Immunostimulatory single cycle SIV Vaccines incorporating TRAF-mediated molecular

结合 TRAF 介导分子的免疫刺激单周期 SIV 疫苗

基本信息

批准号：
7495856
负责人：
Geoffrey William Stone
金额：
$ 22.95万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7495856
关键词：
AIDS Vaccines Adjuvant Animal Model Animals Antibody Formation Antigens Attenuated Biological Assay CD4 Positive T Lymphocytes CD40 Antigens CD80 gene California Case Study Cell surface Cells Charities Chemokine (C-C Motif) Ligand 4 Coculture Techniques Code Color Combined Vaccines DNA Vaccines Data Dendritic Cells Dendritic cell activation Development Disease Drug Formulations Evaluation Excision Funding Future Genes Genome Goals Government Guidelines HIV HIV vaccine Human Human body I-antigen IL8 gene Immune Immune response Immune system Immunity Immunization Immunologic Markers Immunosuppressive Agents In Vitro Infection Influenza Intellectual Property Interleukin-6 Internal Ribosome Entry Site Investments LMP1 Legal patent Licensing Life Ligands Link Macaca Macaca mulatta Macrophage Activation Measures Mediating Memory Methodology Methods Microbe Modeling Molecular Mus Mutagenesis Mutate Nature Numbers Pathology Pathway interactions Peripheral Blood Mononuclear Cell Persons Phase Population Preparation Primates Private Sector Process Production Property Proteins Public Health Purpose Range Research SIV SIV Vaccines Safety Signal Pathway Signal Transduction Signaling Molecule Single Parent Solutions Source Staining method Stains System T-Lymphocyte TNF gene TNFRSF5 gene TNFSF5 gene Technology Testing United States National Institutes of Health Universities Up-Regulation Vaccinated Vaccination Vaccine Adjuvant Vaccine Antigen Vaccines Viral Viral Genome Viral Load result Viral Proteins Viral Vaccines Viral Vector Virion Virus Virus Diseases Week abstracting base chemokine concept cytokine design efficacy evaluation enzyme linked immunospot assay human study improved in vivo interest macrophage monocyte mouse model nef Genes novel novel vaccines particle pathogen pre-clinical prevent receptor reconstitution research study response vaccine development vaccine efficacy vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): Two components are essential for a vaccine: an "antigen," which is typically a protein from a pathogenic microbe; and an adjuvant, which is a molecular signal to the immune system that the antigen is important and should be defended against. Typically, live attenuated viral vaccines for diseases such as influenza utilize the immunostimulatory nature of the virus itself to adjuvant the immune response. However, HIV virions typically do not induce dendritic cell activation following infection. In addition, the virus can actively suppress the immune response with accessory proteins such as Nef. Therefore, a challenge for live attenuated HIV vaccine development is to find an adjuvant capable of inducing strong immune stimulation that can also be encoded within the HIV genome. A potential source of adjuvant is the human immune system itself. Both the human body and viral pathogens are known to produce adjuvant molecules that can initiate and amplify human immune responses. These include CD40, GITR, OX40 and various genes that utilize the TRAF intracellular signaling pathway to activate immune cells. However, it was not previously known that these TRAF-mediated receptor molecules must be clustered. Such clustering can be artificially induced via a "multimeric" ligand where many trimeric ligand molecules are linked together. The main goal of this proposal is to identify TRAF-mediated intracellular signaling systems such as CD40L/CD40 that have the potential to induce dendritic cell immune activation. The project will then encode these genes within a single cycle SIV vaccine to enhance CD40 and other TRAF-mediated intracellular signaling pathways. The hypothesis is that this immunostimulatory single cycle SIV vaccine will result in increased dendritic cell licensing and maturation in vitro, and enhanced vaccine efficacy in animal models. PUBLIC HEALTH RELEVANCE: This project will develop new forms of immune-stimulating attenuated SIV that could significantly improve the strength of experimental AIDS vaccines. The result of these studies will establish whether attenuated HIV vaccines can be boosted using key components of the mammalian immune system or viral mimics of these molecules.

描述（由申请人提供）：两个组成部分对于疫苗至关重要：一种“抗原”，通常是病原微生物的蛋白质；辅助物是对免疫系统的分子信号，抗原很重要，应防止。通常，诸如流感疾病的疾病的活体病毒疫苗利用病毒本身的免疫刺激性来辅助免疫反应。但是，HIV病毒体通常不会在感染后诱导树突状细胞激活。此外，该病毒可以用NEF等辅助蛋白积极抑制免疫反应。因此，对活减弱的HIV疫苗发育的挑战是找到能够诱导强大免疫刺激的辅助物，也可以在HIV基因组中进行编码。佐剂的潜在来源是人类免疫系统本身。已知人体和病毒病原体都会产生可以引发和扩增人免疫反应的辅助分子。其中包括使用TRAF细胞内信号通路激活免疫细胞的CD40，GITR，OX40和各种基因。但是，以前尚不清楚这些TRAF介导的受体分子必须聚集。这种聚类可以通过“多聚体”配体人为诱导，其中许多三聚体配体分子被链接在一起。该建议的主要目的是鉴定有可能诱导树突状细胞免疫激活的TRAF介导的细胞内信号传导系统，例如CD40L/CD40。然后，该项目将在单个循环SIV疫苗中编码这些基因，以增强CD40和其他TRAF介导的细胞内信号通路。假设是，这种免疫刺激单周期SIV疫苗将导致树突状细胞许可和体外成熟，并在动物模型中提高疫苗功效。公共卫生相关性：该项目将开发新形式的免疫刺激性衰减SIV，可以显着提高实验艾滋病疫苗的强度。这些研究的结果将确定使用哺乳动物免疫系统的关键成分还是这些分子的病毒模拟物可以增强HIV疫苗。