EFFECTS OF CD154 EXPRESSION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。CD 154（CD 40配体）是由活化的CD 4 + T细胞表达的共刺激分子，其结合存在于树突状细胞、B细胞和巨噬细胞上的细胞表面分子CD 40。这项提案将研究影响SIV感染的细胞免疫反应的机制。具体而言，我们将研究共刺激分子CD 154在感染恒河猴与重组减毒SIV表达恒河猴CD 154（SIVCD 154）的作用。我们已经证明SIVCD 154能够在感染的恒河猴T细胞表面表达CD 154。我们推测，在SIV感染过程中，CD 154的信号转导失调，并且SIVCD 154感染的细胞表达CD 154可能恢复T细胞依赖性抗原的活化途径：1）SIVCD 154感染的DC将在细胞表面结合CD 154和CD 40，并上调其他共刺激分子; 2）SIVCD 154感染的CD 4 + T细胞将使其CD 154与B细胞上的CD 40结合，导致B细胞活化和扩增;和3）SIVCD 154感染的巨噬细胞将在细胞表面结合CD 154和CD 40，导致活化，释放细胞因子和NO，以及APC功能。这些实验的结果可能至少在两个方面导致HIV疫苗设计的改进：i）更好地理解HIV感染期间免疫失调的机制，或ii）更安全的减毒活疫苗的前景。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. CD154 (CD40 ligand) is a costimulatory molecule expressed by activated CD4+ T cells that binds to the cell-surface molecule CD40, present on dendritic cells, B cells, and macrophages. This proposal will study mechanisms that affect cellular immune responses to SIV infection. Specifically, we will study the role of the costimulatory molecule CD154 during infection of rhesus macaques with a recombinant live-attenuated SIV that expresses rhesus CD154 (SIVCD154). We already showed that SIVCD154 is able to express CD154 on the surface of infected rhesus T cells. We hypothesize that signaling by CD154 is dysregulated during SIV infection, and that expression of CD154 by SIVCD154-infected cells may restore the activation pathway for T cell-dependent antigens: 1) SIVCD154-infected DCs will engage CD154 and CD40 at the cell surface and upregulate other costimulatory molecules; 2) SIVCD154-infected CD4+ T cells will engage their CD154 with CD40 on B cells, leading to B cell activation and expansion; and 3) SIVCD154-infected macrophages will engage CD154 and CD40 at the cell surface, leading to activation, release cytokines and NO, and APC function. Results from these experiments may lead to improvements in HIV vaccine design in at least two ways: i) better understanding of the mechanisms of immune dysregulation during HIV infection, or ii) prospect for safer live-attenuated vaccines.