Optizimizing Listeria for use as an HIV Vaccine

描述：（改编自申请人摘要）全球新发HIV感染 正在以惊人的速度发生。溶细胞性T淋巴细胞介导的免疫 细胞毒性T淋巴细胞（CTL）和抗体可以防止感染和限制疾病。李斯特菌 单核细胞增多症是一种细胞内微生物， 细胞介导的免疫诱导的范例多年来， 作为流感和LCMV的疫苗载体有效 感染和用于治疗模型癌症。李斯特菌也可能被证明 是一个有用的工具，以产生针对艾滋病毒的免疫反应。然而，李斯特菌 是一种病原体，因此我们构建了一种完全减毒的 然而，可以诱导有效免疫力的生物体， 适当的免疫条件。该毒株的HIV-1 gag重组体 在小鼠中诱导强烈的、持久的全身和粘膜CTL应答， 脾脏、派伊尔淋巴结和肠系膜淋巴结， 系统或粘膜攻击的重组牛痘病毒表达 HIV-1 gag基因。因为有证据表明抗体的保护作用 针对艾滋病毒感染，我们将尝试修改我们的超减毒株， 李斯特菌，以产生抗艾滋病毒抗体反应，增强其 CTL的诱导。我们将构建李斯特菌重组体， 或最近通过噬菌体展示鉴定的gp 120/gp 41的构象模拟表位 在小鼠中诱导中和抗体的技术。这些将被表达为 作为与T辅助细胞表位在不同环境中的融合， 表面或可溶形式。免疫小鼠的血清和肠分泌物 将测试含有抗-env抗体的抗体的中和能力 HIV-1的主要分离株。

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.