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: 10398171
• 负责人: Leslie J Parent
• 金额: $ 17.19万
• 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/10398171
• 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; Persons; 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.

摘要

项目成果

Liquid-liquid phase separation of nucleocapsid proteins during SARS-CoV-2 and HIV-1 replication.

• DOI: 10.1016/j.celrep.2022.111968
• 发表时间: 2023-01-31
• 期刊: Cell reports
• 影响因子: 8.8

Virus induced membraneless organelles and biomolecular condensates.

• DOI: 10.1016/j.jmb.2023.168213
• 发表时间: 2023-07
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: A. Mouland;L. Parent;Stephane C. Weber;A. Holehouse