NONPEPTIDIC VACCINES IN AIDS

艾滋病中的非肽疫苗

• 批准号: 2878031
• 负责人: MIROSLAV MALKOVSKY
• 金额: $ 19.04万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2878031
• 关键词: AIDS vaccines; Macaca mulatta; T lymphocyte; apoptosis; cellular immunity; disease /disorder model; pyrophosphates; simian immunodeficiency virus; vaccine development; virus infection mechanism; virus load

DESCRIPTION (adapted from applicant's abstract): An important feature of infections with immunodeficiency viruses - human (HIV) or simian (SIV), is the host failure to mount an effective immunological defense against the virus despite the presence of very vigorous cellular and humoral immune reactions. Nevertheless, the host's immunosurveillance pathways usually curtail virus replication in the initial stages of infection, but do not eliminate virus from the body. It has been suggested that cell-mediated immunity plays a central role in these pathways. The applicants have shown that gamma/delta T-lymphocytes are: (i) the most potent killers of HIV/SIV infected cells (Vaccine Res. 1: 183-191, 1992; Clin. Exp. Immunol. 103:177-184, 1996); and (ii) become anergic in many asymptomatic HIV-infected persons and long-term nonprogressors (J. Immunol. 157:4449-4461, 1996; Moleciilar Medicine 3:60-71, 1997). To explain these seemingly contradictory observations, the applicants have proposed that gamma/delta T cells are important "first-line defense players" contributing substantially to the initial control of the vital infection, but their chronic activation also helped (probably through the cytokine release) to maintain the persistent overactivation of the immune system, which in turn may result in immune dysfunctions associated with AIDS. In this application, the investigators propose to develop and test nonpeptidic vaccines that either positively or negatively influence the activity of gamma/delta T cells in their SIV model infection of rhesus monkeys. Specifically, in Specific Aim 1, they propose to test whether vaccines containing potent nonpeptide phosphoantigens for gamma/delta T cells (such as, for example, isopentenyl pyrophosphate) alone or together with irradiated Daudi cells (expressing the most effective cell-bound antigen for gamma/delta T cells) can influence the clearance of the virus in in vivo acute infections of rhesus monkeys (Macaca mulatta). In Specific Aim 2, the applicants plan to test whether a functional deletion of 16 T cells (achieved through either in vivo vaccination with nonpeptidic phosphorylated molecules for gamma/delta T cells, such as 2,3-diphosphoglyceric acid, or by gamma/delta T cell-specific antibody-mediated depletion) will result in better prognosis and survival. The efficacy of the in vivo and the in vitro testing will be analyzed and documented. Successful outcomes may lead to selecting novel vaccination strategies and compounds for clinical testing in human AIDS.

描述（改编自申请人摘要）： 感染免疫缺陷病毒-人类（HIV）或猿猴（SIV）， 宿主未能对病毒进行有效的免疫防御， 尽管存在非常有力的细胞和体液免疫 反应. 尽管如此，宿主的免疫监视途径通常 在感染的最初阶段减少病毒复制，但不 将病毒从体内清除。 有人认为，细胞介导的 免疫在这些途径中起着核心作用。 申请人已经证明 γ/δ T淋巴细胞是：（i）HIV/SIV最强有力的杀手 感染的细胞（Vaccine Res. 1：183-191，1992; Clin.Exp. Immunol. 103：177-184，1996）;和（ii）在许多无症状的患者中变得无反应性。 HIV感染者和长期无进展者（J. Immunol. 157：4449-4461，1996; Moleciilar Medicine 3：60-71，1997）。 解释这些 尽管观察结果似乎相互矛盾，但申请人提出， γ/δ T细胞是重要的“第一线防御球员”， 基本上对重要感染的初步控制，但他们的 慢性激活也有助于（可能通过细胞因子释放） 维持免疫系统的持续过度激活， 可能导致与艾滋病相关的免疫功能障碍。 在这 应用，研究人员建议开发和测试非肽 疫苗，无论是积极或消极影响的活动， γ/δ T细胞在恒河猴SIV感染模型中的作用。 具体而言，在具体目标1中，他们建议测试疫苗是否 含有针对γ/δ T细胞的有效非肽磷酸化抗原（如 例如异戊烯基焦磷酸）单独或与 照射的Daudi细胞（表达最有效的细胞结合抗原， γ/δ T细胞）可以影响体内病毒的清除 恒河猴（Macaca mulatta）的急性感染。 具体目标2 申请人计划测试16个T细胞的功能缺失是否 （通过用非肽磷酸化的 用于γ/δ T细胞的分子，如2，3-二磷酸甘油酸，或 γ/δ T细胞特异性抗体介导的耗竭）将导致 更好的预后和生存。 体内和体外的功效 将对测试进行分析， 记录在案。 成功的结果可能导致选择新的疫苗接种 用于人类艾滋病临床试验的策略和化合物。