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: 6632464
• 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/6632464
• 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感染的发病率仍在继续 世界人口的增长，尽管发展， 候选疫苗和高效抗逆转录病毒疗法（I-IAART）。是 现在很清楚，HIV-1在人类中建立了一种慢性感染， 尽管存在HIV特异性细胞，但免疫系统未能根除 介导和体液免疫应答。HIV- 1利用各种机制， 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，维持潜伏状态和突变， 其免疫原性包膜蛋白，gp 120。我们认为，HIV-1蛋白，如 gp 120干扰免疫细胞迁移，使HIV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， 因子-I（SDF-1）和HIV-1 IIIB gp 120，在CXCR 4受体介导的和 浓度依赖性的方式在体外和体内。此外，我们还展示了 细胞内的信号传导途径将静止的T细胞 从SDF-1或HIV-1 gp 120中的表达与向 化学动力学试剂。根据这些初步发现，我们打算定义 已知免疫效应细胞对HIV-1 gp 120的迁移反应 直接参与体内HJV感染的免疫控制。在这 我们提出的方法是确定免疫效应细胞的运动 远离HIV-1gp 120有助于一种新的机制，通过这种机制，HIV-1逃避了HIV-1gp 120。 免疫系统该提案有三个目标：（1） 活化T细胞的迁移反应，包括HIV特异性细胞毒性 淋巴细胞（CTL）和单核细胞远离CCR 5结合趋化因子和CCR 5 使用许多已建立的体外迁移结合HIV-1 gp 120 测定。2)免疫效应物迁移的生化特征 使用一系列信号转导使细胞远离结合HIV-1 gp 120的CCR 5 途径抑制剂、gp 120分子的突变体和针对 针对GP 120及其趋化因子共受体结合位点3）。的定义 HIV-1 gp 120诱导免疫效应细胞迁移调节在 使用表达HIV-1 gp 120的动物模型系统， 定量对WV-1蛋白的免疫应答的调节。在这些 我们希望通过这些方法来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， 有助于根除HIV感染者体内的病毒。