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: 6706359
• 负责人: Fred Robert Frankel
• 金额: $ 35.9万
• 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/6706359
• 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

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）全球范围内正在发生新的艾滋病毒感染 艾滋病毒疫苗似乎是唯一的长期治疗方法 解决方案。单核细胞增生李斯特氏菌是一种有潜力用作口服的载体 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的范例，并且是有效的 用于模型癌症、流感、LCMV 和牛痘病毒的疫苗载体 感染。为了在人类中使用这种活载体来对抗艾滋病毒，该生物体 必须既安全又有效。我们构建了一个高度衰减的、 需要 D-丙氨酸的李斯特菌菌株，当 提供了足够的 D-丙氨酸来引发感染，并且有 表征了它在小鼠体内产生的全身和粘膜 CD8 T 细胞反应 艾滋病毒堵嘴。通过重组完全保护免受粘膜攻击 口服或全身免疫后可见痘苗病毒。在 在此应用中，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： 1）检查细胞和细胞因子基础 用于转基因 huEcad 小鼠的粘膜保护，这是一种新的小鼠模型 李斯特菌感染比小鼠更适合人类比较 以前使用过的菌株； 2) 研究新策略以开发减毒药物 独立于研究者提供的 D-丙氨酸的李斯特菌菌株；和 3) 检查使用减毒李斯特菌来提供 DNA 疫苗。 4）我们会 还使用正常细胞探索人类 CD4 和 CD8 T 细胞对李斯特菌的反应 和艾滋病毒感染的人类血液样本，以及这些细胞中诱导的细胞因子。 在此资助期间，我们将特别强调性质和 CD4 反应对减毒李斯特菌的作用，因为 CD4 细胞似乎 对HIV起到保护作用。