NONPEPTIDIC VACCINES IN 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)，是 宿主未能对该病毒进行有效的免疫防御 病毒，尽管存在非常强大的细胞和体液免疫 反应。尽管如此，宿主的免疫监视途径通常 在感染的初始阶段抑制病毒复制，但不 清除体内的病毒。已有研究表明，细胞介导的 免疫在这些途径中起着核心作用。申请者已经证明了 伽马/德尔塔T淋巴细胞是：(I)HIV/SIV最有效的杀手 感染细胞(疫苗研究报告1：183-191,1992；临床实验免疫系统。 103：177-184,1996)；和(Ii)在许多无症状的患者中变得无能 艾滋病毒感染者和长期无进展者(J. 157：4449-4461,1996；Moleciilar Medicine 3：60-71,1997)。为了解释这些 看似相互矛盾的观察，申请人提出 伽马/德尔塔T细胞是重要的“一线防守队员” 基本上是对生命感染的初步控制，但他们 慢性激活也有助于(可能通过释放细胞因子) 维持免疫系统的持续过度激活，进而 可能会导致与艾滋病相关的免疫功能障碍。在这 应用，研究人员建议开发和测试非肽类药物 对病毒活性有正面或负面影响的疫苗 GAMA/Delta T细胞在恒河猴SIV模型感染中的作用 具体地说，在具体目标1中，他们建议测试疫苗 含有对伽马/德尔塔T细胞(如 例如，异戊烯基焦磷酸盐)单独或与 照射后的Daudi细胞(表达最有效的细胞结合抗原 T细胞)可影响体内病毒的清除 猕猴(猕猴)的急性感染。在具体目标2中， 申请者计划测试16个T细胞的功能性缺失 (通过体内接种非肽磷酸化疫苗来实现 γ/增量T细胞的分子，如2，3-二磷酸甘油酸，或通过 Gamma/Delta T细胞特异性抗体介导的耗竭)将导致 预后和存活率均较好。体内和体外的药效研究 测试将被分析并 有记录在案。成功的结果可能导致选择新的疫苗接种 人类艾滋病临床检测的策略和化合物。

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.