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）：疫苗有两个成分必不可少：“抗原”，通常是来自病原微生物的蛋白质；佐剂是向免疫系统发出的分子信号，表明抗原很重要并且应该防御。通常，针对流感等疾病的减毒活病毒疫苗利用病毒本身的免疫刺激性质来辅助免疫反应。然而，HIV病毒颗粒在感染后通常不会诱导树突状细胞活化。此外，该病毒还可以利用 Nef 等辅助蛋白主动抑制免疫反应。因此，HIV减毒活疫苗开发的一个挑战是找到一种能够诱导强烈免疫刺激且也可以在HIV基因组内编码的佐剂。佐剂的潜在来源是人类免疫系统本身。众所周知，人体和病毒病原体都会产生可以启动和放大人类免疫反应的佐剂分子。其中包括 CD40、GITR、OX40 以及利用 TRAF 细胞内信号通路激活免疫细胞的各种基因。然而，之前并不知道这些 TRAF 介导的受体分子必须聚集在一起。这种聚类可以通过“多聚体”配体人工诱导，其中许多三聚体配体分子连接在一起。该提案的主要目标是鉴定 TRAF 介导的细胞内信号系统，例如 CD40L/CD40，其具有诱导树突状细胞免疫激活的潜力。然后，该项目将在单周期 SIV 疫苗中编码这些基因，以增强 CD40 和其他 TRAF 介导的细胞内信号传导途径。假设这种免疫刺激性单周期 SIV 疫苗将导致体外树突状细胞许可和成熟的增加，并增强动物模型中的疫苗功效。公共健康相关性：该项目将开发新形式的免疫刺激减毒 SIV，可以显着提高实验性艾滋病疫苗的强度。这些研究的结果将确定是否可以使用哺乳动物免疫系统的关键成分或这些分子的病毒模拟物来增强HIV减毒疫苗。