Galectin-3与HIV-1感染的单核-巨噬细胞凋亡

HIV-1 virus can persist in cellular reservoirs by means of viral latency and cryptic ongoing replication, which is a big challenge in AIDS therapy. Monocyte-macrophage is one of the HIV-1 cellular reservoirs. How to eliminate the monocyte-macrophages infected by HIV-1 has received much attention. Galectin plays roles in regulating many significant biological actions including apoptosis induction. Galectin-3, as an important member of galectin family, has been reported to be able to induce T cell and mast cell death. In our previous study, we have found that THP1-originated macrophages were resistant to HIV-1 infection-induced apoptosis, but HIV-1 infection resulted in increased binding of galectin-3 to the cells, which induced cell apoptosis. We also observed apoptosis induction of macrophages from peripheral blood of SIVmac251-infected rhesus macaques by galectin-3. These phenomena have not been observed yet in literature. Based on our previous observations, we will go deep into the relationship among galectin-3, HIV-1 infection and monocyte-macrophages apoptosis and explore the unique mechanisms by examining membrane protein glycosylation, cell responses to FasL, TRAIL or TNF-α at the presence of galectin-3, death signaling, and expression of pro-/anti-apoptosis genes, etc. Through the study we will make the potential action of galectin-3 in elimination of HIV-1-infected cellular reservoirs clearer and provide theoretical and application basis for seeking new procedures for AIDS therapy.

艾滋病毒的潜伏感染是艾滋病治疗的最大挑战之一。单核-巨噬细胞是艾滋病毒重要的潜伏感染靶细胞，如何清除被HIV-1感染的单核-巨噬细胞是目前国际上的研究热点。半乳糖凝集素（galectin）能诱导包括凋亡在内等多种生物学效应。其中，galectin-3是该家族的重要成员，能诱导T细胞、肥大细胞等凋亡。我们前期的研究发现galectin-3与HIV-1感染的THP-1源性巨噬细胞结合增强并可诱导其凋亡，这一结果也在艾滋病恒河猴外周血单核-巨噬细胞得到证实，该结果在国际上尚无报道。本项目中，我们将在前期工作的基础上深入研究galectin-3、HIV-1感染与单核-巨噬细胞凋亡的关系，从细胞膜蛋白糖基化改变、凋亡信号传导通路及促/抗凋亡基因表达变化等角度探讨其独特的作用机制，并进一步明确其清除HIV-1潜伏感染靶细胞的潜在作用，为寻找艾滋病治疗的新药提供理论及应用依据。

艾滋病毒的潜伏感染是艾滋病治疗的最大挑战之一。单核巨噬细胞是艾滋病毒重要的潜伏感染靶细胞，如何清除被HIV-1感染的单核巨噬细胞是目前国际上的研究热点。半乳糖凝集素（Galectin）能诱导包括凋亡在内等多种生物学效应。其中，Galectin-3是该家族的重要成员，能诱导T细胞、肥大细胞等凋亡。首先，我们以HIV-1感染的THP1单核细胞和THP1源性巨噬细胞作为体外细胞模型，探讨Galectin-3能否诱导HIV-1感染的巨噬细胞发生细胞死亡。我们的研究证实THP1源性巨噬细胞对HIV-1感染具有凋亡抵抗作用，这与其细胞内的Mcl-1、Bcl-2、Bcl-xL等抗凋亡蛋白密切相关。此外，本项目首次发现Galectin-3能够诱导HIV-1感染的THP1源性巨噬细胞发生细胞死亡，而经典的凋亡诱导分子FasL、TRAIL和TNF-α均不能诱导其死亡。这一现象再次通过人外周血单核源性巨噬细胞得到证实。我们还从健康猴和SIVmac251感染猴的外周血中获得猴单核源性巨噬细胞，结果显示：与健康猴分离的巨噬细胞相比，Galectin-3能够诱导培养上清病毒RNA阳性的巨噬细胞发生大量细胞死亡。在上述基础上，我们还深入探索Galectin-3诱导HIV-1感染巨噬细胞的死亡机制。我们发现Galectin-3诱导的THP1单核细胞与HIV-1感染的THP1源性巨噬细胞的死亡通路均与Caspase通路无关。我们进一步研究发现Endo G的蛋白表达在Galectin-3处理后细胞浆中明显减少，细胞核中明显增加，提示Endo G蛋白经Galectin-3处理后发生了核转移，从而使细胞发生死亡。我们的结果提示了Galectin-3在清除艾滋病毒潜伏感染靶细胞中的潜在作用，为寻找艾滋病治疗的新药提供理论及应用依据。