Targeting of cytotoxic T-cells to HIV infected cells

细胞毒性 T 细胞靶向 HIV 感染细胞

• 批准号: 5422175
• 负责人: Professorin Dr. Barbara Sabine Schnierle
• 金额: --
• 依托单位: Paul-Ehrlich-Institut - Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5422175?language=en
• 关键词: Targeting; cytotoxic; cells; HIV; infected

Experimental and clinical data present good evidence that T-cell mediated immune response plays a major role in controlling human immunodeficiency virus (HIV) infection. Cytotoxic T-cells can be engineered to express chimeric receptors directed against HIV infected cells and can serve as HIV specific, MHC-unrestricted effector cells. We will use the designed entry inhibitor 5-Helix to redirect cytotoxic effector cells to HIV infected cells. This HIV binding domain has several advantages over previously used ligands, like CD4 or antibody fragments: 5-Helix mimics the carboxyl-terminal region of the gp41 envelope glycoprotein ectodomain but lacks one helix of the six-helix bundle. It is therefore a high affinity binding domain for gp41 and binds a wide variety of HIV strains. Most importantly, surface exposure of 5-Helix does not support entry of HIV into the cells. A chimeric 5-Helix-zeta receptor gene will be constructed and stably transduced into human T lymphocytes. Specific cytotoxicity of genetically modified T-cells towards HIV Env expressing cells or HIV infected cells will be first tested in vitro and subsequently in vivo. A mouse model with HIV Env expressing cells will be established. The project should prove the feasibility of this targeting approach and should provide the pre-clinical requirements for a future clinical application of this strategy. Gene mo dified autologous T lymphocytes should eliminate residual HIV infected cells in patients under HAART (highly active antiretroviral therapy) treatment or during STI (structured treatment interruption).

实验和临床数据提供了充分的证据，表明 T 细胞介导的免疫反应在控制人类免疫缺陷病毒 (HIV) 感染中发挥着重要作用。细胞毒性 T 细胞可以被设计为表达针对 HIV 感染细胞的嵌合受体，并可以充当 HIV 特异性、MHC 非限制性效应细胞。我们将使用设计的进入抑制剂 5-Helix 将细胞毒性效应细胞重定向到 HIV 感染细胞。与以前使用的配体（例如 CD4 或抗体片段）相比，这种 HIV 结合结构域具有多个优点：5-螺旋模拟 gp41 包膜糖蛋白胞外域的羧基末端区域，但缺少六螺旋束中的一个螺旋。因此，它是 gp41 的高亲和力结合结构域，并结合多种 HIV 毒株。最重要的是，5-螺旋的表面暴露不支持 HIV 进入细胞。将构建嵌合5-螺旋-zeta受体基因并将其稳定转导至人T淋巴细胞中。转基因 T 细胞对 HIV Env 表达细胞或 HIV 感染细胞的特异性细胞毒性将首先在体外进行测试，随后在体内进行测试。将建立具有HIV包膜表达细胞的小鼠模型。该项目应证明这种靶向方法的可行性，并应为该策略未来的临床应用提供临床前要求。基因修饰的自体 T 淋巴细胞应消除接受 HAART（高效抗逆转录病毒治疗）治疗或 STI（结构化治疗中断）期间患者体内残留的 HIV 感染细胞。