TRANSFER OF HIV-SPECIFIC CD4+ T CELL CLONES WITH GENES INHIBITING HIV

转移具有抑制 HIV 基因的 HIV 特异性 CD4 T 细胞克隆

• 批准号: 6344654
• 负责人: PHILIP D GREENBERG
• 金额: $ 25.13万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344654
• 关键词: AIDS therapy; HIV envelope protein gp160; HIV infections; biomarker; cell migration; cellular immunity; clinical research; clinical trials; combination therapy; gene expression; gene therapy; genetic manipulation; genetic transduction; helper T lymphocyte; human immunodeficiency virus; human subject; human therapy evaluation; lymph nodes; lymphocyte proliferation; passive immunization; transfection /expression vector; virus genetics; virus load; virus replication

Clearance of the very high levels of plasma viremia that generally accompany acute infection with HIV is a consequence of host immune responses to the virus. Despite this ability of the immune system to mediate a profound decline in viral burden, HIV eventually evades immunologic control. CD4+ T helper responses have been shown to be necessary for containment of chronic viral infections, and one hallmark of HIV infection is the deficiency from very early in disease of a substantial CD4+ T cell response to the virus. Thus, strategies to correct this deficiency, particularly if combined with new antiretroviral drug therapies, might result in improved control of HIV. Our laboratory has developed methods to isolate, clone, and expand virus-specific CD4+ T cells in vitro, and has demonstrated that adoptive transfer of such T cells can reconstitute deficient CD4+ T cell responses in vivo. There are several obstacles to applying this technology to the treatment of HIV-- most significantly, transferred HIV-specific CD4+ T cells would likely localize to sites of infection and be at risk for rapid deletion. Therefore, methods are being explored to modify these cells prior to infusion by the introduction of genes that render them resistant to HIV infection, a technique termed intracellular immunization (IC-imm). The administration to HIV-infected individuals of large numbers of such autologous, protected, HIV-specific CD4+ T cells should provide a unique opportunity to assess the impact of a competent immune response on HIV. The proposed studies include preclinical experiments to develop improved molecular strategies to protect CD4+ T cells from infection by HIV, and clinical trials to determine the in vivo biologic activity of CD4+ T cells expressing these genes. The specific aims are to: (1) evaluate in vitro the ability of IC-imm genes designed to prevent infection to preserve the survival and function of HIV-specific CD4+ T cells exposed to infectious HIV and to compare this antiviral activity with IC-imm genes designed to inhabit viral replication; (2) evaluate the ability of IC-imm genes to protect and preserve the function of adoptive transferred HIV-specific CD4+ T cells in patients with CD4+ counts greater than 200 and with greater than 1000 copies of HIV/ml; (3) evaluate the ability of adoptively-transferred gp-160-specific CD4+ T cell clones expressing IC- imm genes to persist and modulate antiviral immunity in individuals on anti-retroviral therapy with CD4+ counts greater than 200 and plasma viremia between 50 and 500 copies of HIV/ml; and (4) determine if the transfer of HIV-specific CD4+ T cells resistant to HIV and of HIV-specific CD8+ CTL in patients with primary HIV infection can provide persistent cellular immunity to HIV.

清除非常高水平的血浆病毒血症， 伴随急性感染HIV是宿主免疫的结果， 对病毒的反应。尽管免疫系统有能力 介导病毒负荷的深刻下降，艾滋病毒最终逃避 免疫控制CD 4+辅助性T细胞反应已被证明是 控制慢性病毒感染所必需的， 艾滋病病毒感染是一种从疾病的早期就缺乏的疾病， CD 4 + T细胞对病毒的反应。因此， 这种缺陷，特别是如果与新的抗逆转录病毒药物结合使用， 治疗，可能会改善对艾滋病毒的控制。本实验室 开发了分离、克隆和扩增病毒特异性CD 4 + T细胞的方法 细胞在体外，并已证明，过继转移这样的T 细胞可以在体内重建缺陷的CD 4 + T细胞应答。有 将这项技术应用于艾滋病治疗的几个障碍-- 最重要的是，转移的HIV特异性CD 4 + T细胞可能 定位于感染部位并有快速缺失的风险。 因此，正在探索方法以在将这些细胞转化为细胞之前对其进行修饰。 通过引入使其对艾滋病毒具有抵抗力的基因进行输液 感染，一种称为细胞内免疫（IC-imm）的技术。的 向HIV感染者施用大量的这种 自体的，受保护的，HIV特异性的CD 4 + T细胞应该提供一种独特的， 有机会评估一个合格的免疫反应对艾滋病毒的影响。 拟议的研究包括临床前实验，以开发改进的 保护CD 4 + T细胞免受HIV感染的分子策略，以及 确定CD 4 + T细胞体内生物活性的临床试验 表达这些基因。具体目的是：（1）体外评价 IC-imm基因设计用于预防感染， HIV特异性CD 4 + T细胞暴露于感染性 并将这种抗病毒活性与IC-imm基因进行比较， 抑制病毒复制;（2）评估IC-imm基因抑制病毒复制的能力。 保护和维护过继转移的艾滋病毒特异性 CD 4 + T细胞计数大于200且 大于1000拷贝/ml的HIV;（3）评估 过继转移的表达IC-160的gp-160特异性CD 4 + T细胞克隆 imm基因持续存在并调节个体的抗病毒免疫 抗逆转录病毒治疗，CD 4+计数大于200，血浆 病毒血症在50和500拷贝HIV/ml之间;和（4）确定 HIV特异性CD 4 + T细胞的转移 原发性HIV感染患者中的CD 8 + CTL可以提供持续的 对艾滋病病毒的细胞免疫。