Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes.
Loss of Niemann Pick type C proteins 1 and 2 greatly enhances HIV infectivity and is associated with accumulation of HIV Gag and cholesterol in late endosomes/lysosomes.
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DOI：
10.1186/1743-422x-9-31
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发表时间：
2012-01-24
期刊：
影响因子：
4.8
通讯作者：
Hildreth JE
中科院分区：
文献类型：
--
作者：
Coleman EM;Walker TN;Hildreth JE
胆固醇途径在HIV-1感染周期的多个阶段发挥着重要作用。在这里，我们使用Niemann-Pick C型疾病(NPCD)细胞作为模型系统，研究了胆固醇运输在HIV-1复制中的作用。我们使用了一种独特的NPC2缺陷细胞系(NPCD55)，该细胞株在HIV感染后表现出GAG积聚和NPC1表达减少。NPCD55细胞的病毒释放效率与对照细胞相似。然而，我们观察到从这些细胞释放的病毒的传染性增加了3到4倍。荧光显微镜显示GAG蛋白与胆固醇在这些细胞的晚期内小体/溶酶体(LE/L)区积聚并共存。在NPCD55细胞中产生的病毒粒子中，病毒粒子相关的胆固醇比对照细胞中产生的病毒粒子高4倍。用胆固醇外流诱导药物TO-9013171治疗受感染的NPCD55细胞，将病毒感染性降低到对照水平。这些结果表明，胆固醇的运输和定位可以通过调节病毒粒子的胆固醇含量来深刻地影响HIV-1的传染性。
Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. Here, we investigated the role of cholesterol trafficking in HIV-1 replication utilizing Niemann-Pick Type C disease (NPCD) cells as a model system. We used a unique NPC2-deficient cell line (NPCD55) that exhibited Gag accumulation as well as decreased NPC1 expression after HIV infection. Virus release efficiency from NPCD55 cells was similar to that from control cells. However, we observed a 3 to 4-fold enhancement in the infectivity of virus released from these cells. Fluorescence microscopy revealed accumulation and co-localization of Gag proteins with cholesterol in late endosomal/lysosomal (LE/L) compartments of these cells. Virion-associated cholesterol was 4-fold higher in virions produced in NPCD55 cells relative to virus produced in control cells. Treatment of infected NPCD55 cells with the cholesterol efflux-inducing drug TO-9013171 reduced virus infectivity to control levels. These results suggest cholesterol trafficking and localization can profoundly affect HIV-1 infectivity by modulating the cholesterol content of the virions.