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）：HIV-1感染的当前抗逆转录病毒疗法（ART）方案可以阻止病毒复制并提供可观的临床益处，但是长期治疗可能与显着毒性有关，并且似乎无法消除病毒。增强感染个体免疫系统的策略可能会提供一种方法来改善对艺术的残留病毒复制的控制，并最终使减少艺术需求成为可能。如果实现所需抗病毒所需的反应的性质和反应的性质和大小，则可以促进有效的基于免疫疗法的发展[可以定义活性。我们的小组在隔离，体外扩张和人类病毒特异性CD8+ T细胞克隆的隔离，体外扩张和过继转移方面具有丰富的经验艾滋病毒感染者的组织和粘膜组织。我们的初步研究表明，通过输注HIV特异性的CD8+ T细胞克隆，在有效的病毒负担的有效ART中，对HIV感染的人来说，对HIV的CD8+反应非常高，对HIV的反应可能是可以实现的，然后是短剂量的低剂量IL2。因此，我们建议确定在病毒生命周期早期表达的GAG或调节病毒蛋白的功能分化CD8+效应细胞的高频率是否可以有助于遏制持续的病毒复制和持续病毒储层的持续减少。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细胞的下降以及CD28+ CD8+ T细胞的积累。 CD28共刺激分子的表达丧失，大概是由于抗原驱动的分化，对CD8+ T细胞功能产生了重大影响，从而使细胞越来越依赖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，并且此类细胞重新验证产生IL2并在特定目标识别后增殖的能力增殖。因此，我们建议在遗传上修改HIV特异性CD28+ CD8+效应细胞，并确定转移的CD28+ CD8+ T细胞是否表现出可检测到的血浆病毒性患者的生存率，功能和抗病毒活性的改善。