SAFE VACCINE STRAIN OF LISTERIA MONOCYTOGENES FOR HIV

艾滋病毒单核细胞增生李斯特氏菌的安全疫苗株

• 批准号: 2649221
• 负责人: Fred Robert Frankel
• 金额: $ 31.9万
• 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: 1998-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2649221
• 关键词: AIDS vaccines; Listeria; MHC class I antigen; antigen presentation; attenuated microorganism; cytotoxic T lymphocyte; human immunodeficiency virus 1; laboratory mouse; simian immunodeficiency virus; tissue /cell culture; transfection; vaccine development; vector vaccine; virus antigen

DESCRIPTION: A vaccine that is able to target HIV proteins to the class I restricted pathway of antigen recognition could be a powerful prophylactic and possibly therapeutic agent for HIV infections. Antigens secreted by Listeria monocytogenes, a gram-positive bacterium that can grow within the cytoplasm of macrophages and adjoining cells, will have direct access to the MHC class I pathway to cytotoxic T cells. Previous studies have established that recombinant Listeria have the capacity to express foreign antigens and can be used to successfully protect mice against infection and tumor cell challenge. However, infection by L. monocytogenes, while rare and controlled by antibiotics, can cause serious illness, particularly in immune suppressed or pregnant patients. For these reasons, experiments are proposed to develop a hyper- attenuated strain of L. monocytogenes as an HIV/SIV vaccine vector. In preliminary studies the investigator has isolated a strain of L. monocytogenes that is unable to synthesize D-alanine, an amino acid required for the synthesis of the cell wall. The use of this hyper- attenuated L. monocytogenes will form the foundation for the following experimental aims: Specific Aim 1: To develop a hyper-attenuated strain of L. monocytogenes expressing HIV/SIV proteins. Specific Aim2: To evaluate the ability of the attenuated strains to deliver HIV/SIV DNA vaccines. Specific Aim 3: To optimize the cell mediated immune response in mice to HIV/SIV antigens expressed or delivered by the attenuated strains. Specific Aim 4: To examine a human model of antigen presentation: to access the ability of infected PBMCs to expand patient HIV-1-specific CTLs.

描述：一种能够靶向HIV蛋白的疫苗， I限制性抗原识别途径可能是一种强大的 HIV感染的预防剂和可能的治疗剂。抗原 单核细胞增生李斯特菌分泌的一种革兰氏阳性细菌， 在巨噬细胞和相邻细胞的细胞质内生长， 直接进入MHC I类途径至细胞毒性T细胞。 先前 研究已经确定重组李斯特菌具有 表达外源抗原，可成功保护小鼠， 抵抗感染和肿瘤细胞攻击。 但L. 单核细胞增多症虽然罕见，并由抗生素控制，但可导致 严重疾病，特别是免疫抑制或妊娠患者。 出于这些原因，实验被提议开发超- 减毒株单核细胞增多症作为HIV/SIV疫苗载体。 在 初步研究，研究人员已经分离出一种L。 不能合成D-丙氨酸（一种氨基酸）的单核细胞增多症 合成细胞壁所需的蛋白质。 使用这种超- 减毒L.单核细胞增多症将形成以下基础 实验目的： 具体目标1：建立一个高减毒株。 表达HIV/SIV蛋白的单核细胞增多症。 具体目标2：评价 减毒株递送HIV/SIV DNA疫苗的能力。 具体目标3：优化小鼠中细胞介导的免疫应答 针对由减毒株表达或递送的HIV/SIV抗原。 具体目的4：检查抗原呈递的人模型： 评估受感染PBMC扩增患者HIV-1特异性 CTL。