HARC: HIV accessory and regulatory complexes

HARC：HIV 附件和调节复合物

• 批准号: 10666644
• 负责人: Nevan J Krogan
• 金额: $ 660.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666644
• 关键词: APOCEC3G gene; Acquired Immunodeficiency Syndrome; Address; Antibodies; Award; Biochemical; Biological Assay; Biological Sciences; CD4 Positive T Lymphocytes; CRISPR screen; CRISPR/Cas technology; Carrier Proteins; Cell division; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Collaborations; Communication; Complex; Cryoelectron Microscopy; Data; Dependence; Development; Drug Targeting; Enabling Factors; Environment; Enzymes; Event; Evolution; Fostering; Funding Opportunities; Gene Expression; Genetic; Genetic Transcription; Goals; HIV; HIV-1; HIV/AIDS; Heterochromatin; Human; Immune response; Infection; Integration Host Factors; Interdisciplinary Study; Internships; Intervention; Knowledge; Leadership; Macrophage; Membrane; Mentors; Mentorship; Messenger RNA; Methods; Modality; Modeling; Molecular; Mutation; NF-kappa B; Pathway interactions; Pharmaceutical Preparations; Point Mutation; Proteins; Proteomics; RNA Transport; Regimen; Regulation; Research; Research Personnel; Research Project Grants; Roentgen Rays; Role; Route; Scientist; Series; Site; Structure; System; Systems Biology; T-Lymphocyte; Techniques; Technology; Therapeutic; Training; Validation; Viral; Viral Genes; Viral Proteins; Virus; Virus Replication; antagonist; arms race; career; career development; data integration; drug efficacy; equity, diversity, and inclusion; experience; flexibility; genetic regulatory protein; genome-wide; improved; innovation; latent infection; lectures; mRNA Export; member; mutation screening; new technology; new therapeutic target; novel; novel therapeutic intervention; outreach; pathogen; preference; programs; protein complex; protein structure; screening; structural biology; structural determinants; symposium; therapeutic development; therapeutic target; training opportunity; transcription factor; vif Gene Products

THE HARC CENTER: HIV ACCESSORY AND REGULATORY COMPLEXES OVERALL SUMMARY The HARC Center is an interdisciplinary program that aims to improve our understanding of the interactions between HIV accessory and regulatory proteins and host cellular systems, with the ultimate goal to expand on therapeutic targets and treatment modalities for HIV/AIDS. The HARC Center will focus its efforts on the determination of structures of the accessory and regulatory proteins of HIV-1, with a focus on Tat, Vif and Rev, in complex with their cellular partners, which have not been targets of HIV therapeutic modalities until now. A better molecular understanding of the functions and mechanisms of virus-host complexes may reveal new therapeutic strategies for intervention, including strategies of host-directed therapies, which may escape the limitations of current drug regimens where mutations in the targeted HIV enzymes can diminish drug efficacy. The HARC Center will determine the structures of these virus-host complexes using an integrated “Systems-to- Structure” platform that includes (1) Discovery, through novel methods of functional proteomics and genetics being developed in the HARC Center, (2) Validation through breakthrough CRISPR methods in primary T cells as well as targeted biochemical and functional assays, and (3) Structure Determination using a synthesis of innovative structural techniques developed in previous iterations of the HARC Center to address the large, flexible, heterogeneous and sometimes membrane-associated systems we study. The proposed Research Projects are centered around three themes that serve the Center’s goal. We will explore how HIV inhibits Host restriction factors (Theme 1), study the factors regulating HIV transcription and latency (Theme 2) and investigate virus-host Evolution (Theme 3) across three projects: Structure and evolution of Vif and APOBEC3 (Project 1), Regulation of HIV transcription and latency (Project 2), and Genetics and evolution (Project 3). The HARC Center projects are supported by 4 technology cores covering proteomic approaches (Core 1 - Proteomics), CRISPR screens and endogenous tagging in primary cells to study virus- host function (Core 2 - Genetics), structural biology using cryo-Electron Microscopy, X-ray screening and antibody technologies to determine the structures of HIV virus-host complexes (Core 3 - Structural Biology), and integrative modeling of virus-host complexes (Core 4 - Computational). The overall goals, progress, and administration as well as outreach activities and communications will be overseen by the Administrative Core (Core 5). The Developmental Core (Core 6) will provide training opportunities to young investigators and HARC Center members and award the Collaborative Opportunity Fund to enhance the Center’s overall research theme.

HARC中心：HIV配件和监管综合体 总结 HARC中心是一个跨学科计划，旨在提高我们对互动的理解 在HIV配件和调节蛋白和宿主细胞系统之间，其最终目标是扩展 艾滋病毒/艾滋病的治疗靶标和治疗方式。 HARC中心将重点放在 确定HIV-1附件和调节蛋白的结构，重点是TAT，VIF和REV， 与他们的细胞伴侣复杂，到目前为止，这还不是HIV治疗方式的靶标。一个 更好地分子理解病毒宿主复合物的功能和机制可能揭示了新的 干预的治疗策略，包括宿主指导疗法的策略，这可能逃脱 目前的药物方案的局限性在靶向HIV酶中的突变会降低药物效率。 HARC中心将使用综合的“系统到 - 结构”平台，包括（1）通过功能蛋白质组学和遗传学的新方法发现的结构平台 在HARC中心开发，（2）通过主要T细胞中的突破性CRISPR方法验证 以及有针对性的生化和功能测定，以及（3）结构确定 在HARC中心以前的迭代中开发了创新的结构技术，以解决大型， 我们研究的灵活，异质，有时是与膜相关的系统。 拟议的研究项目集中在三个为中心目标的主题围绕。我们将探索 HIV如何抑制宿主限制因素（主题1），研究调节艾滋病毒转录和潜伏期的因素 （主题2）并研究三个项目的病毒宿主进化（主题3）：VIF的结构和演变 和APOBEC3（项目1），HIV转录和潜伏期的调节（项目2）以及遗传学以及 进化（项目3）。 HARC中心项目得到了覆盖蛋白质组学的4个技术核心的支持 方法（核1-蛋白质组学），crispr筛选和原代细胞中的内源性标记，以研究病毒 - 宿主功能（核2-遗传学），使用冷冻电子显微镜的结构生物学，X射线筛选和 确定HIV病毒宿主复合物（核心3-结构生物学）的结构的抗体技术， 和病毒宿主复合物的集成建模（核心4-计算）。总体目标，进度和 行政和宣传活动和沟通将由行政核心监督 （核心5）。发展核心（核心6）将为年轻的调查人员和HARC提供培训机会 中心成员并授予协作机会基金，以增强中心的整体研究主题。