NONPEPTIDIC VACCINES IN AIDS

艾滋病中的非肽疫苗

• 批准号: 2555666
• 负责人: MIROSLAV MALKOVSKY
• 金额: $ 19.52万
• 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 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2555666
• 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（改编自申请人的摘要）：一个重要特征 感染免疫缺陷病毒 - 人类 (HIV) 或猿猴 (SIV) 宿主未能建立有效的免疫防御 尽管存在非常活跃的细胞和体液免疫，但病毒 反应。 然而，宿主的免疫监视途径通常 在感染的初始阶段减少病毒复制，但不 消除体内病毒。 有人提出，细胞介导的 免疫在这些途径中发挥着核心作用。 申请人已表明 γ/δ T 淋巴细胞是： (i) HIV/SIV 最有效的杀手 感染细胞（Vaccine Res. 1: 183-191, 1992；Clin. Exp.Immunol. 103:177-184, 1996); (ii) 许多无症状患者变得无反应 HIV 感染者和长期无进展者 (J.Immunol. 157:4449-4461, 1996;分子医学 3:60-71, 1997)。 为了解释这些 看似矛盾的观察，申请人提出 γ/δ T 细胞是重要的“一线防御者”，贡献 基本上对重要感染的初步控制有帮助，但它们 慢性激活也有助于（可能通过细胞因子释放） 维持免疫系统持续过度激活，进而 可能会导致与艾滋病相关的免疫功能障碍。 在这个 应用，研究人员建议开发和测试非肽 疫苗对活性产生积极或消极的影响 γ/δ T 细胞在恒河猴 SIV 模型感染中的作用。 具体来说，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抗原（例如 例如，异戊烯基焦磷酸酯）单独或与 受辐射的 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。 在具体目标 2 中， 申请人计划测试16个T细胞是否功能性缺失 （通过使用非肽磷酸化的体内疫苗接种来实现 γ/δ T 细胞分子，例如 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 将分析测试并 记录在案。 成功的结果可能会导致选择新的疫苗接种 人类艾滋病临床测试的策略和化合物。