BLOCKADE OF CD8+ T CELL DEATH BY CXCR4 INHIBITORS

描述：联合抗逆转录病毒治疗(HAART)可导致持续 减少人类免疫缺陷病毒(艾滋病毒)的增长三到四年。 即使HAART成功，免疫系统也不能完全恢复， 这表明如果治疗包括免疫系统损害可能是不可逆转的 仅限HAART。因此，HAART应与替代疗法相结合 加强抗HIV免疫反应以清除残留物的方法 病毒仍然存在于组织间隔中，如淋巴结节。在早些时候 研究表明，ALX40-4C或N-α-乙酰-诺纳-D-精氨酸酰胺，a 针对趋化因子受体CXCR4的小分子抑制剂 抑制HIV毒株的感染，标记为合胞体诱导(SI)，使用 此共受体(J.Exp.Med.186：1395,1997)。最近，我们已经获得了 分离的CD8+T细胞的程序性细胞死亡或凋亡的证据 HIV感染患者通过相互作用由巨噬细胞(M约)介导 在HIV包膜和趋化因子受体CXCR4之间(自然395：189， 1998年)。我们还观察到，在初步实验中，一个小分子 CXCR4抑制剂双环AMD3100阻断MO介导的CD8+T细胞死亡 体外培养。小分子CXCR4抑制剂，如ALX40-4C和AMD3100， 潜在地干扰病毒复制和免疫细胞损失，以及 因此可能会促进免疫系统的恢复。具体目标如下 以下是： 目的1.比较小分子CXCR4抑制剂与 不同化学结构对HIV诱导的CD8+T细胞的阻断作用 细胞凋亡，我们将测试AMD3100，ALX40-4C和多毛蛋白II的类似物， T134，用于预防CD8+T细胞死亡。 目的2.研究CD8+阻断的分子机制 小分子CXCR4抑制剂在HIV感染中的T细胞凋亡，我们将 首次确定小分子CXCR4抑制剂在阻断血管内皮细胞生长中的作用 CD8+T细胞激活，因为细胞凋亡通常是由T细胞激活引起的。 我们还将评估小分子CXCR4抑制剂在封锁中的作用 Caspase介导的CD8+T细胞凋亡。我们将最终确定是否 小分子CXCR4抑制剂通过阻断HIV诱导的CD8+T细胞凋亡 核因子-kappaB激活增强抗凋亡信号 和/或Bcl-2家族成员的参与。

DESCRIPTION: Combination antiretroviral therapy (HAART) can result in sustained reduction in human immunodeficiency virus (HIV) growth for three to four years. The immune system does not completely recover even with successful HAART, suggesting that immune system damage may be irreversible if treatment consists of HAART only. Therefore HAART should be coupled with alternative therapeutic approaches that strengthen the anti-HIV immune response to clear the residual virus still present in tissue compartments, such as lymph nodes. In earlier studies, we demonstrated that, ALX40-4C or N-a-acetyl-nona-D-arginine amide, a small-molecule inhibitor directed against the chemokine receptor CXCR4, can inhibit infection by HIV strains, labeled syncytium-inducing (SI), that use this co-receptor (J.Exp.Med. 186:1395, 1997). More recently, we have obtained evidence that programmed cell death or apoptosis of CD8+ T cells isolated from HIV-infected patients is mediated by macrophages (M about), via interaction between the HIV envelope and the chemokine receptor CXCR4 (Nature 395:189, 1998). We also observed, in preliminary experiments, that a small-molecule CXCR4 inhibitor, the bicyclam AMD3100, blocks MO-mediated CD8+ T cell death in vitro. Small-molecule CXCR4 inhibitors, such as ALX40-4C and AMD3100, potentially interfere with both viral replication and immune cell loss, and therefore might improve immune system recovery. The specific aims are as follows: Aim 1. To compare the efficiency of small-molecule CXCR4 inhibitors with different chemical structures for the blockade of HIV-induced CD8+ T cell apoptosis, we will test AMD3100, ALX40-4C and an analog of polyphemusin II, T134, for the prevention of CD 8+T cell death. Aim 2. To characterize the molecular mechanisms underlying the blockade of CD8+ T cell apoptosis by small-molecule CXCR4 inhibitors in HIV infection, we will first determine the role of small-molecule CXCR4 inhibitors in the blockade of CD8+ T cell activation, since apoptosis often results from T cell activation. We will also assess the role of small-molecule CXCR4 inhibitors in the blockade of caspase-mediated CD8+ T cell apoptosis. We will ultimately determine whether small-molecule CXCR4 inhibitors block HIV-induced CD8+ T cell apoptosis by enhancing anti-apoptotic signals mediated via nuclear factor-kappa B activation and/or involvement of members of the Bcl-2 family.