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研究揭示宿主免疫细胞调控HIV-1感染的机制
发布日期:2013/10/8      浏览:1821

关键词: HIV-1 ADAP T细胞

9月18日,Retrovirology在线发表了中科院上海生科院生物化学与细胞生物学研究所王红艳研究组的研究成果Immune adaptor ADAP in T cells regulates HIV-1 transcription and cell-cell viral spread via different co-receptors。该成果揭示了在HIV-1感染T细胞的过程中,免疫衔接蛋白ADAP通过参与不同共刺激分子CD28或LFA-1的信号通路,分别调控HIV-1在T细胞内的转录、HIV-1在树突状细胞DC-T细胞之间的播散。

当T细胞受体(TCR)信号通路被激活后,ADAP与上游信号分子SLP76结合,构建TCR介导的inside-out信号通路,导致T细胞表面整合素(integrin)粘附能力增强,并促进T细胞活化。该研究发现:(1)在HIV-1感染的DC向未感染的T细胞播散病毒时,降低T细胞中ADAP的表达或阻止SLP76-ADAP信号复合体,通过抑制整合素LFA-1介导的病毒突触(Virological Synapse)的形成,进而阻止HIV-1在免疫细胞间的传播;(2)T细胞的活化能促进HIV-1的感染。当T细胞接受来自共刺激分子CD28的信号后,利用SLP76-ADAP信号复合体,活化转录因子NF-κB,促进HIV-1的转录。但此转录过程不依赖整合素LFA-1的活化。该研究从宿主免疫细胞的角度出发,首次揭示免疫衔接蛋白ADAP利用不同信号通路,多环节参与HIV-1转录、HIV-1在细胞间播散的感染过程。这项研究提示靶向宿主免疫细胞中的SLP76-ADAP信号复合体,可能作为控制HIV-1感染的新靶点。

该研究课题与英国剑桥大学Christopher E Rudd教授合作共同完成,并获得中科院上海巴斯德所王建华研究组的大力帮助。

该课题得到国家科技部、国家自然科学基金委、浦江人才计划和中国科学院分子病毒与免疫重点实验室的经费支持。

推荐的英文摘要

Retrovirology           doi:10.1186/1742-4690-10-101

Immune adaptor ADAP in T cells regulates HIV-1 transcription and cell-cell viral spread via different co-receptors

Bin Wei, Lei Han, Truus E Abbink, Elisabetta Groppelli, Daina Lim, Youg Raj Thaker, Wei Gao, Rongrong Zhai, Jianhua Wang, Andrew Lever, Clare Jolly, Hongyan Wang and Christopher E Rudd

Background

Immune cell adaptor protein ADAP (adhesion and degranulation-promoting adaptor protein) mediates aspects of T-cell adhesion and proliferation. Despite this, a connection between ADAP and infection by the HIV-1 (human immunodeficiency virus-1) has not been explored.

Results

In this paper, we show for the first time that ADAP and its binding to SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) regulate HIV-1 infection via two distinct mechanisms and co-receptors. siRNA down-regulation of ADAP, or expression of a mutant that is defective in associating to its binding partner SLP-76 (termed M12), inhibited the propagation of HIV-1 in T-cell lines and primary human T-cells. In one step, ADAP and its binding to SLP-76 were needed for the activation of NF-kappaB and its transcription of the HIV-1 long terminal repeat (LTR) in cooperation with ligation of co-receptor CD28, but not LFA-1. In a second step, the ADAP-SLP-76 module cooperated with LFA-1 to regulate conjugate formation between T-cells and dendritic cells or other T-cells as well as the development of the virological synapse (VS) and viral spread between immune cells.

Conclusions

These findings indicate that ADAP regulates two steps of HIV-1 infection cooperatively with two distinct receptors, and as such, serves as a new potential target in the blockade of HIV-1 infection.

 
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