Immunization Strategies for Autologous HIV Immunotherapy

自体 HIV 免疫治疗的免疫策略

基本信息

批准号：
8223184
负责人：
Louis D Falo
金额：
$ 37.12万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2008-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223184
关键词：
Address Adjuvant Adoptive Transfer Animal Model Antigen-Presenting Cells Antigens Autoantigens Autologous Autologous Dendritic Cells Biological CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Cellular Immunity Cellular biology Chronic Clinical Research Clinical Trials Cutaneous DNA DNA Vaccines Data Dendritic Cell Vaccine Dendritic Cells Derivation procedure Development Drug Formulations Economics Effectiveness Engineering Failure Foundations Genetic Genetic Engineering HIV HIV Antigens HIV Infections HIV-1 Health Human Human Development Immune Immune response Immunity Immunization Immunologic Monitoring Immunotherapy In Situ Individual Infection Knowledge Laboratories Learning Ligation Link Maintenance Mediating Modeling Mus Natural Immunity Nature Particulate Patients Peptides Plasmids Play Pre-Clinical Model Prevention Primates Principal Investigator Production Proteins Resources Role Skin Study models System T-Lymphocyte Technology Testing Time Transfection Transgenic Organisms Translations Vaccination Vaccines Variant Viral Virus Virus Diseases acquired immunity base cellular engineering clinically relevant design experience gag Gene Products genetic vaccine immunogenicity improved in vivo model design novel novel strategies particle patient population programs response targeted delivery vaccine delivery vaccine development

项目摘要

DESCRIPTION (provided by applicant): The diversity of the HIV virus is a major obstacle to the development of an effective HIV immunotherapy. Several recent studies demonstrate an important role for cell-mediated immunity in both the prevention and control of HIV infection. Failure of HIV-specific immunity has been correlated with "CTL escape" in both primate and human vaccination and immunotherapy studies. Establishment and maintenance of effective CTL- mediated immune responses generally depends on the presence of CD4+ T-cell help, and a Th1 type response is critical for induction and maintenance of cell-mediated immunity. Dendritic cells (DCs) play critical roles in the development and control of immunity. Besides being the most potent antigen-presenting cells (APC), they determine the nature and magnitude of immune responses and provide an essential link between innate and acquired immunity. The studies proposed here will build on our previous efforts utilizing DNA expression constructs encoding autologous patient-derived HIV antigens and novel DC transfection approaches to address major obstacles to effective HIV immunotherapy. Specifically, we propose to genetically engineer skin DCs in vivo to both efficiently present patient-specific Nef and Gag antigens, and express enhanced DC1 type polarized immune-stimulatory function essential for optimal activation of Th1 T- cells in HIV infected individuals. This proposal will develop novel in vivo antigen delivery systems based on the delivery of particulate and DNA formulations encoding HIV-1 antigens to: 1) drive the expression of transgenic (tg) antigens in DCs, 2) favor presentation of tg Ag peptides to CD8+ CTL and CD4+ Th cells and 3) elicit Th1 polarizing DC function. We will test the hypothesis that autologous dendritic cells, genetically engineered to present transgenic patient-derived HIV antigens in the context of Th1 skewing costimulatory function, will induce effective Th1 type patient-specific HIV immune responses. This will be accomplished using both murine models, and unique in situ human skin models we have developed to facilitate translation to clinical trials. In addition to testing this hypothesis, the studies we propose have the potential to overcome major limitations of existing HIV immunotherapies, and to define an immunization strategy capable of containing or eradicating infection in chronically infected patients. Importantly, the studies we propose include translational preclinical models designed as a direct prelude to human clinical trials. PUBLIC HEALTH RELEVANCE: The diversity of the HIV virus is a major obstacle to the development of an effective HIV immunotherapy. We will test the hypothesis that DNA-based immunization strategies that target delivery of autologous antigen to dendritic cells in the context of Th1 skewing adjuvants will induce effective Th1 type patient-specific HIV-1 immune responses. This will be accomplished using both murine models, and unique in situ human skin models we have developed to facilitate translation to clinical trials. The studies we propose have the potential to overcome major limitations of existing HIV immunotherapies, and to define an immunization strategy capable of containing or eradicating infection in chronically infected patients. The studies we propose include translational preclinical models designed as a direct prelude to human clinical trials.

描述（由申请人提供）：HIV病毒的多样性是开发有效的HIV免疫疗法的主要障碍。最近的几项研究表明细胞介导的免疫在预防和控制艾滋病毒感染中发挥着重要作用。在灵长类动物和人类疫苗接种和免疫治疗研究中，HIV 特异性免疫的失败与“CTL 逃逸”相关。有效 CTL 介导的免疫反应的建立和维持通常取决于 CD4+ T 细胞的帮助，而 Th1 型反应对于诱导和维持细胞介导的免疫至关重要。树突状细胞（DC）在免疫的发展和控制中发挥着关键作用。除了是最有效的抗原呈递细胞 (APC) 之外，它们还决定免疫反应的性质和程度，并在先天性免疫和获得性免疫之间提供重要联系。这里提出的研究将建立在我们之前的努力的基础上，利用编码自体患者来源的 HIV 抗原的 DNA 表达结构和新型 DC 转染方法来解决有效 HIV 免疫治疗的主要障碍。具体来说，我们建议对体内皮肤 DC 进行基因改造，以有效地呈现患者特异性 Nef 和 Gag 抗原，并表达增强的 DC1 型极化免疫刺激功能，这对于 HIV 感染者中 Th1 T 细胞的最佳激活至关重要。该提案将开发基于编码 HIV-1 抗原的颗粒和 DNA 制剂的新型体内抗原递送系统：1) 驱动 DC 中转基因 (tg) 抗原的表达，2) 有利于将 tg Ag 肽呈递给 CD8+ CTL 和 CD4+ Th 细胞以及 3) 引发 Th1 极化 DC 功能。我们将测试这样的假设：自体树突状细胞经过基因工程改造，在 Th1 倾斜共刺激功能的背景下呈现转基因患者来源的 HIV 抗原，将诱导有效的 Th1 型患者特异性 HIV 免疫反应。这将使用小鼠模型和我们开发的独特的原位人类皮肤模型来完成，以促进临床试验的转化。除了检验这一假设之外，我们提出的研究还有可能克服现有艾滋病毒免疫疗法的主要局限性，并确定一种能够遏制或根除慢性感染患者感染的免疫策略。重要的是，我们提出的研究包括旨在作为人体临床试验直接前奏的转化临床前模型。公共卫生相关性：HIV 病毒的多样性是开发有效的 HIV 免疫疗法的主要障碍。我们将测试以下假设：基于 DNA 的免疫策略，在 Th1 倾斜佐剂的背景下将自体抗原靶向递送至树突状细胞，将诱导有效的 Th1 型患者特异性 HIV-1 免疫反应。这将使用小鼠模型和我们开发的独特的原位人类皮肤模型来完成，以促进临床试验的转化。我们提出的研究有可能克服现有艾滋病毒免疫疗法的主要局限性，并确定能够遏制或根除慢性感染患者感染的免疫策略。我们提出的研究包括旨在作为人体临床试验直接前奏的转化临床前模型。