Enhancing HIV-specific CD8+ T cells with IL-15.

使用 IL-15 增强 HIV 特异性 CD8 T 细胞。

• 批准号: 6884433
• 负责人: PETER D KATSIKIS
• 金额: $ 33.98万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6884433
• 关键词: CD8 molecule; CD95 molecule; HIV infections; apoptosis; biological signal transduction; cell population study; cell sorting; clinical research; cytotoxic T lymphocyte; cytotoxicity; gene expression; human subject; immunogenetics; immunomodulators; immunoregulation; immunotherapy; interleukin 15; leukocyte activation /transformation; microarray technology; microorganism immunology; patient oriented research; phosphorylation; protein structure function; virus infection mechanism; western blottings

DESCRIPTION (provided by applicant):HIV-specific cytotoxic CD8+ T cell responses play an important protective role against HIV infection. A number of studies, however, have indicated that HIV-specific CDS+ T cells may be functionally impaired. In addition, we recently have shown that HIV-specific CDS+ T cells exhibit increased susceptibility to undergo CD95/Fas-mediated apoptosis. This is of particular importance as HIV upregulates FasL on infected cells, while at the same time inhibits CD95/Fas-mediated apoptosis of infected cells. Indeed we have recently shown that HIV-infected macrophages can induce apoptosis of HIV-specific CDS+ T cells and this is largely due to CD95/Fas-mediated apoptosis. Furthermore HIV-specific CDS+ T cells lack the terminally differentiated CD45RA+CD62L- effector memory phenotype and this may affect the function of these cells in vivo. We recently have found evidence that CD95/Fas-mediated apoptosis may be responsible for this lack of differentiation. Thus HIV, by manipulating CD95/Fas-induced apoptosis, may be setting up an intricate CTL evasion and counterattack mechanism. Enhancing effector function, differentiation and/or survival of HIV-specific CDS+ T cells would enhance the efficiency of HIV-specific CD8+ T cells to control or clear HIV virus. Interleukin 15 (IL-15) is a pluripotent cytokine that expands in vivo memory CD8+ T cells, enhances their survival, and inhibits CD95/Fas-induced apoptosis. To date, no in depth investigation has been carried out on the effect of IL-15 on HIV-specific CD8+ T cells. We hypothesize that IL-15 treatment can enhance cytotoxic CDS+ T cells immunity against HIV This hypothesis is based on the known effects of lL-15 on mouse memory CDS+ T cells, and our own preliminary data that show that IL-15 can inhibit apoptosis and enhance effector function of HIV-specific CDS+ T cells. We propose to investigate the in vitro effect of IL-15 on effector function, differentiation, proliferation, and apoptosis of HIV-specific CDS+ T cells. We will also investigate the potential mechanism of action of IL-15 by examining the ASK1 signaling pathway and also examining gene expression using gene arrays. The studies in this proposal are novel and will provide valuable information on potential approaches to enhance the CD8+ T cell response against HIV in infected individuals. Information yielded from these studies will fill a knowledge gap as to the effect of IL-15 on anti-viral cytotoxic CDS+ T cell responses, and may prove useful for both novel therapeutic strategies and vaccine development for HIV infection and other viral infections.

描述（由申请人提供）：HIV特异性的细胞毒性CD8+ T细胞反应起着针对HIV感染的重要保护作用。然而，许多研究表明，HIV特异性CDS+ T细胞在功能上可能受损。此外，我们最近表明，HIV特异性的CDS+ T细胞表现出增加患有CD95/FAS介导的凋亡的敏感性。 这是尤其重要的，因为HIV在感染细胞上上调FASL，而同时抑制了受感染细胞的CD95/FAS介导的凋亡。确实，我们最近表明，感染HIV的巨噬细胞可以诱导HIV特异性CDS+ T细胞凋亡，这主要是由于CD95/FAS介导的凋亡。此外，HIV特异性的CDS+ T细胞缺乏终端分化的CD45RA+ CD62L-效应的记忆表型，这可能会影响这些细胞在体内的功能。我们最近发现的证据表明，CD95/FAS介导的细胞凋亡可能导致这种缺乏分化。因此，通过操纵CD95/FAS诱导的细胞凋亡，HIV可能正在建立复杂的CTL逃避和反击机制。增强HIV特异性CDS+ T细胞的效应子功能，分化和/或存活将提高HIV特异性CD8+ T细胞对控制或清除HIV病毒的效率。 白介素15（IL-15）是一种多能细胞因子，可扩展体内记忆CD8+ T细胞，增强其存活并抑制CD95/FAS诱导的凋亡。迄今为止，尚未对IL-15对HIV特异性CD8+ T细胞的影响进行深入研究。我们假设IL-15治疗可以增强抗HIV的细胞毒性CDS+ T细胞免疫性，该假设基于LL-15对小鼠记忆CDS+ T细胞的已知作用，而我们自己的初步数据表明，IL-15可以抑制凋亡和增强HIV特异性CDS CDS+ T细胞功能。我们建议研究IL-15对HIV特异性CDS+ T细胞效应子功能，分化，增殖和凋亡的体外作用。我们还将通过检查ASK1信号传导途径并使用基因阵列检查基因表达来研究IL-15的作用机理。该提案中的研究是新颖的，将提供有关潜在方法增强受感染个体艾滋病毒反应的潜在方法的宝贵信息。从这些研究中产生的信息将填补有关IL-15对抗病毒细胞毒性CDS+ T细胞反应的影响的知识差距，并且可能被证明对新型治疗策略和HIV感染和其他病毒感染的疫苗开发有用。