ROLE OF MEMORY T CELL DYNAMICS IN SIV INFECTION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们的工作提供了令人信服的证据，表明SIVmac239感染猕猴(RM)的免疫缺陷的发生与CD4记忆T细胞动力学模式密切相关，反映了病毒直接细胞致病性和持续免疫激活对CD4记忆T细胞增殖、分化和存活的间接影响的复杂相互作用。我们的数据有力地表明，效应部位、CD4效应记忆(TEMs)数量低于关键阈值是显性免疫缺陷的主要近端机制，但值得注意的是，也表明在CCR5嗜好的SIV感染中，即使病毒介导的大规模破坏CD4TEMs，也很少(如果有的话)足以导致该人群的功能衰竭。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(Medics)产生新的TM的能力决定的，而这反过来又取决于CD4Medics群体本身的维持。在慢性SIV感染中，我们发现CD4Tcm数量的缓慢下降和通常的增殖活性是导致CD4TEM群衰竭的基础，并为临床疾病的发病设定了时钟。最近的工作集中在导致CD4中医体内平衡失稳的机制，特别是IL-7和IL-15在维持CD4中医体内平衡中的作用，以及在进行性SIV感染期间，从新的中药室补充新的中药材与再生原有的中药材在维持CD4中医药室中的相对贡献。在胸腺切除的猴子中，通过mAb介导的CD4T细胞的耗尽，我们在没有胸腺的情况下记忆细胞再生后创造了“无幼稚的CD4细胞”RM。重要的是，在SIV感染后，缺乏NAVE的CD4T细胞隔间对维持CD4Memory T细胞几乎没有可测量的影响，这表明这一群体的维持主要依赖于先前存在的记忆细胞的再生，而不是NAVE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CD8T细胞影响SIV复制和发病的机制。

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.