Biologic Activity of Transferred HIV-specific CD8 Clones

转移的 HIV 特异性 CD8 克隆的生物活性

• 批准号: 6723761
• 负责人: PHILIP D GREENBERG
• 金额: $ 57.72万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6723761
• 关键词: CD28 molecule; HIV infections; biopsy; cellular immunity; clinical research; clinical trials; clone cells; cooperative study; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; human immunodeficiency virus 1; human subject; immunocytochemistry; immunotherapy; interleukin 2; leukapheresis; lymphatic tissue; microorganism disease chemotherapy; mucosal immunity; patient oriented research; tissue /cell culture; virus replication

DESCRIPTION (provided by applicant): Current antiretroviral therapy (ART) regimens for HIV-1 infection can block viral replication and provide substantial clinical benefit, but long-term therapy can be associated with significant toxicities and does not appear capable of eradicating the virus. Strategies to boost the immune system of infected individuals might provide a means to improve control of residual viral replication on ART, and eventually make it possible to reduce the requirement for ART. Development of effective immune-based therapies would be facilitated if the nature and magnitude of responses required to achieve the desired antiviral[ activity could be defined. Our group has extensive experience with the isolation, in vitro expansion, and adoptive transfer of human virus-specific CD8+ T cell clones as a strategy for establishing strong, functional CD8+ T cell responses, and with modification of CD8+ T cells to introduce genes that enhance T cell function, as well as with highly sensitive molecular techniques to detect viral reservoirs and persistent HIV replication in PBMC, lymphoid tissue, and mucosal tissue of HIV-infected individuals on potent ART. Our preliminary studies suggest that very high and sustained CD8+ responses to HIV might be achievable in HIV-infected individuals on potent ART with low viral burdens by infusion of HIV-specific CD8+ T cell clones followed by a brief course of low dose IL2. Thus, we propose to determine if providing such patients with a high frequency of functional differentiated CD8+ effector cells, specific for either gag or regulatory viral proteins expressed early in the viral life cycle, can contribute to containment of ongoing viral replication and reduction in persistent viral reservoirs. Additionally, one hallmark of HIV infection in comparison to other chronic viral infections is the decline of HIV-specific CD28+CD8+ T cells and accumulation of CD28+CD8+ T cells. The loss of expression of the CD28 costimulatory molecule, presumably from antigen-driven differentiation, has significant consequences on CD8+ T cell function, rendering the cells increasingly dependent on CD4+ T cell help. Our preliminary studies demonstrate that CD28 can be re-expressed in CD28+CD8+ T cells, and that such cells reacquire the ability to produce IL2 and proliferate following specific target recognition. Thus, we propose to genetically modify HIV-specific CD28+CD8+ effector cells and determine if transferred CD28+CD8+ T cells exhibit improved survival, function, and antiviral activity in individuals with detectable plasma viremia.

描述（由申请人提供）：目前针对 HIV-1 感染的抗逆转录病毒治疗 (ART) 方案可以阻止病毒复制并提供显着的临床益处，但长期治疗可能会产生显着的毒性，并且似乎无法根除病毒。增强感染者免疫系统的策略可能提供一种方法来改善对 ART 中残留病毒复制的控制，并最终有可能减少对 ART 的需求。如果能够确定实现所需抗病毒活性所需反应的性质和程度，将有助于开发有效的免疫疗法。我们的团队在人类病毒特异性 CD8+ T 细胞克隆的分离、体外扩增和过继转移方面拥有丰富的经验，作为建立强大的功能性 CD8+ T 细胞反应的策略，并通过修饰 CD8+ T 细胞以引入增强 T 细胞功能的基因，以及使用高度灵敏的分子技术来检测 PBMC、淋巴中的病毒库和持续的 HIV 复制 HIV感染者的组织和粘膜组织接受有效的ART治疗。我们的初步研究表明，通过输注 HIV 特异性 CD8+ T 细胞克隆，然后短期注射低剂量 IL2，接受低病毒负荷的有效 ART 治疗的 HIV 感染者可能可以实现非常高且持续的 CD8+ 对 HIV 的反应。因此，我们建议确定为此类患者提供高频率的功能性分化 CD8+ 效应细胞（针对病毒生命周期早期表达的 gag 或调节病毒蛋白）是否有助于遏制正在进行的病毒复制和减少持久性病毒库。此外，与其他慢性病毒感染相比，HIV 感染的一个标志是 HIV 特异性 CD28+CD8+ T 细胞的减少和 CD28+CD8+ T 细胞的积累。 CD28 共刺激分子表达的丧失（可能是由抗原驱动的分化引起）对 CD8+ T 细胞功能具有显着影响，使细胞越来越依赖 CD4+ T 细胞的帮助。我们的初步研究表明，CD28可以在CD28+CD8+T细胞中重新表达，并且此类细胞在特定靶标识别后重新获得产生IL2和增殖的能力。因此，我们建议对 HIV 特异性 CD28+CD8+ 效应细胞进行基因修饰，并确定转移的 CD28+CD8+ T 细胞在可检测到血浆病毒血症的个体中是否表现出改善的存活、功能和抗病毒活性。