A Safe Vaccine Strain of Listeria Monocytogenes for HIV

描述：(申请人提供)全球范围内正在发生新的艾滋病毒感染 以惊人的速度，艾滋病毒疫苗似乎是唯一的长期 解决方案。单核细胞增多性李斯特菌是一种具有口服潜力的载体 预防这种疾病的疫苗。李斯特菌是一种胞内微生物， 是一种诱导细胞免疫的范例，是一种有效的 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抗艾滋病毒的活载体，生物体 必须既安全又有效。我们已经构建了一个高度衰减的 需要D-丙氨酸的李斯特菌菌株，在以下情况下可诱导强大的免疫力 只要有足够的D-丙氨酸引发感染，并有 鉴定其在小鼠体内产生的系统和粘膜CD8 T细胞反应 为了艾滋病病毒的恶作剧。重组人对黏膜攻击的完全保护 口服或全身免疫后可见牛痘-盖格病毒。在……里面 在此应用中，我们建议进一步探讨口述的反应 以下列方式进行免疫：1)检查细胞和细胞因子基础 为了对转基因huecad小鼠的粘膜保护，一种新的小鼠模型 比老鼠更适合人类比较的李斯特菌感染 以前使用的菌株；2)检查新的策略，以开发减毒 独立于研究人员提供的D-丙氨酸的李斯特氏菌菌株；以及 3)检查使用减毒李斯特菌交付DNA疫苗的情况。4)我们会 同时探讨正常人外周血中CD4和CD8T细胞对李斯特氏菌的反应 以及感染艾滋病毒的人类血液样本，以及在这些细胞中诱导的细胞因子。 在这一批款期内，我们将特别重视自然和 CD4细胞对减毒李斯特菌的应答作用，因为CD4细胞似乎 对艾滋病病毒起到保护作用。

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.