CD4 MEDIATED IMMUNE RECONSTITUTION IN SIV INFECTION

CD4 介导的 SIV 感染免疫重建

• 批准号: 8357450
• 负责人: Francois J Villinger
• 金额: $ 8.92万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357450
• 关键词: Adoptive Transfer; Affect; Aliquot; Animals; Area; Autologous; Behavior; CCR5 gene; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; Cells; Chemotaxis; Collecting Cell; Cyclic AMP; Data; Funding; Grant; Homing; Immune; In Vitro; Infection; Investigation; Macaca; Mediating; Memory; National Center for Research Resources; Pathway interactions; Phase; Phenotype; Primates; Principal Investigator; Property; Regulatory T-Lymphocyte; Research; Research Infrastructure; Resources; SIV; Signal Transduction; Source; Time; United States National Institutes of Health; Viral Load result; Virus; Virus Diseases; base; chemokine; chemotherapy; cost; cytokine; pinacolyl methylphosphonic acid; reconstitution

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.

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。 该项目旨在对感染 SIV 的猕猴进行免疫重建，比较 SIV 感染前和感染后收集的自体 CD4+ T 细胞，并使用抗 CD3/抗 CD28 包被的免疫珠在体外进行扩增。数据表明，在 SIV 感染后早期收集的 CD4+ T 细胞，无论是在 PMPA 化疗的保护下还是在没有 PMPA 化疗的情况下，都显示出与 SIV 感染前收集的细胞相似的扩增和免疫恢复功能。然而，数据明确表明，在开始自体 CD4 T 细胞过继转移之前，必须显着减少病毒载量，以诱导对 SIV 复制的有效控制。 研究的另一个主要领域是 CD4+ T 细胞在扩增过程中的表征，以及在回输给动物时超出扩增阶段后的行为。虽然这些细胞一致地表现出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表达的效应器谱。此外，虽然 CCR5 表达在扩增后恢复，并且这些细胞再次对 SIV 感染敏感，但与相同等份的非扩增 CD4 T 细胞相比，病毒复制似乎效率低下。这种特性仅限于 R5 热带病毒，初步发现将这种“缺陷”归因于通过相关 Gai/cAMP 途径改变的 CCR5 介导的信号传导，而控制趋化因子信号传导和趋化性的 Gaq 途径似乎没有受到影响。对此机制的进一步调查正在进行中。