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

描述（由申请方提供）：HIV特异性细胞毒性CD 8 + T细胞应答对HIV感染具有重要的保护作用。然而，许多研究表明，艾滋病毒特异性CDS+ T细胞可能在功能上受到损害。此外，我们最近发现HIV特异性CDS+ T细胞对CD 95/Fas介导的细胞凋亡的易感性增加。 这是特别重要的，因为HIV上调感染细胞上的FasL，同时抑制CD 95/Fas介导的感染细胞凋亡。事实上，我们最近已经表明，HIV感染的巨噬细胞可以诱导HIV特异性CDS+ T细胞的凋亡，这在很大程度上是由于CD 95/Fas介导的凋亡。此外，HIV特异性CDS+ T细胞缺乏终末分化的CD 45 RA + CD 62 L效应记忆表型，这可能影响这些细胞在体内的功能。我们最近发现的证据表明，CD 95/Fas介导的细胞凋亡可能是负责这种缺乏分化。因此，HIV通过操纵CD 95/Fas诱导的细胞凋亡，可能建立了复杂的CTL逃避和反击机制。增强HIV特异性CD 8 + T细胞的效应子功能、分化和/或存活将增强HIV特异性CD 8 + T细胞控制或清除HIV病毒的效率。 白细胞介素15（IL-15）是一种多能性细胞因子，其扩增体内记忆性CD 8 + T细胞，增强其存活，并抑制CD 95/Fas诱导的细胞凋亡。迄今为止，尚未对IL-15对HIV特异性CD 8 + T细胞的作用进行深入研究。我们假设IL-15处理可以增强细胞毒性CDS+ T细胞对HIV的免疫力。该假设基于IL-15对小鼠记忆CDS+ T细胞的已知作用，以及我们自己的初步数据，该数据显示IL-15可以抑制细胞凋亡并增强HIV特异性CDS+ T细胞的效应子功能。我们建议研究IL-15对HIV特异性CDS+ T细胞的效应子功能、分化、增殖和凋亡的体外作用。我们还将通过检查ASK 1信号通路和使用基因阵列检查基因表达来研究IL-15的潜在作用机制。该提案中的研究是新颖的，并将提供有关增强感染个体中针对HIV的CD 8 + T细胞应答的潜在方法的有价值的信息。从这些研究中获得的信息将填补关于IL-15对抗病毒细胞毒性CDS+ T细胞应答的作用的知识空白，并且可以证明对于HIV感染和其他病毒感染的新型治疗策略和疫苗开发都是有用的。

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.