MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom.
PLoS Pathog. 2011 Sep;7(9):e1002226. doi: 10.1371/journal.ppat.1002226. Epub 2011 Sep 1.
Direct cell-cell spread of Human Immunodeficiency Virus type-1 (HIV-1) at the virological synapse (VS) is an efficient mode of dissemination between CD4(+) T cells but the mechanisms by which HIV-1 proteins are directed towards intercellular contacts is unclear. We have used confocal microscopy and electron tomography coupled with functional virology and cell biology of primary CD4(+) T cells from normal individuals and patients with Chediak-Higashi Syndrome and report that the HIV-1 VS displays a regulated secretion phenotype that shares features with polarized secretion at the T cell immunological synapse (IS). Cell-cell contact at the VS re-orientates the microtubule organizing center (MTOC) and organelles within the HIV-1-infected T cell towards the engaged target T cell, concomitant with polarization of viral proteins. Directed secretion of proteins at the T cell IS requires specialized organelles termed secretory lysosomes (SL) and we show that the HIV-1 envelope glycoprotein (Env) localizes with CTLA-4 and FasL in SL-related compartments and at the VS. Finally, CD4(+) T cells that are disabled for regulated secretion are less able to support productive cell-to-cell HIV-1 spread. We propose that HIV-1 hijacks the regulated secretory pathway of CD4(+) T cells to enhance its dissemination.
人类免疫缺陷病毒 1 型（HIV-1）在病毒突触（VS）中的直接细胞间传播是 CD4(+)T 细胞之间有效传播的方式，但 HIV-1 蛋白如何被定向到细胞间接触尚不清楚。我们使用共聚焦显微镜和电子断层扫描，结合正常个体和 Chediak-Higashi 综合征患者的原代 CD4(+)T 细胞的功能病毒学和细胞生物学，报告 HIV-1 VS 显示出受调控的分泌表型，与 T 细胞免疫突触（IS）中的极化分泌具有共同特征。VS 处的细胞间接触使微管组织中心（MTOC）和感染 HIV-1 的 T 细胞内的细胞器重新定向到被感染的靶 T 细胞，同时病毒蛋白发生极化。在 T 细胞 IS 处的蛋白质定向分泌需要专门的细胞器，称为分泌溶酶体（SL），我们表明 HIV-1 包膜糖蛋白（Env）与 CTLA-4 和 FasL 一起定位于与 SL 相关的隔室和 VS 处。最后，调节性分泌功能失调的 CD4(+)T 细胞更难以支持有效的细胞间 HIV-1 传播。我们提出 HIV-1 劫持 CD4(+)T 细胞的受调控分泌途径来增强其传播。
