PD-1 MODULATION OF SIV SPECIFIC CD4 AND CD8 T CELL RESPONSES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 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。 在未感染和SIV感染的恒河猴上进行的CD 4+和CD 8 + T细胞上的PD-1分子的研究揭示了3个主要发现：A）感染后早期，来自MamuA.01+ SIV感染的恒河猴的四聚体阳性CD 8 + T细胞上的PD-1表达快速上调，而总CD 8 + T细胞上的PD-1上调不可检测。B）相比之下，慢性感染期间总CD 4 + T细胞中CD 4 + T细胞的PD-1表达明显更高，c）初始和中枢记忆CD 4 + T细胞上的PD-1表达水平与病毒载量水平之间存在相关性。在抗逆转录病毒治疗开始后不久，四聚体阳性CD 8+和CD 4 + T细胞上的PD-1表达显著降低，病毒复制下调。我们克隆了rMamu PD-1，并将其融合到修饰的恒河猴IgG 2 Fc分子上，该分子不能结合NK细胞上的补体或FcR。来自慢性感染猴的CD 8但主要是CD 4 T细胞的SIV特异性增殖在添加PD-1拮抗剂的情况下以剂量依赖性方式显著扩增。我们将首先在体外研究PD-1配体阻断对CD 4和CD 8 + T细胞的影响，以及PD-1连接对Treg细胞和负责此类信号传导的潜在DC的作用。我们还将在早期和晚期慢性SIV感染期间阻断PD 1-配体相互作用，以研究治疗尝试是否具有恢复抗病毒CD 4和CD 8 + T细胞效应器应答的能力。

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. Studies of the PD-1 molecule on CD4+ and CD8+ T cells performed on uninfected and SIV infected rhesus macaques revealed 3 major findings: A) rapid upregulation of PD-1 expression on tetramer positive CD8+ T cells from MamuA.01+ SIV infected macaques early post infection while upregulation of PD-1 on total CD8+ T cells was undetectable. B) In contrast, CD4+ T cells PD-1 expression was markedly higher in total CD4+ T cells during chronic infection and c) there was a correlation between the level of PD-1 expression on naive and central memory CD4+ T cells and the levels of viral loads. There was marked decrease of PD-1 expression on tetramer positive CD8+ and CD4+ T cells shortly after initiation of antiretroviral therapy and downregulation of viral replication. We have cloned rMamu PD-1 and fused it to a modified Rhesus IgG2 Fc molecule that is unable to bind complement or FcR on NK cells. SIV specific proliferation of CD8 but predominantly CD4 T cells from chronically infected monkeys was markedly amplified with the addition of PD-1 antagonist in a dose dependent manner. We will address the effect of PD-1-ligand blockade first in vitro on CD4 and CD8+ T cells as well as the role of PD-1 ligation on Treg cells and the potential DC responsible for such signaling. We will also block the PD1-ligand interaction during early and late chronic SIV infection in to investigate if therapeutic attempts have the capability of restoring anti-viral CD4 and CD8+ T cell effectors responses.