Contact-induced mitochondrial polarization supports HIV-1 virological synapse formation.
Contact-induced mitochondrial polarization supports HIV-1 virological synapse formation.
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DOI：
10.1128/jvi.02425-14
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发表时间：
2015-01
影响因子：
5.4
通讯作者：
Jolly C
中科院分区：
文献类型：
--
作者：
Groppelli E;Starling S;Jolly C
HIV-1在CD 4 T淋巴细胞之间的快速传播发生在逆转录病毒诱导的免疫细胞接触，称为病毒学突触（VS）。VS与显著的T细胞极化和接触部位的局部病毒出芽有关，这有助于细胞-细胞传播。除此之外，以前已经显示了细胞器（包括线粒体）在接触区的空间聚集。然而，细胞-细胞接触是否特异性诱导VS形成过程中的动态T细胞重塑，以及是什么调控了这一过程仍不清楚。在这里，我们报告说，HIV-1感染的T细胞和未感染的靶T细胞之间的接触，特别是触发线粒体的极化，伴随着主要的HIV-1结构蛋白Gag的招聘网站的细胞-细胞接触。使用固定和活细胞成像，我们表明，在HIV-1感染的T细胞中，线粒体和Gag极化发生在与靶T细胞接触的几分钟内，需要形成稳定的细胞-细胞接触，并且是一个活跃的钙依赖性过程。我们还发现，线粒体极化的扰动损害了细胞间传播的HIV-1在VS。总之，这些数据表明，HIV-1感染的T细胞能够感知和响应与易感靶细胞的接触，并进行动态细胞质重塑，以创建一个突触环境，支持有效的HIV-1 VS之间的CD 4 T淋巴细胞的形成。重要性HIV-1仍然是现代全球主要健康挑战之一。HIV-1引起疾病的能力取决于病毒在免疫细胞之间传播的能力，特别是CD 4 T淋巴细胞。细胞-细胞传播是HIV-1传播的最有效方式，发生在病毒突触（VS）。VS在感染细胞和未感染细胞之间的接触部位形成，其特征在于病毒体的极化组装和出芽以及细胞器（包括线粒体）的聚集。在这里，我们表明，细胞-细胞接触诱导线粒体的快速招聘的接触网站，这支持有效的VS形成，因此细胞-细胞传播。此外，我们观察到细胞-细胞接触诱导细胞内钙离子依赖性增加，这表明细胞信号传导。综上所述，我们的数据表明，VS的形成是一个受调控的过程，因此是阻断HIV-1细胞间传播的潜在靶点。
Rapid HIV-1 spread between CD4 T lymphocytes occurs at retrovirus-induced immune cell contacts called virological synapses (VS). VS are associated with striking T cell polarization and localized virus budding at the site of contact that facilitates cell-cell spread. In addition to this, spatial clustering of organelles, including mitochondria, to the contact zone has been previously shown. However, whether cell-cell contact specifically induces dynamic T cell remodeling during VS formation and what regulates this process remain unclear. Here, we report that contact between an HIV-1-infected T cell and an uninfected target T cell specifically triggers polarization of mitochondria concomitant with recruitment of the major HIV-1 structural protein Gag to the site of cell-cell contact. Using fixed and live-cell imaging, we show that mitochondrial and Gag polarization in HIV-1-infected T cells occurs within minutes of contact with target T cells, requires the formation of stable cell-cell contacts, and is an active, calcium-dependent process. We also find that perturbation of mitochondrial polarization impairs cell-cell spread of HIV-1 at the VS. Taken together, these data suggest that HIV-1-infected T cells are able to sense and respond to contact with susceptible target cells and undergo dynamic cytoplasmic remodeling to create a synaptic environment that supports efficient HIV-1 VS formation between CD4 T lymphocytes. IMPORTANCE HIV-1 remains one of the major global health challenges of modern times. The capacity of HIV-1 to cause disease depends on the virus's ability to spread between immune cells, most notably CD4 T lymphocytes. Cell-cell transmission is the most efficient way of HIV-1 spread and occurs at the virological synapse (VS). The VS forms at the site of contact between an infected cell and an uninfected cell and is characterized by polarized assembly and budding of virions and clustering of cellular organelles, including mitochondria. Here, we show that cell-cell contact induces rapid recruitment of mitochondria to the contact site and that this supports efficient VS formation and consequently cell-cell spread. Additionally, we observed that cell-cell contact induces a mitochondrion-dependent increase in intracellular calcium, indicative of cellular signaling. Taken together, our data suggest that VS formation is a regulated process and thus a potential target to block HIV-1 cell-cell spread.