MEASUREMENT OF T CELL TURNOVER IN SIV INFECTION AND FOLLOWING INTERVENTIONS

直接测量SIV感染及随访中的T细胞更新 药理学和免疫学干预。 我们假设，免疫低反应性的演变， HIV/SIV感染可以通过TR细胞替换的动力学来解释。 一些间接的证据指向一个过程， 病毒介导的CD 4 + T细胞的损失被T细胞替代所抵消 一开始是成功的，但最终失败了。结果免疫 缺乏最终进展为临床AIDS或SAIDS。是 本建议的目的是直接测试假设， 疾病特征是新生代的高比率， 替代T细胞（CD 4+和CD 8+），以及高凋亡率， 其结果是新产生的短 存活的初始T细胞我们假设CD 4 + T细胞记忆的侵蚀 隔室导致T淋巴细胞生成与快速周转动力学： 大多数新产生的成熟T细胞不能接受存活 信号（由预先存在的CD 4+记忆细胞和树突细胞提供） 和果糖，然后它们可以进行抗原驱动的选择， 成熟为效应细胞。这一假设只能通过直接检验。 T细胞更新的测量和表型的确定， 替代T细胞的功能能力和命运。为此我们 建议应用多参数流式细胞术方法， 同时测定细胞表面免疫表型、生长 SIV/恒河猴模型的细胞凋亡动力学。营业额将是 在SIV感染前、感染早期和晚期， 感染，以及化疗和免疫治疗后。第二和 该项目的相关目标是顺序监控 感染和治疗的动物，以建立抗原特异性回忆和原发性 T细胞和抗体反应。拟议的研究旨在 直接与本计划项目的项目I和项目II接口， 哪两种不同的SIV特异性辅助免疫治疗方法将 得到考验

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.