EFFECTS OF CD154 EXPRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 CD154(CD40配体)是一种共刺激分子，由活化的CD4+T细胞表达，与细胞表面分子CD40结合，存在于树突状细胞、B细胞和巨噬细胞上。这项建议将研究影响SIV感染的细胞免疫反应的机制。具体地说，我们将研究共刺激分子CD154在表达恒河猴CD154(SIVCD154)的重组减毒SIV感染恒河猴过程中的作用。我们已经证明SIVCD154能够在感染的恒河猴T细胞表面表达CD154。我们推测，在SIV感染过程中，CD154的信号转导失调，感染SIVCD154的细胞表达CD154可能恢复T细胞依赖抗原的激活途径：1)感染SIVCD154的DC与细胞表面的CD154和CD40结合，并上调其他共刺激分子；2)感染SIVCD154的CD4+T细胞与B细胞表面的CD154和CD40结合，导致B细胞的激活和扩增；3)感染SIVCD154的巨噬细胞与细胞表面的CD154和CD40结合，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艾滋病毒疫苗设计的改进：i)更好地了解艾滋病毒感染期间免疫失调的机制，或ii)开发更安全的减毒活疫苗。

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.