ROLE OF MEMORY T CELL DYNAMICS IN SIV INFECTION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心赠款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子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，致病性SIVmac 239感染恒河猴（RM）的免疫缺陷的发病与CD 4+记忆T细胞动力学模式密切相关，并反映了直接病毒致细胞病变的复杂相互作用，以及持续免疫激活对CD 4+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了效应位点的下降，CD 4+效应记忆（TEM）群体低于一个关键阈值，作为明显免疫缺陷的一个主要的近似机制，但重要的是，也证明了在CCR 5嗜性SIV感染，即使是大规模的病毒介导的CD 4 + TEM的破坏很少，如果有的话，足以使这个群体的功能衰竭。相反，我们的数据表明，这种失败在很大程度上是由CD 4+中央记忆T细胞（TCM）产生新的TEM的能力决定的，这反过来又取决于CD 4 + TCM群体本身的维持。 在慢性SIV感染中，我们发现CD 4 + TCM的数量和增殖活性的缓慢下降是CD 4 + TEM群体失败的基础，并为明显疾病的发作“设置时钟”。 最近的工作集中在负责CD 4 + TCM稳态失败的机制，特别是IL-7和IL-15在维持CD 4 + TCM稳态中的作用，以及在进行性SIV感染期间，从幼稚室募集新的TCM与先前存在的TCM再生在维持CD 4 + TCM室中的相对贡献。 通过单克隆抗体介导的胸腺切除猴的CD 4 + T细胞耗竭，我们在记忆细胞在胸腺缺失的情况下再生后创建了“CD 4幼稚”RM。 重要的是，缺乏幼稚CD 4 + T细胞区室对SIV感染后CD 4+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预先存在的记忆细胞的再生，而不是幼稚细胞的募集。 该项目的其他工作着眼于SIV感染中的B细胞动力学和CD 8 + 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.