HARC: HIV accessory and regulatory complexes

HARC：HIV 附件和调节复合体

• 批准号: 10506980
• 负责人: Nevan J Krogan
• 金额: $ 574.01万
• 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/10506980
• 关键词: AIDS/HIV problem; 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; Heterochromatin; Human; Immune response; Infection; Institutes; Integration Host Factors; Interdisciplinary Study; Internships; Intervention; Knowledge; Leadership; Light; 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; diversity and equity; drug efficacy; experience; flexibility; genetic evolution; genetic regulatory protein; genome-wide; improved; innovation; latent infection; lectures; mRNA Export; macrophage; member; mutation screening; new technology; new therapeutic target; novel; novel therapeutic intervention; outreach; pathogen; preference; programs; protein complex; protein structure; screening; structural biology; symposium; therapeutic development; therapeutic target; training opportunity; transcription factor; treatment strategy; 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：艾滋病毒附件和调节复合物 总体汇总 HARC中心是一个跨学科的项目，旨在提高我们对相互作用的理解。 HIV辅助蛋白和调节蛋白与宿主细胞系统之间的关系，最终目标是扩大 艾滋病毒/艾滋病的治疗目标和治疗方式。HARC中心将集中精力 确定HIV-1的辅助蛋白和调节蛋白的结构，重点是达特、Vif和Rev， 与它们的细胞伙伴复合，直到现在还不是HIV治疗方式的目标。一 对病毒-宿主复合物的功能和机制的更好的分子理解可能揭示新的 干预的治疗策略，包括宿主导向疗法的策略，这可能会逃避 当前药物方案的局限性，其中靶向HIV酶的突变可能会降低药物功效。 HARC中心将使用一个集成的“系统-到-系统”来确定这些病毒-宿主复合物的结构。 结构”平台，包括（1）通过功能蛋白质组学和遗传学的新方法进行发现 HARC中心正在开发，（2）通过突破性CRISPR方法在原代T细胞中进行验证 以及靶向生物化学和功能测定，以及（3）使用合成的 创新的结构技术在HARC中心以前的迭代中开发， 灵活的，异质的，有时膜相关的系统，我们研究。 拟议的研究项目围绕着服务于中心目标的三个主题。我们将探讨 HIV如何抑制宿主限制性因子（主题1），研究HIV转录和潜伏期的调控因子 （主题2）和研究病毒宿主进化（主题3）通过三个项目：Vif的结构和进化 和APOBEC 3（项目1），HIV转录和潜伏期的调节（项目2），遗传学和 进化（项目3）。HARC中心的项目由4个技术核心支持，涵盖蛋白质组学 方法（核心1 -蛋白质组学），CRISPR筛选和原代细胞中的内源性标记来研究病毒- 宿主功能（核心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-宿主复合物结构的抗体技术（核心3 -结构生物学）， 和病毒-宿主复合物的综合建模（核心4 -计算）。总体目标、进展和 行政以及外展活动和沟通将由行政核心监督 (Core 5）。发展核心（核心6）将为年轻研究人员和HARC提供培训机会 中心成员和奖励合作机会基金，以提高中心的整体研究主题。