EFFECTS OF CD154 EXPRESSION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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细胞和巨噬细胞中。本课题将研究影响SIV感染细胞免疫应答的机制。具体来说，我们将研究共刺激分子CD154在表达恒河CD154的重组减毒SIV （SIVCD154）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。我们假设在SIV感染期间，CD154的信号通路失调，sivcd154感染的细胞表达CD154可能恢复T细胞依赖性抗原的激活途径：1)sivcd154感染的dc会在细胞表面与CD154和CD40结合，并上调其他共刺激分子；2) sivcd154感染的CD4+ T细胞将其CD154与B细胞上的CD40结合，导致B细胞活化和扩增；3) sivcd154感染的巨噬细胞会在细胞表面与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改善艾滋病毒疫苗的设计：1)更好地了解艾滋病毒感染期间免疫失调的机制，或2)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.