Active Movement of Immune Cells Away From HIV-1 gp120

免疫细胞主动运动远离 HIV-1 gp120

• 批准号: 6867443
• 负责人: MARK Coleman POZNANSKY
• 金额: $ 34.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867443
• 关键词: HIV envelope protein gp120; HIV infections; biological signal transduction; cell migration; cellular immunity; chemokine; chemotaxis; clinical research; cytokine receptors; cytotoxic T lymphocyte; human subject; laboratory mouse; microorganism immunology; monocyte; receptor binding

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.

描述：（由申请人提供）HIV-1感染的发病率继续 尽管发展 候选疫苗和高度活跃的抗逆转录病毒疗法（I-IAART）。这是 现在清楚地表明，艾滋病毒 - 我在人类中建立了慢性感染 尽管存在HI V特异性细胞，免疫系统仍无法消除 介导的和体液免疫反应。 HIV-1利用各种机制 为了逃避免疫系统，包括感染和杀害 艾滋病毒特异性助手T细胞，维持潜在状态和突变 它的免疫原性蛋白GP120。我们建议HIV-1蛋白（例如 GP120干扰免疫细胞迁移，使感染HIV的细胞得以 宿主免疫效应细胞逃脱挑战。我们最近证明了 静止的T细胞脱离趋化因子的基质细胞衍生 因子I（SDF-1）和HIV-1IIIB GP120，在介导的CXCR4受体中 浓度依赖于体外和体内。此外，我们显示了 静止T细胞移动的细胞内信号通路 从SDF-1或HIV-1 GP120均与向朝向的运动不同 趋化剂。鉴于这些初步发现，我们打算定义 免疫效应细胞对HIV-1 GP120的迁移反应，这是已知的 直接参与体内HJV感染的免疫控制。在这个 我们建议确定免疫效应细胞的运动是否 远离HIV-1GP120有助于HIV-1逃避的新机制 免疫系统。该提议有三个目标。 1）表征 活化的T细胞的迁移响应，包括HI V特异性细胞毒性 淋巴细胞（CTL）和单核细胞远离CCR5结合趋化因子和CCR5 使用许多已建立的体外转移的结合HIV-1 GP120 测定。 2）免疫效应子迁移的生化表征 使用一系列信号转导的细胞远离CCR5结合HIV-1 GP120 途径抑制剂，GP120分子的突变体和抗体 针对GP120及其趋化因子共受体结合位点3）。定义 HIV-L GP120诱导免疫效应细胞迁移的调节的作用 使用HIV-1 GP120的动物模型系统的体内，并 定量对WV -1蛋白的免疫反应的调节。在这些 我们希望扩大对人类为什么不遏制HIV-1的理解的方式 感染并促进新型疗法的设计，最终将 协助在HI V感染的个体中消除病毒。