Pittsburgh Center for HIV Protein Interactions (PCHPI)

匹兹堡 HIV 蛋白质相互作用中心 (PCHPI)

• 批准号: 10653242
• 负责人: ANGELA M. GRONENBORN
• 金额: $ 541.82万
• 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/10653242
• 关键词: Acceleration; 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-1; HIV/AIDS; 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; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Productivity; 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; Viral Reverse Transcription; Virion; Virus; Work; antiretroviral therapy; career; career development; chromatin protein; 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.

全面的 抗逆转录病毒治疗已将艾滋病毒/艾滋病变成一种慢性疾病，但耐药变异体的出现 长期 ART 后的合并症仍然令人担忧。因此，抑制感染的替代方法 并需要治愈艾滋病。拟议的“匹兹堡艾滋病毒蛋白质相互作用中心”（U54 PCHPI）非常适合 定位于成功寻找急需的 HIV-1 抑制替代靶标。 U54 PCHPI 是一个高度集成的协作项目，建立在已建立的富有成效的合作基础上。这 基础研究计划将重点关注 HIV-1 蛋白和蛋白核酸的结构特征 涉及感染三个方面的复合体：HIV-1组装和成熟、侵入和核进入，以及 一体化。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 专注于这些领域之一和四个科学核心（计算、冷冻电镜/电子断层扫描、核磁共振和病毒学） 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 成熟和变构整合酶抑制剂活性的基础，以促进机制理解 并寻求确定耐药性发展的路径。此外，我们将确定抑制艾滋病毒的新靶点 1 通过定义参与运输的衣壳-宿主蛋白/核酸复合物内的相互作用界面， 核进入和整合，特别关注天然预整合复合物（PIC）。我们还将 开发在接近天然条件下检查衣壳相互作用的工具（原位核磁共振波谱和 HIV-1 的单分子 CLEM）。此外，通过行政部门实施的强有力的管理计划 核心，将通过频繁和透明的沟通确保凝聚力，同时我们的使命是促进 研究职业发展将通过协作发展计划、指导计划、 以及研究人员嵌入计划以及发展核心的其他举措。完成后 我们的目标，我们希望能够以高分辨率确定和描述以前的几个目标 HIV-1蛋白复合物中的未知/未表征的相互作用界面，单独的和与抑制剂的相互作用， HIV-1 RNA 和蛋白质，以及 PIC 成分，包括逆转录病毒嵌体与宿主的相互作用 染色质。对此类界面的详细了解将有助于抑制剂设计的结构引导改进 以及确定潜在的新抑制目标。