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

HIV-1感染的进展与浆细胞样树突状细胞（PDC）计数和功能的显著丧失相关。PDC是血液中I型干扰素的主要产生者，对于协调病毒和细菌感染中的先天和适应性免疫反应至关重要。我们已经表明，HIV感染患者PDC的表型和功能缺陷，这至少部分恢复了新的Pclass CpG寡核苷酸刺激。在一项后续研究中，我们已经确定了HIV-1感染中可溶性和细胞CD 40配体（CD 40 L）水平升高，这降低了体外IFN α的产生。因此，我们推测，慢性免疫刺激，反映了增加CD 40 L的表达，是负责沉默PDC先天免疫反应在HIV-1感染。为了验证这一假设，我们将集中在三个方面：（i）表征CD 40 L对PDC的功能和表型的影响，（ii）通过基于芯片的基因表达谱和途径分析获得PDC沉默的全面图片，以及（iii）在HIV感染患者的翻译研究中研究低剂量皮质激素对CD 40和CD 40 L表达的影响。因此，我们的研究将免疫刺激作为HIV-1发病机制的主要因素。

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.