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CD40L-mediated defect of the interferon system in HIV-1 infection

HIV-1感染中CD40L介导的干扰素系统缺陷

基本信息

批准号：
165239902
负责人：
Professorin Dr. Barbara Schmidt
金额：
--
依托单位：
Institut für Mikrobiologie und Hygiene
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2011-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/165239902?language=en
关键词：
CD40L mediated defect interferon system

项目摘要

The progress of HIV-1 infection is associated with a significant loss in plasmacytoid dendritic cell (PDC) counts and function. PDC, the major producers of type I interferons in the blood, are crucial in coordinating innate and adaptive immune responses in viral and bacterial infections. We have shown phenotypic and functional deficits in PDC of HIV-infected patients, which were restored at least partially by stimulation with a new Pclass CpG oligonucleotide. In a follow-up study, we have identified elevated levels of soluble and cellular CD40 ligand (CD40L) in HIV-1 infection, which reduced the IFNalpha production in vitro. Therefore, we hypothesize that the chronic immune stimulation, reflected by increased CD40L expression, is responsible for the silencing of PDC innate immune responses in HIV-1 infection. To verify this hypothesis, we will focus on three aspects: (i) characterize the effects of CD40L on the function and phenotype of PDC, (ii) obtain a comprehensive picture of PDC silencing via chip-based gene expression profiling and pathway analysis, and (iii) investigate the effects of low-dose corticoids on the expression of CD40 and CD40L in a translational study of HIV-infected patients. Thus, our study will target immune stimulation as a major factor of HIV-1 pathogenesis.

HIV-1感染的进展与血浆细胞样树突状细胞(PDC)数量和功能的显著丧失有关。PDC是血液中I型干扰素的主要产生者，在协调病毒和细菌感染的先天性和获得性免疫反应方面至关重要。我们已经显示了HIV感染患者的PDC的表型和功能缺陷，这些缺陷至少可以通过一种新的PClass CpG寡核苷酸刺激而部分恢复。在一项后续研究中，我们发现HIV-1感染中可溶性和细胞CD40配体(CD40L)水平升高，从而减少了体外IFNpha的产生。因此，我们推测，在HIV-1感染中，以CD40L表达增加反映的慢性免疫刺激是导致PDC天然免疫反应沉默的原因。为了验证这一假说，我们将集中在三个方面：(I)表征CD40L对PDC功能和表型的影响，(Ii)通过基于芯片的基因表达谱和通路分析获得PDC沉默的全面图像，以及(Iii)在HIV感染患者的翻译研究中考察小剂量皮质激素对CD40和CD40L表达的影响。因此，我们的研究将把免疫刺激作为HIV-1发病的一个主要因素。