Pittsburgh Center for HIV Protein Interactions (PCHPI)

匹兹堡 HIV 蛋白质相互作用中心 (PCHPI)

• 批准号: 10506945
• 负责人: ANGELA M. GRONENBORN
• 金额: $ 496.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506945
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Area; Award; Binding; Capsid; Capsid Proteins; Cell Nucleus; Cell membrane; Cells; Chromatin; Chronic Disease; Collaborations; Communication; Complement; Complex; Computing Methodologies; Cryoelectron Microscopy; Cyclophilin A; Cytoplasmic Tail; Data; Dependence; Development; Drug Targeting; Drug resistance; Ensure; Fostering; Generations; Genome; Goals; HIV; HIV Infections; HIV-1; Immune Evasion; Immunologic Factors; In Situ; Individual; Infection; Institution; Integrase; Integrase Inhibitors; Integration Host Factors; Knowledge; Laboratories; Length; Mentors; Methodology; Methods; Microscopy; Mission; Modeling; Molecular; Molecular Conformation; NMR Spectroscopy; National Institute of Allergy and Infectious Disease; Nuclear; Nuclear Import; Nucleic Acids; Pathway interactions; Play; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Program Development; Proteins; Proviruses; Quality of life; RNA; Recombinants; Research; Research Personnel; Research Support; Resistance development; Resolution; Ribonucleoproteins; Role; Scientist; Structural Biologist; Structure; Technology; Time; Training; Variant; Viral; Viral Genome; Virion; Virus; Work; antiretroviral therapy; career; career development; chromatin protein; cohesion; comorbidity; design; expectation; experience; fundamental research; glycoprotein 41; graduate student; improved; inhibitor; insight; novel; programs; protein complex; single molecule; small molecule inhibitor; structural biology; tool; trafficking; virology; virus host interaction

OVERALL Antiretroviral therapy has turned HIV/AIDS into a chronic disease, yet the emergence of drug-resistant variants and comorbidities after long-term ART remain a concern. Therefore, alternative approaches to inhibit infection and cure AIDS are needed. The proposed “Pittsburgh Center for HIV Protein Interactions” (U54 PCHPI) is well- positioned to succeed in the search for the much-needed alternative targets for HIV-1 suppression. The U54 PCHPI is a highly integrated, collaborative effort, building on established productive collaborations. The fundamental research program will focus on structurally characterizing HIV-1 protein and protein-nucleic acid complexes involved in three aspects of infection: HIV-1 assembly and maturation, ingress and nuclear entry, and integration. Studies to address these stages of the infection cycle will be carried out in three projects, each focused on one of these areas, and in four scientific cores (Computational, Cryo-EM/ET, NMR and Virology) along with Administrative and Developmental cores. Importantly, our program will work to define the structural basis underlying maturation and allosteric integrase inhibitor activities to promote a mechanistic understanding and seeks to identify paths of resistance development. Further, we will identify new targets for inhibition of HIV- 1 by defining interaction interfaces within capsid-host protein/nucleic acid complexes involved in trafficking, nuclear entry, and integration, with a particular focus on native pre-integration complexes (PICs). We will also develop tools for examining capsid interactions under near-native conditions (in situ NMR spectroscopy and single-molecule CLEM for HIV-1). In addition, a robust management plan, implemented via an Administrative Core, will ensure a cohesive effort with frequent and transparent communications, while our mission to facilitate research career development will be enabled by a collaborative development program, a mentoring program, and a researcher embedding program, among other initiatives in the Developmental Core. Upon completion of our aims, we expect to have identified and characterized, at high resolution, several previously unknown/uncharacterized interaction interfaces in HIV-1 protein complexes, alone and with inhibitors, between HIV-1 RNA and proteins, and within PIC components, including retroviral intasome interactions with host chromatin. Detailed knowledge of such interfaces will enable structure-guided improvements in inhibitor design as well as identify potential new targets for inhibition.

总体来说 抗逆转录病毒疗法已使艾滋病毒/艾滋病成为一种慢性病，但出现了抗药性变种 长期接受艺术治疗后的合并症仍然是一个令人担忧的问题。因此，抑制感染的替代方法 和治愈艾滋病是必要的。建议的“匹兹堡艾滋病毒蛋白质相互作用中心”(U54 PCHPI)- 在寻找急需的抑制艾滋病毒-1的替代目标方面取得成功。U54 PCHPI是一项高度整合的协作努力，建立在已建立的富有成效的合作基础上。这个 基础研究计划将重点研究HIV-1蛋白质和蛋白质-核酸的结构特征 参与感染三个方面的复合体：HIV-1组装和成熟，进入和核进入，以及 整合。针对感染周期这些阶段的研究将在三个项目中进行，每个项目 侧重于其中一个领域，并在四个科学核心(计算、冷冻-EM/ET、核磁共振和病毒学)中 以及行政和发展核心。重要的是，我们的计划将致力于定义结构 基础成熟和变构整合酶抑制活性，以促进对机制的理解 并试图找出抗药性发展的路径。此外，我们会找出抑制爱滋病病毒的新目标- 1通过定义参与运输的衣壳-宿主蛋白/核酸复合体内的相互作用界面， 核进入和融合，特别侧重于本土融合前综合体(PIC)。我们还将 开发在近乎自然的条件下检查衣壳相互作用的工具(原位核磁共振波谱和 针对HIV-1的单分子Clem)。此外，通过行政部门实施的稳健的管理计划 核心，将确保以频繁和透明的沟通协调一致的努力，同时我们的使命是促进 研究职业发展将通过合作发展计划、指导计划、 以及研究人员嵌入计划，以及发展核心中的其他倡议。在完成后 我们的目标，我们希望已经以高分辨率确定和描述了之前的几个 HIV-1蛋白复合体中未知的/未描述的相互作用界面，单独和与抑制剂，之间 HIV-1RNA和蛋白质，以及PIC组分内，包括逆转录病毒与宿主的内涵体相互作用 染色质。对这类界面的详细了解将使抑制剂设计中的结构导向改进成为可能 以及确定潜在的新的抑制目标。