CD4 MEDIATED IMMUNE RECONSTITUTION 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。 本项目旨在对SIV感染猕猴的免疫重建进行比较，比较SIV感染前后采集的自体CD4+T细胞，并使用抗CD3/抗CD28包被的免疫珠进行体外扩增。提示SIV感染后早期采集的CD4+T细胞无论是在PMPA化疗的保护伞下还是在没有PMPA化疗的情况下，都表现出与SIV感染前采集的细胞相似的扩增和免疫修复功能。然而，数据明确地表明，在开始过继转移自体CD4T细胞之前，为了诱导有效地控制SIV复制，必须显著减少病毒载量。另一个主要的研究领域是CD4+T细胞在扩增过程中的特性，以及在回输给动物时它们在扩增阶段以外的行为。虽然这些细胞统一表现为中央记忆表型，并表达调节性T细胞的所有标记，但这些细胞在功能上更符合基于细胞因子分泌以及激活和归巢标记的表达的效应器特征。此外，尽管CCR5的表达在扩增后恢复，这些细胞再次变得对SIV感染敏感，但与相同等量的未扩增的CD4T细胞相比，病毒复制似乎效率低下。这一特性仅限于嗜R5病毒，初步发现这种“缺陷”归因于CCR5通过相关的GAI/cAMP途径介导的信号改变，而控制趋化因子信号和趋化作用的Gaq途径似乎没有受到影响。对这一机制的进一步调查正在进行中。

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. This project is aimed at immune reconstitution of SIV infected macaques comparing autologous CD4+ T cells collected prior to versus post SIV infection and expanded in vitro using anti-CD3/anti-CD28 coated immunobeads. The data suggest that CD4+ T cells collected early post SIV infection either under the umbrella of PMPA chemotherapy or in the absence of, show expansion and immune restorative function similar to pre SIV infection collected cells. However, the data unequivocally show that a marked diminution of viral loads is imperative before initiation of adoptive transfer of autologous CD4 T cells in order to induce potent control of SIV replication. Another main area of investigation was the characterization of the CD4+ T cells as they are being expanded and their behavior beyond the expansion phase at the time of reinfusion to the animal. While the cells uniformly display a central memory phenotype and express all markers of regulatory T cells, these cells conform functionally more to an effector profile based on cytokine secretion and the expression of activation and homing markers. Furthermore, while CCR5 expression is restored following the expansion and these cells become again susceptible to SIV infection, the viral replication appears inefficient compared to the same aliquots of non-expanded CD4 T cells. This property was restricted to R5 tropic viruses and preliminary findings ascribe such "deficiency" to altered CCR5 mediated signaling via the associated Gai/cAMP pathway, while the Gaq pathway controlling chemokine signaling and chemotaxis did not appear affected. Additional investigations into this mechanism are ongoing.