ROLE OF MEMORY T CELL DYNAMICS IN SIV INFECTION

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我们的工作提供了令人信服的证据，表明恒河猴 (RM) 致病性 SIVmac239 感染中免疫缺陷的发生与 CD4 记忆 T 细胞动力学模式密切相关，并反映了直接病毒细胞致病性的复杂相互作用，以及持续免疫激活对 CD4 记忆 T 细胞增殖、分化和存活的间接影响。 我们的数据强烈暗示效应位点的下降，CD4效应记忆（TEM）群体低于关键阈值，是明显免疫缺陷的主要近因机制，但重要的是，也证明在CCR5嗜性SIV感染中，即使病毒介导的CD4 TEM的大规模破坏也很少（如果有的话）足以导致该群体的功能衰竭。相反，我们的数据表明，这种失败在很大程度上是由 CD4 中央记忆 T 细胞 (TCM) 产生新 TEM 的能力决定的，而这又取决于 CD4 TCM 群体本身的维持。 在慢性 SIV 感染中，我们发现 CD4 TCM 数量的缓慢下降以及增殖活性的缓慢下降是 CD4 TEM 群体失败的基础，并为明显疾病的发作“设定了时钟”。 最近的工作集中在导致CD4 TCM稳态失败的机制，特别是IL-7和IL-15在维持CD4 TCM稳态中的作用，以及在进行性SIV感染期间从初始区室招募新的TCM与先前存在的TCM再生在维持CD4 TCM区室中的相对贡献。 通过单克隆抗体介导的胸腺切除猴体内 CD4 T 细胞的耗竭，我们在记忆细胞在没有胸腺的情况下再生后创建了“CD4 naiveless”RM。 重要的是，幼稚 CD4 T 细胞区室的缺乏对 SIV 感染后 CD4 记忆 T 细胞的维持几乎没有可测量的影响，这表明该群体的维持主要取决于先前存在的记忆细胞的再生，而不是幼稚细胞的招募。 该项目的其他工作着眼于 SIV 感染中的 B 细胞动力学以及 CD8 T 细胞影响 SIV 复制和发病机制的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our work has provided compelling evidence that the onset of immune deficiency in pathogenic SIVmac239 infection of rhesus macaques (RM) is intimately linked with patterns of CD4+ memory T cell dynamics, and reflects a complex interplay of direct viral cytopathogenicity, and the indirect effects of persistent immune activation on CD4+ memory T cell proliferation, differentiation and survival. Our data have strongly implicated a decline in effector site, CD4+ effector memory (TEM) populations below a crucial threshold as a major proximate mechanism of overt immunodeficiency, but significantly, have also demonstrated that in CCR5-tropic SIV infection, even massive viral-mediated destruction of CD4+ TEM is rarely, if ever, sufficient for functional failure of this population. Instead, our data indicate that this failure is determined in large part by the ability of CD4+ central memory T cells (TCM) to produce new TEM, which in turn depends on the maintenance of the CD4+ TCM population itself. In chronic SIV infection, we found that a slow decline of the number and often, proliferative activity of CD4+ TCM underlies CD4+ TEM population failure, and "sets the clock" for the onset of overt disease. Recent work has focused on the mechanisms responsible for CD4+ TCM homeostatic failure, in particular the role of IL-7 and IL-15 in maintaining CD4+ TCM homeostasis and the relative contribution of recruitment of new TCM from the na¿ve compartment vs. regeneration of pre-existent TCM in the maintenance of the CD4+ TCM compartment during progressive SIV infection. By mAb-mediated depletion of CD4+ T cell in thymectomized monkeys, we have created "CD4 naiveless" RM after memory cells regenerate in the absence of a thymus. Importantly, the lack of a na¿ve CD4+ T cell compartment has little measureable effect on the maintenance of CD4+ memory T cells after SIV infection, suggesting that maintenance of this population depends predominantly on the regeneration of pre-existent memory cells as opposed to na¿ve cell recruitment. Other work in this project has looked at B cell dynamics in SIV infection and mechanisms by which CD8+ T cells affect SIV replications and pathogenesis.