Retroviral Gag Trafficking, Env Incorporation, and Virus Assembly

逆转录病毒堵嘴贩运、Env 合并和病毒组装

• 批准号: 8349150
• 负责人: eric freed
• 金额: $ 53.78万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349150
• 关键词: ADP-Ribosylation Factors; Address; Binding; Cell membrane; Cells; Data; Destinations; Ear; Equine Infectious Anemia Virus; Feline Immunodeficiency Virus; Gagging; Glycoproteins; Goals; Golgi Apparatus; HIV Drug Resistance Program; HIV-1; Life; Lipids; Membrane; Movement; Phosphatidylinositols; Play; Proteins; Reporting; Role; Site; Site Visit; Subfamily lentivirinae; Synapses; Viral; Virion; Virus; Virus Assembly; Work; cell type; cellular imaging; interest; macrophage; trafficking; virological synapse

In most cell types, HIV-1 assembly occurs predominantly on the plasma membrane; however, the itinerary that the Gag precursor follows to reach its destination in the cell and the role that cellular factors play in Gag trafficking remain ill defined. We discovered that a lipid, the phosphoinositide PI(4,5)P2, serves an important function in directing Pr55Gag to the plasma membrane. We are actively engaged in studies that seek to elucidate further the cellular machinery involved in HIV-1 Gag trafficking. This effort builds upon our recent finding that the ADP ribosylation factors (Arfs) and the Golgi-localized, gamma-ear-containing, Arf-binding (GGA) proteins modulate Gag-membrane binding and virus release. Additional Gag partners have recently been identified. These studies, which focus primarily on HIV-1, are also being extended to the nonprimate lentiviruses equine infectious anemia virus (EIAV) and feline immunodeficiency virus (FIV). We recently reported live-cell imaging data demonstrating the movement of HIV-1 Gag to the cell-cell contact site (virological synapse) in infected macrophages; we are currently working to define both viral and cellular determinants that direct Gag to the macrophage synapse. We are also pursuing a long-term interest in the mechanism by which the viral envelope (Env) glycoproteins are incorporated into virus particles. The role of host cell factors in Env incorporation, which remains unresolved and controversial, is being addressed in ongoing studies. [Corresponds to Freed Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]

在大多数细胞类型中，HIV-1组装主要发生在质膜上;然而，Gag前体到达其在细胞中的目的地所遵循的路线以及细胞因子在Gag运输中所起的作用仍然不清楚。我们发现一种脂质，即磷酸肌醇PI（4，5）P2，在将Pr 55 Gag引导至质膜方面发挥着重要作用。我们正在积极参与研究，以进一步阐明参与HIV-1 Gag贩运的细胞机制。这项工作建立在我们最近的发现，ADP核糖基化因子（Arfs）和高尔基体定位，γ-耳，Arf结合（GGA）蛋白调节GAG膜结合和病毒释放。最近又确定了更多的Gag合作伙伴。这些研究主要集中在HIV-1，也正在扩展到非灵长类慢病毒、马传染性贫血病毒（EIAV）和猫免疫缺陷病毒（FIV）。我们最近报道了活细胞成像数据，证明了HIV-1 Gag在受感染的巨噬细胞中移动到细胞-细胞接触位点（病毒学突触）;我们目前正在努力定义将Gag引导到巨噬细胞突触的病毒和细胞决定因素。我们也在追求病毒包膜（Env）糖蛋白被纳入病毒颗粒的机制的长期利益。宿主细胞因子在Env掺入中的作用仍未得到解决和有争议，正在进行的研究中得到解决。 [对应于2007年4月艾滋病毒耐药性方案现场访问报告中的Freed项目1]