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: 6201437
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201437
• 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.

清除通常情况下非常高水平的血浆病毒血症 伴随急性艾滋病毒感染是宿主免疫的结果 对病毒的反应。尽管免疫系统有这种能力 介导病毒负荷的大幅下降，艾滋病毒最终逃脱 免疫控制。 CD4+ T 辅助反应已被证明是 遏制慢性病毒感染所必需的，也是 HIV 感染是一种从疾病早期就出现的缺陷 CD4+ T 细胞对病毒有大量反应。因此，纠正策略 这种缺陷，特别是与新的抗逆转录病毒药物联合使用时 疗法，可能会改善对艾滋病毒的控制。我们实验室有 开发了分离、克隆和扩展病毒特异性 CD4+ T 的方法 体外细胞，并已证明此类 T 细胞的过继转移 细胞可以在体内重建缺陷的 CD4+ T 细胞反应。有 将这项技术应用于治疗艾滋病毒的几个障碍—— 最重要的是，转移的 HIV 特异性 CD4+ T 细胞可能会 定位于感染部位并面临快速删除的风险。 因此，正在探索在之前修改这些细胞的方法 通过引入使它们对艾滋病毒具有抵抗力的基因进行输注 感染，一种称为细胞内免疫（IC-imm）的技术。这 向艾滋病毒感染者施用大量此类药物 自体、受保护、HIV 特异性 CD4+ T 细胞应提供独特的 评估有效免疫反应对艾滋病毒影响的机会。 拟议的研究包括临床前实验，以开发改进的 保护 CD4+ T 细胞免受 HIV 感染的分子策略，以及 确定 CD4+ T 细胞体内生物活性的临床试验 表达这些基因。具体目标是：（1）体外评价 IC-imm 基因旨在预防感染以保存 暴露于感染性病毒的 HIV 特异性 CD4+ T 细胞的存活和功能 HIV 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)评价IC-imm基因的能力 保护和保存过继转移的艾滋病毒特异性功能 CD4+ 计数大于 200 且患有以下疾病的患者中的 CD4+ T 细胞 HIV/ml 超过 1000 个拷贝； (3)评估能力 过继转移的 gp-160 特异性 CD4+ T 细胞克隆表达 IC- imm 基因持续存在并调节个体的抗病毒免疫力 CD4+计数大于200且血浆的抗逆转录病毒治疗 病毒血症介于 50 至 500 个 HIV 拷贝/毫升之间； (4) 确定是否 转移 HIV 特异性 CD4+ T 细胞，抵抗 HIV 和 HIV 特异性 原发性 HIV 感染患者中的 CD8+ CTL 可以提供持续的治疗 对艾滋病毒的细胞免疫。