MEASUREMENT OF T CELL TURNOVER IN SIV INFECTION AND FOLLOWING INTERVENTIONS

SIV感染后T细胞周转率的直接测定 药理和免疫治疗干预。 我们假设免疫低反应性的进化是在 HIV/SIV感染可以用T细胞替换的动态过程来解释。 几条间接的证据表明，在这个过程中 病毒介导的CD4+T细胞丢失可通过T细胞替代来对抗 它起初是成功的，但最终失败了。随之而来的免疫 缺乏最终会发展为临床艾滋病或SAID。它是 这一提议的目的是直接检验后期的假设 这种疾病的特点是新生代的比率很高 替代T细胞(CD4+和CD8+)，以及高凋亡率， 其结果是新产生的空头逐渐占据主导地位 活着的幼稚T细胞。我们假设对CD4+T细胞记忆的侵蚀 隔室导致T淋巴细胞生成和快速周转动力学： 大多数新生成的成熟T细胞无法存活 信号(由原有的CD4+记忆细胞和树突状细胞提供) 在它们可以接受抗原驱动的选择和 成熟为效应细胞。这一假设只能通过直接 T细胞周转率测量和表型测定， 替代T细胞的功能能力和命运。为此，我们 建议将多参数流式细胞仪方法应用于 同时测定细胞表面免疫表型、生长和 SIV/恒河猴模型的细胞凋亡动力学。营业额将是 在SIV感染之前、在SIV感染早期和晚期对动物进行测量 感染，化疗和辅助免疫治疗后。一秒钟，然后 该项目的相关目标是顺序监测 感染和治疗的动物安装抗原特异性召回和初级 T细胞和抗体反应。拟议的研究旨在 直接与该计划项目的项目I和II对接，在 哪两种不同的SIV特异性辅助免疫治疗方法将 接受测试。

Direct measurement of T-cell turnover in SIV infection and following pharmacologic and immunotherapeutic interventions. We have hypothesized that the evolution of immune hyporesponsiveness in HIV/SIV infection can be explained by the dynamics of TR cell replacement. Several indirect lines of evidence point to a process in which chronic virus mediated loss of CD4+ T cells is countered by T cell replacement which is successful at first, but ultimately fails. The consequent immune deficiency culminates in progression to clinical AIDS or SAIDS. It is the purpose of this proposal to directly test the hypothesis that late stage disease is characterize by a high rate of de novo generation of replacement T cells (CD4+ and CD8+), and a high apoptosis rate, the consequence of which is the gradual dominance of newly generated short lived naive T cells. We hypothesize that erosion of the CD4+ T cell memory compartment results in T lymphopoiesis with rapid turnover kinetics: the majority of newly generated mature T cells fail to receive survival signals (provided by preexisting CD4+ memory cells and dendritic cells) and apoptose before they can undergo antigen driven selection and maturation to effector cells. This hypothesis can only be tested by direct measurement of T-cell turnover and determination of the phenotype, functional capacity and fate of replacement T cells. To this end we propose to apply multi-parametric flow cytometric methods suitable for the simultaneous determination of cell surface immunophenotype, growth and apoptosis kinetics to the SIV/rhesus macaque model. Turnover will be measured in animals before SIV infection, at early and late stages of infection, and after chemo- and adjunctive immuno-therapy. A second and related goal of this project is to sequentially monitor the ability of infected and treated animals to mount antigen specific recall and primary T cell and antibody responses. The proposed studies are designed to directly interface with projects I and II of this program project, in which two distinct approaches to SIV-specific adjuvant immunotherapy will be tested.