A Safe Vaccine Strain of Listeria Monocytogenes for 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 溶液单核细胞增多性李斯特菌是一种有潜力用作口服 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， 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HIV的活载体， 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-丙氨酸来启动感染， 表征了它在小鼠中产生的全身和粘膜CD 8 T细胞应答， 艾滋病毒的恶作剧重组蛋白对粘膜攻击的完全保护作用 在口服或全身免疫后可见牛痘-gag病毒。在 本申请中，我们建议进一步探讨对口头 1）检查细胞和细胞因子的基础 对于转基因huEcad小鼠的粘膜保护， 李斯特菌感染更适合人类比较，而不是小鼠 2）研究新的策略，以开发减毒的 不依赖于发酵剂供应的D-丙氨酸的李斯特菌菌株;以及 3)研究使用减毒李斯特菌递送DNA疫苗。4)我们将 我们还使用正常的人CD 4和CD 8 T细胞对李斯特菌的反应进行了研究。 和HIV感染的人血液样品，以及在这些细胞中诱导的细胞因子。 在此期间，我们将特别强调的性质， 由于CD 4细胞似乎 在艾滋病病毒中起保护作用。

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.