Evidence showing that tetraspanins inhibit HIV-1-induced cell-cell fusion at a post-hemifusion stage.
Evidence showing that tetraspanins inhibit HIV-1-induced cell-cell fusion at a post-hemifusion stage.
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DOI：
10.3390/v6031078
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发表时间：
2014-03-07
期刊：
影响因子：
--
通讯作者：
Thali M
中科院分区：
文献类型：
--
作者：
Symeonides M;Lambelé M;Roy NH;Thali M
人类免疫缺陷病毒1型（HIV-1）的传播主要通过细胞间的接触，即病毒学突触进行。感染细胞和未感染细胞之间的这些短暂粘附的形成可导致病毒颗粒的传播，随后是细胞的分离。或者，细胞可以融合，从而形成合胞体。四跨膜蛋白是一种富含HIV-1病毒粒子并活跃募集到病毒组装位点的小支架蛋白，已发现其负调控HIV-1 Env诱导的细胞-细胞融合。然而，这些跨膜蛋白如何抑制膜融合目前尚不清楚。作为阐明四跨膜蛋白抑制融合机制的第一步，CD 9和CD 63，我们试图确定他们运作的融合过程中的阶段。使用化学上位性方法，四种融合抑制剂与CD 9过表达串联使用。发现过表达CD 9的细胞对靶向前发夹和半融合中间体的抑制剂敏感，而它们对孔扩张阶段的抑制剂脱敏。连同基于显微镜的染料转移试验的结果，揭示了CD 9-和CD 63-诱导的半融合停滞，我们的调查强烈表明，四跨膜蛋白阻断HIV-1诱导的细胞-细胞融合的过渡从半融合孔开放。
Human immunodeficiency virus type 1 (HIV-1) transmission takes place primarily through cell-cell contacts known as virological synapses. Formation of these transient adhesions between infected and uninfected cells can lead to transmission of viral particles followed by separation of the cells. Alternatively, the cells can fuse, thus forming a syncytium. Tetraspanins, small scaffolding proteins that are enriched in HIV-1 virions and actively recruited to viral assembly sites, have been found to negatively regulate HIV-1 Env-induced cell-cell fusion. How these transmembrane proteins inhibit membrane fusion, however, is currently not known. As a first step towards elucidating the mechanism of fusion repression by tetraspanins, e.g., CD9 and CD63, we sought to identify the stage of the fusion process during which they operate. Using a chemical epistasis approach, four fusion inhibitors were employed in tandem with CD9 overexpression. Cells overexpressing CD9 were found to be sensitized to inhibitors targeting the pre-hairpin and hemifusion intermediates, while they were desensitized to an inhibitor of the pore expansion stage. Together with the results of a microscopy-based dye transfer assay, which revealed CD9- and CD63-induced hemifusion arrest, our investigations strongly suggest that tetraspanins block HIV-1-induced cell-cell fusion at the transition from hemifusion to pore opening.
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