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.

整体 抗逆转录病毒疗法已将艾滋病毒/艾滋病转变为一种慢性疾病， 长期抗逆转录病毒治疗后的合并症仍然是一个问题。因此，抑制感染的替代方法 和治愈艾滋病是必要的。匹兹堡HIV蛋白质相互作用中心（U 54 PCHPI） 有能力成功地寻找急需的HIV-1抑制替代靶点。U54 PCHPI是一个高度集成的协作努力，建立在已建立的生产合作基础上。的 基础研究计划将集中在HIV-1蛋白和蛋白核酸的结构特征上 复合体涉及感染的三个方面：HIV-1组装和成熟，进入和核进入， 一体化将在三个项目中开展针对感染周期这些阶段的研究， 专注于这些领域之一，并在四个科学核心（计算，冷冻EM/ET，NMR和病毒学） 沿着行政和发展核心。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，以促进对机制的理解 并试图确定耐药性发展的途径。此外，我们将确定抑制HIV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， 核进入和融合，特别关注本土融合前复合体（PIC）。我们还将 开发用于在接近天然条件下检查衣壳相互作用的工具（原位NMR光谱和 用于HIV-1的单分子CLEM）。此外，还通过一个行政管理方案实施了一项强有力的管理计划， 我们的使命是促进和加强我们的合作， 研究职业发展将通过合作发展计划，指导计划， 和一个研究人员嵌入计划，以及发展核心的其他举措。完成后 我们的目标，我们希望已经确定和特点，在高分辨率，几个以前 HIV-1蛋白复合物中未知/未表征的相互作用界面，单独使用和与抑制剂一起使用， HIV-1 RNA和蛋白质，以及PIC组分内，包括逆转录病毒整合体与宿主的相互作用 染色质对这些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 以及识别潜在的新抑制靶点。