CYTOLYTIC T-CELL RESPONSES IN AIDS VACCINE RECIPIENTS

艾滋病疫苗接种者的溶细胞 T 细胞反应

• 批准号: 2067743
• 负责人: ROBERT F SILICIANO
• 金额: $ 28.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-15 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2067743
• 关键词: AIDS; AIDS vaccines; B lymphocyte; CD4 molecule; MHC class I antigen; MHC class II antigen; T cell receptor; cell mediated lymphocytolysis test; cell migration; chromium; clone cells; cytotoxic T lymphocyte; gene expression; human immunodeficiency virus 1; leukocyte activation /transformation; pore forming protein; tumor necrosis factor alpha; virus protein

The long range goals of this project are to determine whether the vaccination of HIV-1-seronegative and seropositive human volunteers with candidate AIDS vaccines results in the generation of HIV-1-specific cytolytic T lymphocyte (CTL) responses, to analyze individual variation in the strength and duration of vaccine-induced CTL responses, and to examine important functional aspects of the CTL response at clonal level. We have previously shown that seronegative volunteers immunized with HIV-1 envelope protein subunit vaccines develop CD4+, MHC class II-restricted CTL that lyse HIV-1-infected cells in rapid, efficient, and highly specific fashion. In addition, we have recently found that individuals vaccinated with live vaccinia virus carrying the HIV-1 env gene have an extremely high level of CD8+, class I-restricted CTL activity specific for the HIV-1 envelope protein. In the proposed studies, both MHC class I- and class II-restricted CTL responses will be analyzed in human volunteers participating in all current and future NIAID-sponsored Phase I AIDS vaccine clinical trials. Assays to detect both active circulating CTL and resting memory CTL will be used. We will compare the ability of various vaccines to induce class I- and class II- restricted CTL and determine the duration of the memory response for each type of CTL. HIV-1-specific CTL clones will be isolated from vaccine recipients at multiple time points during the trials. The availability of stable, long term T cell clones will permit us to characterize in detail important parameters of vaccine-induced CTL response including phenotype, HLA restriction, epitopes recognized, cross-reactivity with various strains, and cytokines produced. Studies with CTL clones will focus on properties likely to influence ability of vaccine-induced clones to control the spread of HIV-1 infection in vivo such as capacity to lyse HIV-1-infected cells and secretion of cytokines such as TNF-alpha that upregulate HIV-1 gene expression. Finally, because class II-restricted CTL may play an important role in vaccine- induced immune response by virtue of their ability to destroy infected cells and to downregulate specific antibody responses, we will attempt to define molecular markers for the subset of CD4+ T cells with cytolytic activity and to analyze key aspects of the CD4+ CTL response, including the ontogeny of CD4+ CTL, the antigen receptor repertoire of these cells, their trafficking patterns, their role in regulation of B cell responses, and mechanism of cytolysis by these CTL.

该项目的远距离目标是确定 与HIV-1-副疫苗接种和血清阳性人类志愿者的疫苗接种 候选AIDS疫苗会导致HIV-1特异性的产生 细胞溶解T淋巴细胞（CTL）反应，分析个体 疫苗诱导的CTL反应的强度和持续时间变化， 并检查CTL响应的重要功能方面 克隆水平。我们以前已经表明了血清神经志愿者 用HIV-1包络蛋白亚基疫苗免疫的CD4+，MHC II类限制的CTL，在快速的HIV-1感染细胞中， 高效，高度特定的时尚。此外，我们最近有 发现用带有活乳清病毒接种的个体携带 HIV-1 env Gene具有极高的CD8+，I类限制性 CTL活性特异于HIV-1包膜蛋白。在提议中 研究，MHC I类和II类限制的CTL响应都将是 分析了参与所有当前和未来的人类志愿者 NIAID赞助的I期AIDS疫苗临床试验。检测的测定 将使用主动循环CTL和静止存储器CTL。我们将 比较各种疫苗诱导I类和II类的能力 - 限制CTL并确定记忆响应的持续时间 每种类型的CTL。 HIV-1特异性CTL克隆将与 试验期间多个时间点的疫苗接收者。这 稳定的长期T细胞克隆的可用性将使我们能够 详细表征疫苗诱导的CTL的重要参数 响应包括表型，HLA限制，表位，认可的表位， 与各种菌株的交叉反应性，并产生细胞因子。研究 使用CTL克隆将集中在可能影响能力的属性上 疫苗诱导的克隆以控制HIV-1感染在体内的传播 例如裂解HIV-1感染细胞的能力和细胞因子的分泌 例如上调HIV-1基因表达的TNF-α。最后， 因为II类限制的CTL可能在疫苗中起重要作用 诱发免疫反应造成破坏感染的能力 细胞并下调特定的抗体反应，我们将尝试 定义与CD4+ T细胞子集的分子标记 细胞溶解活性并分析CD4+ CTL响应的关键方面， 包括CD4+ CTL的个体发育，抗原受体库 这些细胞，它们的运输模式，它们在调节B的调节中的作用 这些CTL的细胞反应和细胞溶解的机制。