In vitro stimulation of HIV specific CD8+ T cells

描述（由申请人提供）：尽管细胞毒性CD 8 + T细胞（CTL）在HIV感染期间发挥重要的保护作用，但许多研究表明，这些细胞可能存在功能缺陷，影响其控制HIV病毒的效率。我们实验室的研究表明，HIV特异性CD 8 + T细胞对CD 95/Fas诱导的凋亡表现出增加的易感性，并且HIV感染的巨噬细胞可以通过CD 95/Fas依赖性机制杀死HIV特异性CD 8 + T细胞。此外，HIV特异性CD 8 + T细胞缺乏终末分化，CD 95/Fas凋亡可能参与这种分化的偏斜。因此，HIV特异性CD 8 + T细胞杀死感染细胞的能力及其分化可能由于CD 95/Fas介导的这些细胞的凋亡而受到损害。最近，我们发现抗凋亡分子Bcl-2和Bcl-xL在HIV特异性CD 8 + T细胞中减少，这可能至少部分地解释了它们增加的凋亡敏感性。我们发现白细胞介素15（IL-15）可以抑制CD 95/Fas介导的HIV特异性CD 8 + T细胞的凋亡，并可以恢复这些细胞中Bcl-2和Bcl-xL的水平。基于我们的研究结果，我们假设，促凋亡因子和抗凋亡因子的失衡与线粒体的增加相结合！mass和促凋亡CD 95/Fas信号通路导致HIV特异性CD 8 + T细胞的凋亡敏感性。我们推测IL-15通过作用于CD 95/Fas死亡受体信号的非常早期的步骤来抑制CD 95/Fas介导的HIV特异性CD 8 + T细胞的凋亡。在本研究中，我们将研究HIV特异性CD 8 + T细胞凋亡敏感性增加的分子机制，以及IL-15如何抑制这种凋亡。理解HIV特异性CD 8 + T细胞的这种缺陷背后的机制可以允许恢复HIV特异性CD 8 + T细胞的存活或功能，这反过来将对控制或清除HIV产生深远的影响。最后，这样的理解将是至关重要的疫苗，提供持久的CTL免疫的发展。 外行语言描述：这些研究将调查为什么可以杀死HIV感染细胞的免疫细胞对死亡敏感，以及增加这些细胞存活和功能的方法。这些杀伤细胞在控制HIV感染方面起着关键作用，因此增加它们的存活率将使HIV感染患者受益。这些研究可能会导致新的治疗艾滋病毒感染的一个严重的公共卫生问题.

DESCRIPTION (provided by applicant): Although cytotoxic CD8+ T cells (CTL) play an important protective role during HIV infection, a number of studies have suggested that these cells may suffer from functional defects that impair their efficiency in controlling HIV virus. Studies from our laboratory have revealed that HIV-specific CD8+ T cells exhibit increased susceptibility to CD95/Fas-induced apoptosis and that HIV-infected macrophages can kill HIV- specific CD8+ T cells by a CD95/Fas-dependent mechanism. In addition, HIV-specific CD8+ T cells lack terminal differentiation and CD95/Fas apoptosis may be involved in this skewing of differentiation. The ability of HIV-specific CD8+ T cells therefore to kill infected cells and their differentiation may be compromised due to CD95/Fas-mediated apoptosis of these cells. Recently, we have found a decrease in the anti-apoptotic molecules Bcl-2 and Bcl-xL in HIV-specific CD8+ T cells, and this may account at least partially for their increased apoptosis sensitivity. Interleukin 15 (IL-15) we found can inhibit CD95/Fas- mediated apoptosis of HIV-specific CD8+ T cells and can restore the levels of Bcl-2 and Bcl-xL in these cells. Based on our findings we hypothesize that an imbalance of pro- and anti-apoptotic factors combined with increased mitochondria! mass and a pro-apoptotic CD95/Fas signaling pathway result in the apoptosis sensitivity of HIV-specific CD8+ T cells. We hypothesize that IL-15 inhibits CD95/Fas-mediated apoptosis of HIV-specific CD8+ T cells by acting at a very early step of CD95/Fas death receptor signaling. In the current proposal we will investigate the molecular mechanism(s) involved in the increased apoptosis sensitivity of HIV-specific CD8+ T cells and how IL-15 inhibits this apoptosis. Understanding the mechanism behind this defect of HIV-specific CD8+ T cells may allow for the restoration of survival or function of HIV- specific CD8+ T cells which in turn would have a profound effect in controlling or clearing HIV. Finally, such an understanding will be critical for the development of vaccines that provide long lasting CTL immunity. Lay language description: These studies will investigate why immune cells that can kill HIV infected cells are sensitive to dying and ways to increase the survival and function of these cells. These killer cells play a critical role in controlling HIV infection therefore increasing their survival would benefit patients with HIV infection. These studies may lead to new treatments for HIV infection a serious public health problem.