Optimizing Listeria for use as an HIV Vaccine

优化李斯特菌作为 HIV 疫苗的用途

• 批准号: 6511293
• 负责人: Fred Robert Frankel
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-15 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511293
• 关键词: AIDS vaccines; Listeria; active immunization; antibody formation; chimeric proteins; cytotoxic T lymphocyte; helper T lymphocyte; human immunodeficiency virus 1; laboratory mouse; measles virus; vaccine development; vector vaccine; AIDS vaccines; Listeria; active immunization; antibody formation; chimeric proteins; cytotoxic T lymphocyte; helper T lymphocyte; human immunodeficiency virus 1; laboratory mouse; measles virus; vaccine development; vector vaccine

DESCRIPTION: (Adapted from Applicant's Abstract) New HIV infections worldwide are occurring at alarming rates. Immunity mediated by cytolytic T lymphocytes (CTLs) and antibodies may protect against infection and limit disease. Listeria monocytogenes is an intracellular microorganism that has been studied as a paradigm for the induction of cell mediated immunity for many years and has been shown to be effective as a vaccine vector for influenza and LCMV infections and for the treatment of model cancers. Listeria may also prove to be a useful vehicle to generate immune responses against HIV. However, Listeria is a pathogen, and we therefore constructed a completely attenuated strain of the organism that nevertheless can induce effective immunity following appropriate immunization conditions. An HIV-1 gag recombinant of this strain induces in mice a strong, long-lasting systemic and mucosal CTL response in spleen, Peyer's patches and mesenteric lymph nodes that can protect against systemic or mucosal challenge by recombinant vaccinia viruses expressing the HIV-1 gag gene. As there is evidence to suggest a protective role of antibodies against HIV infection, we will attempt to modify our hyper-attenuated strain of Listeria so as to produce an anti-HIV antibody response, augmenting its induction of CTLs. We will construct Listeria recombinants that express linear or conformational mimotopes of gpl20/gp4l recently identified by phage display technology to induce neutralizing antibodies in mice. These will be expressed as fusions with a T helper epitope in different contexts at the bacterial surface or in soluble form. Sera and intestinal secretions of immunized mice that contain anti-env antibodies will be tested for their ability to neutralize primary isolates of HIV-1.

描述：（改编自申请人的摘要）全球新的HIV感染 以惊人的速度发生。由胞溶T淋巴细胞介导的免疫力 （CTL）和抗体可能预防感染并限制疾病。李斯特菌 单核细胞增生是一种细胞内微生物，已被研究为 多年来诱导细胞介导的免疫的范式，并且具有 被证明是流感和LCMV的疫苗载体有效的 感染和用于模型癌的治疗。李斯特菌也可能证明 成为对艾滋病毒产生免疫反应的有用工具。但是，李斯特菌 是一种病原体，因此我们构建了一个完全减弱的应变 然而，可以诱导有效免疫的生物 适当的免疫条件。该菌株的HIV-1 GAG重组 在小鼠中诱导强烈，持久的全身和粘膜CTL反应 脾脏，佩耶的斑块和肠系膜淋巴结，可以预防 重组疫苗病毒表达的全身性或粘膜挑战 HIV-1 GAG基因。有证据表明抗体的保护作用 针对HIV感染，我们将尝试修改我们的超衰减应变 李斯特菌以产生抗HIV抗体反应，增强其 CTL的诱导。我们将构建表达线性的李斯特菌重组者 或最近通过噬菌体显示的GPL20/GP4L的构象表现 诱导小鼠中和抗体的技术。这些将被表达 作为在细菌的不同情况下与T辅助表位的融合 表面或可溶性形式。免疫小鼠的血清和肠分泌物 含有抗ENV抗体的中和能力将测试 HIV-1的主要分离株。