Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
Sci Rep. 2017 Nov 1;7(1):14787. doi: 10.1038/s41598-017-14817-8.
Exosomes are membrane enclosed nano-sized vesicles actively released into the extracellular milieu that can harbor genomic, proteomic and lipid cargos. Functionally, they are shown to regulate cell-cell communication and transmission of pathogens. Though studies have implicated a role for exosomes in HIV-1 pathogenesis, their mechanisms are not well defined. Here, we characterized exosomes derived from uninfected or HIV-1 infected T-cells and DCs. We demonstrate substantial differences in morphological, molecular and biogenesis machinery between exosomes derived from these two immune cell types. In addition, exosomes derived from HIV-1 infected DCs were 4 fold more infective than either cell free HIV-1 or exosomes derived from T-cells. Molecular analysis of exosomes detected the presence of fibronectin and galectin-3 in those derived from DCs, whereas T-cell exosomes lacked these molecules. Addition of anti-fibronectin antibody and β-lactose, a galectin-3 antagonist, significantly blocked DC exosome-mediated HIV-1 infection of T-cells. We also observed increased gene expression of the pro-inflammatory cytokines IFN-γ, TNF-α, IL-1β and RANTES and activation of p38/Stat pathways in T-cells exposed to exosomes derived from HIV-1 infected DCs. Our study provides insight into the role of exosomes in HIV pathogenesis and suggests they can be a target in development of novel therapeutic strategies against viral infection.
外泌体是一种主动释放到细胞外环境中的膜包裹的纳米大小囊泡，可携带基因组、蛋白质组和脂质货物。功能上，它们被证明可以调节细胞间通讯和病原体的传播。尽管研究表明外泌体在 HIV-1 发病机制中起作用，但它们的机制尚未明确。在这里，我们对来自未感染或 HIV-1 感染的 T 细胞和 DC 的外泌体进行了表征。我们证明了这两种免疫细胞类型来源的外泌体在形态、分子和生物发生机制方面存在显著差异。此外，来自 HIV-1 感染的 DC 的外泌体比游离的 HIV-1 或来自 T 细胞的外泌体的感染性高 4 倍。对外泌体的分子分析检测到来自 DC 的外泌体中存在纤维连接蛋白和半乳糖凝集素-3，而 T 细胞外泌体缺乏这些分子。添加抗纤维连接蛋白抗体和β-半乳糖，一种半乳糖凝集素-3 拮抗剂，可显著阻断 DC 外泌体介导的 HIV-1 感染 T 细胞。我们还观察到，暴露于源自 HIV-1 感染的 DC 的外泌体的 T 细胞中促炎细胞因子 IFN-γ、TNF-α、IL-1β 和 RANTES 的基因表达增加，以及 p38/Stat 途径的激活。我们的研究提供了外泌体在 HIV 发病机制中的作用的见解，并表明它们可能成为开发针对病毒感染的新型治疗策略的靶标。
