A Safe Vaccine Strain of Listeria Monocytogenes for HIV

一种安全的艾滋病毒单核细胞增生李斯特菌疫苗株

• 批准号: 6656968
• 负责人: Fred Robert Frankel
• 金额: $ 34.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6656968
• 关键词: AIDS vaccines; Listeria; alanine; antigen presenting cell; attenuated microorganism; biological models; clinical research; cytokine; cytotoxic T lymphocyte; genetically modified animals; helper T lymphocyte; human immunodeficiency virus 1; human subject; immunogenetics; laboratory mouse; model design /development; vaccine development; vector vaccine; virus antigen; AIDS vaccines; Listeria; alanine; antigen presenting cell; attenuated microorganism; biological models; clinical research; cytokine; cytotoxic T lymphocyte; genetically modified animals; helper T lymphocyte; human immunodeficiency virus 1; human subject; immunogenetics; laboratory mouse; model design /development; vaccine development; vector vaccine; virus antigen

DESCRIPTION: (Provided by Applicant) New HIV infections worldwide are occurring at alarming rates, and an HIV vaccine appears to be the only long-term solution. Listeria monocytogenes is a vector with potential for use as an oral vaccine against this disease. Listeria is an intracellular microorganism that is a paradigm for the induction of cell mediated immunity and is effective as a vaccine vector for model cancers, influenza, LCMV, and vaccinia virus infections. For use of this live vector against HIV in humans, the organism must be both safe and effective. We have constructed a highly attenuated, D-alanine-requiring strain of Listeria that can induce strong immunity when provided just sufficient D-alanine to initiate an infection, and have characterized the systemic and mucosal CD8 T cell response it generates in mice to HIV gag. Complete protection against mucosal challenge by recombinant vaccinia-gag virus is seen following either oral or systemic immunization. In this application, we propose to further explore the response to oral immunization in the following ways: 1) Examine the cellular and cytokine basis for mucosal protection in transgenic huEcad mice, a new mouse model for Listeria infection that is more appropriate for human comparisons than mouse strains used previously; 2) Examine new strategies to develop an attenuated strain of Listeria that is independent of investigator-supplied D-alanine; and 3) Examine the use of attenuated Listeria to deliver DNA vaccines. 4) We will also explore the response of human CD4 and CD8 T cells to Listeria using normal and HIV-infected human blood samples, and the cytokines induced in these cells. During this grant period we will place particular emphasis on the nature and role of the CD4 response to the attenuated Listeria, since CD4 cells appear to play a protective function in HIV.

描述：（由申请人提供）全球新的HIV感染正在发生 以惊人的速度，艾滋病毒疫苗似乎是唯一的长期 解决方案。单核细胞增生李斯特菌是一种可能用作口服的载体 针对这种疾病的疫苗。李斯特菌是一种细胞内微生物， 是诱导细胞介导的免疫力的范式，作为A有效 模型癌，流感，LCMV和牛ac病毒的疫苗载体 感染。用于使用人类对艾滋病毒的活媒介使用 必须既安全又有效。我们建造了一个高度衰减的人， D-丙氨酸的李斯特菌菌株，可以诱导强烈的免疫力 提供足够的D-丙氨酸来引发感染，并具有 表征了它在小鼠中产生的全身和粘膜CD8 T细胞反应 艾滋病毒插科打。重组完全保护粘膜挑战 在口服或全身免疫后，可以看到疫苗-GAG病毒。在 该应用程序，我们建议进一步探索对口头的反应 通过以下方式进行免疫接种：1）检查细胞和细胞因子的基础 用于转基因Huecad小鼠的粘膜保护，这是一种新的鼠标模型 与小鼠更适合人类比较的李斯特菌感染 以前使用的菌株； 2）检查开发衰减的新策略 李斯特菌的菌株，独立于研究者供应的D-丙氨酸；和 3）检查使用减毒李斯特菌输送DNA疫苗的使用。 4）我们会的 还可以使用正常探索人CD4和CD8 T细胞对李斯特菌的反应 和HIV感染的人类血液样本，以及这些细胞中诱导的细胞因子。 在此赠款期间，我们将特别强调性质和 CD4对李斯特菌的反应的作用，因为CD4细胞似乎 在艾滋病毒中发挥保护作用。