Virus Transmission

病毒传播

基本信息

批准号：
10221480
负责人：
Pamela J Bjorkman
金额：
$ 50.2万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-27 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221480
关键词：
3-Dimensional AIDS/HIV problem Animal Model Animals Antiviral Therapy Architecture Area Biological Assay Bioluminescence CD4 Positive T Lymphocytes Cell fusion Cell membrane Cells Cellular Membrane Cellular biology Cessation of life Child Cryoelectron Microscopy Data Docking Electrons Elements Event Family Fluorescence Future HIV HIV Infections HIV-1 Health Human Image Imaging Techniques Immune In Vitro Individual Integral Membrane Protein Kinetics Knowledge Laser Scanning Microscopy Letters Light Lipids Mediating Micro Electron Diffraction Microscopy Molecular Conformation Monitor Mothers Moths Optics Pathogenesis Pathogenicity Plastic Embedding Positron-Emission Tomography Preventive vaccine Process Proteins Resolution SIV Serine Surface System T-Cell Depletion Testing Therapeutic Time Tissue Sample Tissues Tropism Vaccines Variant Vesicle Viral Viral Pathogenesis Viral Proteins Virion Virus Visualization X-Ray Crystallography antibody-dependent cell cytotoxicity antiretroviral therapy comparative electron crystallography electron tomography experimental study humanized mouse imaging approach improved in vivo inhibitor/antagonist member mouse model nef Protein pandemic disease particle receptor single-molecule FRET structural biology success trafficking transmission process two-photon viral transmission virology whole animal imaging

项目摘要

ABSTRACT The HIV/AIDS pandemic remains a global burden on human health.1 Although antiretroviral therapy (ART) reduces deaths from HIV infection, prophylactic vaccine(s) and a functional cure for the millions infected are lacking.2 Success in these areas will require improved understanding of HIV transmission and dissemination and the mechanism of CD4 T cell depletion, which is the hallmark of immune deficiency.3 In addition, developing antiviral therapies and vaccines against HIV envelope (Env), the only viral protein on the surface of the HIV virion4,5, requires understanding its conformational dynamics and how it is activated for virus–host cell fusion. We propose to fill these knowledge gaps through imaging experiments that will: 1) Visualize the dissemination of HIV-1 following transmission in humanized mouse models and non-human primates6-9, 2) Determine the cause of CD4 depletion and visualize cellular events underlying viral restriction, 3) Delineate how the HIV Env trimer is activated for fusion10,11, and 4) Define how Env is inhibited by host cell restriction proteins of the SERINC family.12-14 This approach will reveal bottlenecks in virus dissemination, mechanisms of restriction, and vulnerabilities in activating HIV Env that can be exploited therapeutically.

抽象的艾滋病毒/艾滋病的流行仍然是人类健康的全球负担。1 尽管抗逆转录病毒治疗 (ART) 艾滋病毒感染导致的死亡人数减少，预防性疫苗和对数百万感染者的功能性治疗正在取得进展 2 这些领域的成功需要更好地了解艾滋病毒的传播和传播以及 CD4 T 细胞耗竭的机制，这是免疫缺陷的标志。3 此外，开发针对 HIV 包膜 (Env) 的抗病毒疗法和疫苗，HIV 包膜是人体表面唯一的病毒蛋白 HIV病毒体4、5需要了解其构象动力学以及它如何被病毒-宿主细胞激活我们建议通过成像实验来填补这些知识空白，这些实验将：1）可视化。 HIV-1 在人源化小鼠模型和非人类灵长类动物中传播后的传播6-9, 2) 确定 CD4 耗竭的原因并可视化病毒限制下的细胞事件，3) 描绘 HIV Env 三聚体如何被激活以进行融合10,11 和 4) 定义 Env 如何被宿主细胞限制所抑制 SERINC 家族的蛋白质。12-14 这种方法将揭示病毒传播的瓶颈、病毒传播的机制限制，以及激活 HIV 包膜的弱点，可用于治疗。