Innate immunity to adenovirus vectors

对腺病毒载体的先天免疫

• 批准号: 7210742
• 负责人: Dmitry Shayakhmetov
• 金额: $ 28.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210742
• 关键词: Ablation; Acute; Adenovirus Infections; Adenovirus Vector; Adenoviruses; Affect; Animals; Anthrax disease; Antiviral Agents; Binding; Biodistribution; Biological Process; Blood; Capsid; Cell Communication; Cell surface; Cells; Clathrin; Clinical Trials; Complement component C4; Coxsackie Viruses; Coxsackievirus Infections; Cytokine Gene; Cytoplasmic Tail; Data; Development; Endopeptidases; Endosomes; Endothelial Cells; Evaluation; Facility Construction Funding Category; Factor IX; Fatal Outcome; Fiber; Gene Transfer; Genetic Transcription; Goals; Hematopoietic; Hepatic; Hepatocyte; Host Defense Mechanism; Human; Immune; Immune response; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Integrins; Intravenous; Kinetics; Knock-out; Knockout Mice; Knowledge; Kupffer Cells; Lead; Life; Ligand Binding; Liver; Liver Circulation; Low Density Lipoprotein Receptor; Mediating; Mediator of activation protein; Melanoma Cell; Modification; Molecular; Mus; Mutate; Natural Immunity; Organ; Pathway interactions; Peptide Hydrolases; Peptides; Point Mutation; Process; Protein Binding; Proteins; Range; Relative (related person); Role; Satellite Viruses; Signal Transduction; Site; System; Testing; Therapeutic; Tissues; Toxic effect; Tropism; Vaccination; Viral; Virus; Virus Diseases; Virus Receptors; Virus-Cell Membrane Interaction; adenovirus receptor; apolipoprotein B-100; base; cell type; coated pit; complement 4b-binding protein; design; gene therapy; heparin proteoglycan; human disease; improved; in vivo; insight; interest; mouse model; mutant; novel; novel strategies; pathogen; penton base; receptor; receptor binding; response; retinal rods; vector

DESCRIPTION (provided by applicant): This proposal seeks to identify the exact step(s) of adenovirus (Ad) infection that is (are) responsible for the initiation of an anti-Ad acute inflammatory response upon systemic virus application. Over the last two decades numerous Ad-based vectors have been developed for gene therapy applications and many are currently being tested in clinical trials. Most recently, interest in Ad has further expanded due to its potential as a vector for vaccination against life threatening infectious agents such as anthrax. While natural infections with Ad are largely harmless to humans, intravenous Ad administration may result in a severe inflammatory response, which can lead to fatal outcomes. It is currently recognized that the initiation of this acute systemic inflammation depends on interactions of the Ad capsid with host cells. Despite significant knowledge regarding Ad interactions with cells in vitro, the molecular mechanisms governing Ad bio-distribution, hepatic tropism and toxicity in vivo remain poorly understood. Recently, we identified a novel blood factor-dependent pathway of Ad liver cell infection in vivo. This finding explained the observed Ad biodistribution in animals after systemic application and is fundamental for the development of novel strategies to modify both Ad tropism in vivo and virus-associated toxicity. In mouse models, we will analyze the innate immune response to intravenously applied capsid-modified Ad mutants deficient in their ability to undergo the initial steps of virus infection. Our specific aims are to analyze the role of Ad interactions 1) with primary attachment receptors; 2) with integrins, which facilitate Ad initialization; or 3) with cellular factors upon virus escape from endosomes, in the initiation of an anti-Ad inflammatory response. Based on the data obtained, in our fourth specific aim we will construct ah Ad vector ablated for binding to known virus receptors and capable of infecting cells via an alternative receptor, LDLR. By applying this vector in mice and evaluating its toxicity we will test the hypothesis that modification of the Ad capsid represents a feasible approach to reduce acute Ad-mediated inflammation while preserving virus gene transfer ability upon systemic application. These studies will significantly improve our understanding of fundamental mechanisms of the host defense against viral pathogens and may ultimately lead to the development of safe and efficient Ad vectors for the therapy of a wide range of inborn and acquired human diseases.

描述（由申请人提供）：该提案旨在确定腺病毒（Ad）感染的确切步骤，该步骤负责在全身病毒应用后引发抗Ad急性炎症反应。在过去的二十年中，已经开发了许多基于 Ad 的载体用于基因治疗应用，并且许多目前正在临床试验中进行测试。最近，人们对 Ad 的兴趣进一步扩大，因为它有可能作为针对危及生命的传染病（例如炭疽）的疫苗接种载体。虽然自然感染 Ad 基本上对人类无害，但静脉注射 Ad 可能会导致严重的炎症反应，从而导致致命的结果。目前认识到这种急性全身炎症的引发取决于Ad衣壳与宿主细胞的相互作用。尽管人们对 Ad 与细胞的体外相互作用有了丰富的了解，但控制 Ad 生物分布、肝向性和体内毒性的分子机制仍然知之甚少。最近，我们发现了一种新的体内 Ad 肝细胞感染的血液因子依赖性途径。这一发现解释了系统应用后在动物体内观察到的 Ad 生物分布，并且对于开发改变 Ad 体内向性和病毒相关毒性的新策略至关重要。在小鼠模型中，我们将分析对静脉注射衣壳修饰的 Ad 突变体的先天免疫反应，这些突变体缺乏进行病毒感染初始步骤的能力。我们的具体目标是分析 Ad 相互作用的作用：1) 与主要附着受体； 2) 具有整合素，有利于Ad初始化；或3)在病毒从内体逃逸时与细胞因子一起启动抗Ad炎症反应。根据获得的数据，在我们的第四个具体目标中，我们将构建被消融的 Ad 载体，用于与已知病毒受体结合，并能够通过替代受体 LDLR 感染细胞。通过在小鼠中应用该载体并评估其毒性，我们将测试这样的假设：Ad 衣壳的修饰代表了一种减少 Ad 介导的急性炎症的可行方法，同时在全身应用时保留病毒基因转移能力。这些研究将显着提高我们对宿主防御病毒病原体基本机制的理解，并可能最终开发出安全有效的Ad载体，用于治疗各种先天性和后天性人类疾病。