Role of biomolecular condensates in regulating HIV-1 viral ribonucleoprotein complex formation in the setting of substance use disorder

物质使用障碍中生物分子缩合物在调节 HIV-1 病毒核糖核蛋白复合物形成中的作用

• 批准号: 10228358
• 负责人: Leslie J Parent
• 金额: $ 18.84万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228358
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Binding; Biochemical; Biogenesis; Biological; Biology; Biophysics; Cell Nucleus; Cells; Cessation of life; Clinic; Complex; Coupling; Data; Disease; Dissociation; Drug Targeting; Drug resistance; Gene Expression; Genetic; Genetic Determinism; Genetic Transcription; Genome; Goals; HIV; HIV-1; Health; Hela Cells; Immunologic Deficiency Syndromes; In Vitro; Incidence; Infection; Integration Host Factors; Intervention; Knowledge; Lead; Light; Liquid substance; Methods; Molecular; Nuclear; Nuclear Export; Pathway interactions; Pharmacology; Phase; Phase Transition; Physical condensation; Play; Positive Transcriptional Elongation Factor B; Process; Production; Property; Proteins; Proteomics; Proviruses; Publishing; RNA; RNA Processing; RNA chemical synthesis; Regulation; Research Project Grants; Retrovirology; Ribonucleoproteins; Role; Scientist; Site; Structure; Substance Use Disorder; T-Lymphocyte; Testing; Viral; Virion; Virus; Virus Latency; Virus Replication; Virus-Cell Membrane Interaction; Work; antiretroviral therapy; base; biophysical properties; combat; drug of abuse; drug resistant virus; follow-up; gag Gene Products; genomic RNA; in vitro Assay; innovation; knock-down; live cell imaging; new therapeutic target; novel; pandemic disease; reactivation from latency; therapeutic development; transcription factor; treatment strategy; viral RNA

Abstract HIV-1/AIDS is a devastating immunodeficiency disease that has resulted in over 35 million deaths across the globe. There is a compelling ongoing need to develop novel treatment strategies to combat the continuing emergence of drug-resistant viral strains. A drug target that has not yet been successfully brought to the clinic is the interaction of the Gag protein with its RNA genome to form the viral ribonucleoprotein complex, which initiates the process of virion assembly. A deeper understanding of the biochemical and biophysical interactions that drive viral ribonucleoprotein complex formation is needed to advance further therapeutic development. Based on recent findings that viral ribonucleoprotein complexes undergo liquid-liquid phase separation to form biomolecular condensates, this proposal explores the molecular underpinnings of Gag-viral RNA interactions. We have assembled an accomplished interdisciplinary team of scientists to work at the crossroads of retrovirology, RNA biology, biophysics, and pharmacology to shed light on our understanding of viral and cellular biomolecular condensates in HIV-1 infection. Our preliminary results suggesting that HIV-1 ribonucleoprotein complexes form in the nucleus inspired this provocative proposal to investigate the interplay of virus replication machinery with nuclear bodies that form biomolecular condensates. In the R21 phase, we will use innovative methods involving biophysics, genetics, state-of-the-art live cell imaging, and targeted pharmacological interventions to examine whether HIV-1 ribonucleoprotein complexes assemble into biomolecular condensates in the nucleus. In the R33 phase, we will extend these studies to probe mechanistic questions focusing on whether nuclear BMCs play critical roles in regulating HIV-1 transcription, latency reactivation, and genomic RNA packaging. Due to the high incidence of substance use disorder in people with HIV-1/AIDS, we will also investigate whether drugs of abuse influence HIV-1 nuclear biomolecular condensates. Elucidating the genetic determinants of HIV-1 condensate formation could lead to the identification of novel drug targets to treat HIV/AIDS.

抽象的 HIV-1/AIDS是一种毁灭性的免疫缺陷疾病，导致超过3500万人死亡 在全球。迫切需要制定新颖的治疗策略来对抗 持续耐药病毒菌株的持续出现。尚未成功带入的药物目标 该诊所是GAG蛋白与其RNA基因组的相互作用，形成病毒核糖核蛋白复合物， 这启动了病毒体组件的过程。对生化和生物物理的更深入了解 需要驱动病毒核糖核蛋白复合物形成的相互作用以进一步进一步治疗 发展。根据最近的发现，病毒核糖核蛋白复合物经历了液态液相 分离形成生物分子冷凝物，该提案探讨了GAG病毒的分子基础 RNA相互作用。我们已经组建了一支成熟的科学家跨学科团队，以在 逆转录病毒学，RNA生物学，生物物理学和药理学的十字路口，以阐明我们对 HIV-1感染中的病毒和细胞生物分子冷凝物。 我们的初步结果表明，在核中启发的核中形成了HIV-1核糖核蛋白复合物 这项挑衅性的提议，调查病毒复制机制与核体的相互作用 形成生物分子冷凝物。在R21阶段，我们将使用涉及生物物理学的创新方法， 遗传学，最先进的活细胞成像和有针对性的药理学干预措施，以检查是否是否 HIV-1核糖核蛋白复合物组装成核中的生物分子冷凝物。在R33阶段， 我们将把这些研究扩展到探究机械问题，重点是核BMC是否发挥着重要作用 在调节HIV-1转录，潜伏期重新激活和基因组RNA包装方面的作用。由于高 HIV-1/AIDS患者的药物使用障碍的发病率，我们还将调查药物是否存在 滥用会影响HIV-1核生物分子冷凝物。阐明HIV-1的遗传决定因素 凝结物的形成可能导致鉴定出新的药物靶标以治疗艾滋病毒/艾滋病。