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 抗逆转录病毒疗法已将艾滋病毒/艾滋病变成慢性疾病，但抗药性变体的出现 长期艺术后的合并症仍然是一个关注的问题。因此，抑制感染的替代方法 并且需要治愈辅助工具。拟议的“匹兹堡HIV蛋白相互作用中心”（U54 PCHPI）是很好的 在寻找急需的HIV-1抑制替代目标方面的位置。 U54 PCHPI是一项高度集成，合作的努力，建立在既定的产品合作基础上。这 基本研究计划将重点介绍HIV-1蛋白和蛋白核酸的结构表征 涉及感染三个方面的复合物：HIV-1组装和成熟，入口和核进入，以及 一体化。解决感染周期的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，以及四个科学核心（计算，Cryo-EM/ET，NMR和病毒学） 以及行政和发展核​​心。重要的是，我们的计划将努力定义结构性 基础的基础成熟和变构集成酶抑制剂活性，以促进机械理解 并试图确定抵抗发展的途径。此外，我们将确定抑制HIV的新目标 1通过定义与运输相关的capsid-Host蛋白/核酸复合物中的相互作用界面， 核进入和整合，特别关注天然预一体化复合物（图片）。我们也会 开发用于检查近本条件下的衣壳相互作用的工具（原位NMR光谱和 HIV-1的单分子CLEM）。此外，通过行政管理实施的强大管理计划 核心，将通过经常透明的沟通来确保凝聚力的努力，而我们的使命是促进 研究职业发展将由协作发展计划启用，一个心理计划， 以及一个研究人员嵌入计划，以及发展核心中的其他举措。完成后 我们的目标，我们希望以高分辨率确定和表征以前的几个 HIV-1蛋白复合物中的未知/未表征相互作用界面，单独和与抑制剂之间 HIV-1 RNA和蛋白质，以及PIC成分内，包括逆转录病毒Intasome与宿主的相互作用 染色质。此类界面的详细知识将实现结构引导的抑制剂设计改进 以及确定潜在的抑制新目标。