EVALUATION OF ADOPTIVE T CELL THERAPY FOR HIV

HIV特异性CD8+CTL反应与控制密切相关 艾滋病毒感染的可能性。然而，这些CTL反应最终会下降 在疾病进展和病毒控制丧失的过程中。治疗性的 增强部分有效宿主HIV特异性CD8+CTL的策略 应对措施在重新控制艾滋病毒方面可能是有效的。结合 我和实验室里的其他人一起评估了过继免疫疗法 用体外扩增的、自体的、基因修饰的艾滋病毒感染艾滋病毒- 特异性CD8+CTL克隆，以增强CTL反应的效力。 这种最初疗法的有效性是有限的，因为 转移的CTL的存活时间缩短可能部分是由于 这些HIV+患者存在T辅助功能不足。T- 辅助功能有可能通过静脉输液恢复 IL-2，或通过转移自体HIV特异性CD4+T辅助细胞 (Th)克隆。被转移的CD4+Th克隆很可能存活下来 通过遗传修饰表达IC-IMM基因进行改良，该基因 通过干扰使细胞对艾滋病毒复制具有抵抗力 病毒生命周期中的关键步骤。在之前试验的基础上， 我们计划评估CD8+过继免疫疗法对HIV感染的影响 CTL具有T辅助活动。在本申请中，我建议 扩展我之前的研究，进行免疫学和病毒学研究 本试验分析以评价抗病毒效果和潜力 HIV过继免疫治疗疗效受限的原因。这个 具体目标是：评估HIV+个体的HIV免疫治疗 用体外扩增的、自体的、新标记的GAG特异性CD8+CTL 克隆，通过静脉输注IL-2补充或补充 通过转移表达IC-IMM基因的HIV特异性CD4+Th克隆； 并确定转移HIV特异性的CD4+Th克隆是否 单独表达IC-IMM基因将增强HIV特异性免疫。 研究将确定这些干预措施是否促进了持久性， 体内扩增和转移细胞的功能及评价 如果疗效的限制是由于选择HIV变种造成的 随着被转移细胞识别的艾滋病毒表位的突变。 我选择在菲利普·格林伯格博士的实验室继续我的研究 在FHCRC，因为我觉得它提供了一个杰出和独特的 研究宿主对病毒病原体的防御的环境。我的初选 在这个实验室工作的目标是应用现代科学技术 细胞免疫学用于研究宿主对HIV的防御。我的长期目标是 以内科科学家的身份在学术医学中心工作 主要关注艾滋病毒感染的免疫发病机制。

HIV-specific CD8+ CTL responses are strongly implicated in the control of HIV infection. However, these CTL responses eventually decline during disease progression and viral control is lost. Therapeutic strategies to augment the partially effective host HIV-specific CD8+ CTL response may be efficacious in regaining control of HIV. In conjunction with others in the laboratory, I have evaluated adoptive immunotherapy of HIV infection with in vitro expanded, autologous, gene-modified HIV- specific CD8+ CTL clones to enhance the efficacy of the CTL response. The effectiveness of this initial therapy was limited because of shortened survival of the transferred CTL likely due in part to insufficient T-helper function present in these HIV+ individuals. T- helper function could potentially be restored by intravenous infusions of IL-2, or by the transfer of autologous HIV-specific CD4+ T helper (Th) clones. The survival of transferred CD4+ Th clones would likely be improved by genetic modification to express IC-imm genes, which render cells resistant to replication of HIV by interfering with critical steps in the viral life cycle. Building on previous trials, we plan to evaluate adoptive immunotherapy of HIV infection with CD8+ CTL provided with T helper activity. In this application, I propose to extend my previous studies and perform immunologic and virologic analyses of this trial to evaluate the anti-viral effect and potential reasons for efficacy limitations of adoptive immunotherapy for HIV. The specific aims are: To evaluate in HIV+ individuals immunotherapy for HIV with in vitro-expanded, autologous, neo-marked Gag-specific CD8+ CTL clones, supplemented by intravenous infusions of IL-2 or supplemented by the transfer of HIV-specific CD4+ Th clones expressing IC-imm genes; and to determine if the transfer of HIV-specific CD4+ Th clones expressing IC-imm genes alone will augment HIV-specific immunity. Studies will determine if these interventions promote the persistence, in vivo expansion, and function of the transferred cells and evaluate if limitations of efficacy result from the selection of HIV variants with mutation of the HIV epitopes recognized by transferred cells. I have chosen to pursue my research in Dr. Philip Greenberg's laboratory at the FHCRC because I feel that it offers an outstanding and unique environment in which study host defense to viral pathogens. My primary goal in working in this laboratory is to apply techniques of modern T cell immunology to studying host defense to HIV. My long-term goal is to work in an academic medical center as a physician scientist with a primary focus on the immunopathogenesis of HIV infection.