replication cycle: Project 1. Dynamic HIV-1 core interactions with host factors and inhibitors from cytoplasm to nucleus. Aim 1. To discover and characterize novel, dynamic interactions between HIV-1 CA and host cell during virus ingress. Aim 2. To characterize interactions of novel small molecule inhibitors with distinct sites on HIV-1 CA. Project 2. Structural dynamics of HIV-1 nuclear trafficking, integration, and transition to transcription. Aim1. Elucidate dynamic HIV-1 core-host cell interactions crucial for nuclear trafficking, uncoating, and integration. Aim 2. Define the structural and dynamic nuclear events underlying HIV-1 integration site selection. Aim 3. Determine the interplay between integration site and transcriptional latency. Project 3. The dynamics of HIV-1 packaging and assembly. Aim 1. Study the mechanism of HIV-1 RNA genome packaging and the proteins complexed with HIV-1 RNA. Aim 2. Probe the cellular dynamics of the interactions between HIV-1 Gag and identified cellular factors that alter HIV-1 production. Aim 3. Elucidate the dynamics of model Gag assembly and particle formation.

摘要，概述 艾滋病毒在病毒环境中的行为（B-HIVE）中心已经成立，以进一步了解 HIV-1和HIV-1/细胞宿主因子在不同细胞环境中的大分子相互作用， 塑造艾滋病毒复制周期。由于艾滋病毒RNA基因组的大小有限，因此许多艾滋病毒感染者 相同的基因产物在不同的细胞环境中在不同的时间发挥不同的功能 在复制过程中。这些不同的HIV-1-细胞宿主因子相互作用促进细胞发病机制， 最终是以HIV-1/艾滋病为特征的疾病。所有成员都加入了B-HIVE中心， 目的是合作研究动态HIV-1和HIV-1/细胞宿主因子大分子相互作用 在感染期间发生的不同细胞环境中。B-HIVE中心将充分利用- 在顶尖的艾滋病毒研究人员和科学成就之间建立了合作， 提出新的和具有挑战性的问题的理由，并将由前HIVE中心（艾滋病毒互动 和病毒进化），这一组织结构被证明不仅在HIV-1研究方面有效，而且 示范性沟通到培训和外联活动。B-HIVE团队高度协作 研究人员包括结构，生物物理，化学和计算生物学方面的知名专家， 病毒学和合成化学。只有作为一个中心，研究人员才具备必要的综合专业知识 和临界质量，以有效地研究大分子相互作用的动态和机械影响 HIV和细胞宿主因子在不同的细胞环境中的相互作用。B-HIVE的总体目标是 围绕三个互补的项目，重点放在病毒复制周期的特定阶段： 项目1。HIV-1核心与宿主因子和抑制剂从细胞质到细胞核的动态相互作用。 目标1.发现和表征HIV-1 CA与宿主细胞在病毒感染过程中的新型动态相互作用， 入口。目标2.表征新型小分子抑制剂与HIV-1 CA上不同位点的相互作用。 项目2. HIV-1核运输，整合和转录过渡的结构动力学。 目标1.阐明动态HIV-1核心-宿主细胞相互作用对核运输、脱壳和 一体化目标二。定义HIV-1整合位点选择的结构和动态核事件。 目标3.确定整合位点和转录潜伏期之间的相互作用。 项目3。HIV-1包装和组装的动力学。 目标1.研究HIV-1 RNA基因组包装的机制及与HIV-1 RNA复合的蛋白质。 目标二。探索HIV-1 Gag与已鉴定的细胞因子之间相互作用的细胞动力学， 改变HIV-1的产生。目标3.阐明模型Gag组装和颗粒形成的动力学。