EVALUATION OF ADOPTIVE T CELL THERAPY FOR HIV

HIV特异性CD 8 + CTL应答与对照组密切相关。 艾滋病毒感染。 然而，这些CTL应答最终会下降， 在疾病进展和病毒控制丧失期间。 治疗 增强部分有效的宿主HIV特异性CD 8 + CTL的策略 这种反应可能有效地重新控制艾滋病毒。结合 与实验室的其他人一起，我评估了过继免疫疗法， 体外扩增的、自体的、基因修饰的艾滋病毒感染， 特异性CD 8 + CTL克隆以增强CTL应答的功效。 这种初始治疗的有效性有限，因为 转移的CTL的存活期缩短，可能部分是由于 辅助性T细胞功能不足。 T- 辅助功能可能通过静脉输注恢复 IL-2，或通过自体HIV特异性CD 4 + T辅助细胞的转移 (Th)克隆 转移的CD 4 + Th克隆的存活可能 通过基因修饰来表达IC-imm基因， 使细胞通过干扰 病毒生命周期中的关键步骤 在以前审判的基础上， 我们计划评估HIV感染的过继免疫疗法， CTL具有辅助性T细胞活性。 在本申请中，本人建议 扩展了我以前的研究， 本试验的分析，以评估抗病毒作用和潜力 HIV过继免疫疗法疗效有限的原因。 的 具体目标是：在HIV+个体中评估HIV的免疫疗法 用体外扩增的自体新标记的GAG特异性CD 8 + CTL 克隆，通过静脉内输注IL-2或补充 通过转移表达IC-imm基因的HIV特异性CD 4 + Th克隆; 并确定HIV特异性CD 4 + Th克隆的转移是否 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能促进持久性， 体内扩增和转移细胞的功能，并评估 如果疗效的局限性是由于HIV变异体的选择 具有被转移细胞识别的HIV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的和独特的 研究宿主对病毒病原体防御的环境。 我的主要 在这个实验室工作的目标是应用现代T 细胞免疫学研究宿主对HIV的防御。 我的长期目标是 在一个学术医疗中心工作，作为一名医生科学家， 主要关注HIV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.