Active Movement of Immune Cells Away From HIV-1 gp120

描述：(申请人提供)HIV-1感染的发病率仍在继续 尽管……的发展，世界各地的人口仍在增加 候选疫苗和高效抗逆转录病毒疗法(I-IAART)。它是 现在清楚的是，HIV-I在人类中建立了一种慢性感染，宿主 尽管存在HI V特异性细胞，免疫系统仍无法根除 介导性和体液免疫反应。HIV-1利用不同的机制 为了逃避免疫系统，包括感染和杀死 HIV特异性辅助性T细胞潜伏状态的维持和突变 其免疫原膜蛋白gp120。我们认为HIV-1蛋白如 Gp120干扰免疫细胞迁移，使艾滋病毒感染细胞 逃避宿主免疫效应细胞的攻击。我们最近展示了 静止的T细胞远离趋化因子，基质细胞来源 因子I(SDF-1)和HIV-1IIIB gp120，在CXCR4受体介导的和 体外和体内均呈浓度依赖关系。此外，我们还展示了 静息T细胞运动的细胞内信号通路 来自SDF-1或HIV-1的gp120不同于向 化学动剂。鉴于这些初步发现，我们打算定义 已知免疫效应细胞对HIV-1 gp120的迁移反应 直接参与HJV体内感染的免疫控制。在这 我们会提出一种方法来确定免疫效应细胞的运动 远离HIV-1gp120有助于HIV-1逃避 免疫系统。该提案有三个目标：1)对 活化T细胞的迁移反应，包括HI V特异性细胞毒 远离CCR5结合趋化因子和CCR5的淋巴细胞(CTL)和单核细胞 结合HIV-1 gp120的多个已建立的体外移行 化验。2)免疫效应物迁移的生化特征 利用一组信号转导使细胞远离CCR5结合HIV-1 gp120 途径抑制物、gp120分子突变体和抗体 抗gp120及其趋化因子共受体结合位点3)。概念的定义 HIV-L gp120诱导的免疫效应细胞迁移的调节作用 使用在其中表达HIV-1 gp120和 对WV-1蛋白的免疫反应的调节是定量的。在这些 我们希望扩大对人类为什么不能控制HIV-1的理解 并促进新疗法的设计，最终将 协助根除HI V感染者体内的病毒。

DESCRIPTION: (provided by applicant) The incidence of HIV-1 infection continues to rise in populations throughout the world despite the development of candidate vaccines and highly active anti-retroviral therapy (I-IAART). It is now clear that HIV- I establishes a chronic infection in humans which the host immune system fails to eradicate despite the presence of HI V-specific cell mediated and humoral immune responses. HIV- 1 exploits various mechanisms in order to evade the immune system including the infection and killing of HIV-specific helper T-cells, the maintenance of a latent state and mutation of its immunogenic envelope protein, gp120. We propose that HIV-1 proteins such as gp120 interfere with immune cell migration allowing HIV-infected cells to escape challenge by host immune effector cells. We have recently demonstrated that resting T-cells move away from the chemokine, stromal-cell derived factor-I (SDF-1) and HIV-1IIIB gp120, in a CXCR4 receptor mediated and concentration dependent manner in vitro and in vivo. In addition, we showed that the intracellular signaling pathway for movement of resting T-cells away from both SDF-1 or HIV-1 gp120 was distinct from that for movement towards the chemokinetic agents. In view of these preliminary findings we intend to define the migratory responses to HIV-1 gp120 of immune effector cells which are known to be directly involved in the immune control of HJV infection in vivo. In this way we would propose to determine whether movement of immune effector cells away from HIV-1gp120 contributes to a novel mechanism by which HIV-1 evades the immune system. The proposal has three aims; 1) The characterization of the migratory response of activated T-cells, including HI V-specific cytotoxic lymphocytes (CTLs), and monocytes away from CCR5 binding chemokines and CCR5 binding HIV-1 gp120 using a number of established in vitro transmigration assays. 2) The biochemical characterization of the migration of immune effector cells away from CCR5 binding HIV-1 gp120 using a battery of signal transduction pathway inhibitors, mutants of the gp120 molecule and antibodies directed against gp120 and its chemokine co-receptor binding site 3). The definition of the role of HIV-l gp120 induced modulation of immune effector cell migration in vivo using animal model systems in which HIV-1 gp120 is expressed and modulation of the immune response to the WV -1 protein is quantitated. In these ways we hope to expand the understanding of why humans fail to contain HIV- 1 infection and to facilitate the design of novel therapies that will ultimately assist in the eradication of the virus in the HI V-infected individual.