In vitro stimulation of HIV specific CD8+ T cells

HIV 特异性 CD8 T 细胞的体外刺激

• 批准号: 7073861
• 负责人: PETER D KATSIKIS
• 金额: $ 37.5万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-15 至 2006-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073861
• 关键词: BCL2 gene /protein; CD95 molecule; HIV infections; apoptosis; cell differentiation; cell proliferation; clinical research; cytokine; cytotoxic T lymphocyte; flow cytometry; gag protein; histocompatibility antigens; human immunodeficiency virus 1; human subject; laboratory mouse; microorganism immunology; monoclonal antibody; protein binding; virus antigen

Although cytotoxic CD8+ T cells (CTL) play an important protective role during HIV infection, a number of studies have revealed that these important 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 apoptosis. We have shown that HIV-specific CD8+ T cells are very sensitive 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, suggesting that this may account at least partially for the increased apoptosis sensitivity. Based on our findings from in vitro studies of HIV-specific CD8+ T cells we hypothesize that HIV-specific CD8+ T cells are in a proapoptotic state due to an imbalance of pro- and anti-apoptotic factors and that this is the result of priming in the absence of HIV-specific CD4+ T cell help, chronic stimulation or a combination of both. This chronic stimulation, aberrant priming or both, results in increased apoptotic potential and defective proliferative capacity. In the current proposal we will investigate the molecular mechanism(s) involved in the increased apoptosis sensitivity of HIV-specific CD8+ T cells. We will also determine the in vivo mechanisms in mice that result in virus-specific CD8+ T cells that exhibit increased apoptosis sensitivity, functional defects and molecular profiles similar to HIV-specific CD8+ T cells. Understanding the mechanism behind these defects 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.

尽管细胞毒性 CD8+ T 细胞 (CTL) 在 HIV 感染过程中发挥着重要的保护作用，但许多研究表明，这些重要细胞可能存在功能缺陷，从而削弱其控制 HIV 病毒的效率。我们实验室的研究表明，HIV 特异性 CD8+ T 细胞对细胞凋亡的敏感性增加。我们已经证明，HIV 特异性 CD8+ T 细胞对 CD95/Fas 诱导的细胞凋亡非常敏感，并且 HIV 感染的巨噬细胞可以通过 CD95/Fas 依赖性机制杀死 HIV 特异性 CD8+ T 细胞。此外，HIV 特异性 CD8+ T 细胞缺乏终末分化，CD95/Fas 凋亡可能与这种分化偏差有关。 HIV特异性CD8+ T的能力 因此细胞杀死受感染的细胞，并且由于 CD95/Fas 介导的这些细胞的凋亡，它们的分化可能受到损害。最近，我们发现 HIV 特异性 CD8+ T 细胞中抗凋亡分子 Bcl-2 和 Bcl-XL 减少，表明这可能至少部分解释了细胞凋亡敏感性增加。基于我们对 HIV 特异性 CD8+ T 细胞的体外研究结果，我们假设 HIV 特异性 CD8+ T 细胞由于促凋亡因子和抗凋亡因子不平衡而处于促凋亡状态，这是在缺乏 HIV 特异性 CD4+ T 细胞帮助、慢性刺激或 两者的结合。这种慢性刺激、异常启动或两者兼而有之，导致细胞凋亡潜力增加和增殖能力缺陷。在当前的提案中，我们将研究与 HIV 特异性 CD8+ T 细胞凋亡敏感性增加相关的分子机制。我们还将确定小鼠体内产生病毒特异性 CD8+ T 细胞的体内机制，这些细胞表现出与 HIV 特异性 CD8+ T 细胞相似的凋亡敏感性增加、功能缺陷和分子特征。了解 HIV 特异性 CD8+ T 细胞这些缺陷背后的机制可能有助于恢复 HIV 特异性 CD8+ T 细胞的存活或功能，从而对控制或清除 HIV 产生深远的影响。最后，这种理解对于开发提供持久 CTL 免疫的疫苗至关重要。