Clustered receptor-signaling domains as novel HIV vaccine genetic adjuvants

聚集的受体信号传导域作为新型艾滋病毒疫苗遗传佐剂

基本信息

批准号：
8318026
负责人：
Geoffrey William Stone
金额：
$ 19.13万
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：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318026
关键词：
Adjuvant Agonist Antigen Presentation Antigens Avidity Calculi Cell surface Chemicals Chimera organism Chimeric Proteins Coculture Techniques Cytokine Activation DNA DNA Vaccines Data Dendritic Cells Dendritic cell activation Gagging Genes Genetic Goals HIV HIV Infections HIV vaccine HIV-1 Human Immune Immune response Immunity Immunology Immunotherapy In Vitro Individual Infection Interleukin-15 Knowledge LMP1 Laboratories Literature Mediating Methods Modeling Mus Outcome Parents Pattern Poly I-C Proteins Public Health Publishing Receptor Signaling Recombinant Proteins Research Signal Pathway Signal Transduction Surface T cell response T-Lymphocyte TLR2 gene TLR3 gene TLR4 gene TLR7 gene TNFRSF5 gene TRAF6 gene Technology Testing Transmembrane Domain Vaccinated Vaccination Vaccine Adjuvant Vaccine Antigen Vaccine Research Vaccines Vaccinia Vaccinium Viral Viral Load result Viral Proteins Viral Vector base cytokine enzyme linked immunospot assay experience gag Gene Products immune activation improved in vivo innovation macrophage monocyte mouse model novel prophylactic receptor response tumor vector vector vaccine viral DNA

项目摘要

DESCRIPTION (provided by applicant): Currently there are no HIV prophylactic vaccines available that are capable of either generating durable protection from infection or reducing viral load post-infection in humans. Many factors may be involved, including insufficient levels of dendritic cell (DC) 'danger' signals during presentation of antigen by the vaccine, and insufficient DC intracellular signaling induced by these 'danger' (adjuvant) molecules. There is also evidence that combinations of adjuvant signals, such as combinations of TLR agonists, can markedly increase the strength of the antigen-specific immune response. Certain TLR agonist combinations, such as mixtures of TLR2, TLR3, and TLR9 agonists, have been shown to synergistically increase both correlates of immunity and protection from viral challenge in mouse models. Other models have shown protection from tumor challenge with mixtures of TLR7 agonists and CD40 stimulation. This project will test a novel class of vaccine adjuvants composed of chimeric proteins that artificially induce constitutive TLR signaling. Importantly, these chimeric proteins can be encoded within DNA and viral vector vaccines, one of the limitations of TLR agonists. Just as significantly, these chimeric proteins will provide 'always on' costimulatory signals and cannot be downregulated at the level of the TLR receptor. These proteins are anticipated to be constitutively active in the transfected DC, leading to DC-mediated immune activation. Preliminary data will be presented that these chimeric proteins are potent immune activators in dendritic cells and macrophages. This activation leads to a Th1 cytokine response and can adjuvant antigen-specific T cell responses to HIV-1 Gag antigen. These chimeric proteins have never before been tested as HIV adjuvants, and present a novel and innovative class of HIV vaccine adjuvant. In addition, this proposal will explore using these chimeric proteins to replicate the synergy observed with combinations of TLR agonists, or combinations of TLR agonists and CD40 costimulation. Published data is presented supporting the hypothesis that combinations of TLR intracellular signaling are synergistic. It is proposed that combinations of our novel chimeric proteins can be used to generate gene-based TLR-like synergistic combinations. It is also proposed that these combinations can markedly enhance DNA and viral vector based HIV vaccines in vivo in a mouse vaccinia-gag challenge model. Overall, the project aims to improve the strength and efficacy of DNA and viral vector HIV vaccines through the use of these chimeric proteins. Combinations of these chimeric proteins, encoded within DNA and viral vectors, have the potential to replicate the adjuvant effect of TLR agonist combinations and generate a more effective anti-HIV immune response, an immune response with the potential to protect vaccinated individuals from HIV challenge or reduce viral setpoint after HIV infection.

描述（由申请人提供）：目前尚无可用的HIV预防疫苗，能够在人类感染后产生持久的感染或减少病毒载荷的保护。可能涉及许多因素，包括在疫苗呈现抗原期间的树突状细胞（DC）“危险”信号，以及这些“危险”（辅助）分子引起的DC细胞内信号传导不足。也有证据表明，辅助信号的组合，例如TLR激动剂的组合，可以显着提高抗原特异性免疫反应的强度。某些TLR激动剂组合，例如TLR2，TLR3和TLR9激动剂的混合物，已显示出在小鼠模型中协同提高免疫力和免受病毒攻击的保护性的相关性。其他模型显示，与TLR7激动剂和CD40刺激的混合物的肿瘤挑战有关。该项目将测试由嵌合蛋白人为诱导构型TLR信号传导组成的新型疫苗佐剂。重要的是，这些嵌合蛋白可以在DNA和病毒载体疫苗中编码，这是TLR激动剂的局限性之一。同样重要的是，这些嵌合蛋白将在TLR受体的水平上提供“始终在”共刺激信号上。预计这些蛋白质在转染的直流中具有组成性活性，从而导致DC介导的免疫激活。初步数据将显示这些嵌合蛋白是树突状细胞和巨噬细胞中有效的免疫活化剂。这种激活导致Th1细胞因子反应，并可以辅助抗原特异性T细胞对HIV-1 GAG抗原的反应。这些嵌合蛋白从未被用作HIV佐剂，并提出了一种新颖而创新的HIV疫苗辅助剂。此外，该建议将使用这些嵌合蛋白探索，以复制与TLR激动剂组合观察到的协同作用，或TLR激动剂和CD40 Costimulation的组合。介绍了公开的数据，支持了这样一个假设，即TLR细胞内信号传导的组合是协同作用。有人提出，我们的新型嵌合蛋白的组合可用于生成基于基因的TLR样协同组合。还提出，这些组合可以在小鼠疫苗 - GAG挑战模型中显着增强体内DNA和基于病毒载体的HIV疫苗。总体而言，该项目旨在通过使用这些嵌合蛋白来提高DNA和病毒载体HIV疫苗的强度和功效。这些嵌合蛋白的组合，编码在DNA和病毒载体中，具有复制TLR激动剂组合的辅助作用并产生更有效的抗HIV免疫反应的辅助作用，具有保护疫苗接种的个体的免疫反应，可保护接种疫苗的个体免受HIV侵害或减少HIV HIV感染后的病毒攻击点。