9月18日,，Retrovirology在線發(fā)表了中科院上海生科院生物化學(xué)與細(xì)胞生物學(xué)研究所王紅艷研究組的研究成果Immune adaptor ADAP in T cells regulates HIV-1 transcription and cell-cell viral spread via different co-receptors。該成果揭示了在HIV-1感染T細(xì)胞的過程中，免疫銜接蛋白ADAP通過參與不同共刺激分子CD28或LFA-1的信號(hào)通路,，分別調(diào)控HIV-1在T細(xì)胞內(nèi)的轉(zhuǎn)錄,、HIV-1在樹突狀細(xì)胞DC-T細(xì)胞之間的播散。
當(dāng)T細(xì)胞受體（TCR）信號(hào)通路被激活后,，ADAP與上游信號(hào)分子SLP76結(jié)合,，構(gòu)建TCR介導(dǎo)的inside-out信號(hào)通路，導(dǎo)致T細(xì)胞表面整合素（integrin）粘附能力增強(qiáng),，并促進(jìn)T細(xì)胞活化,。該研究發(fā)現(xiàn)：（1）在HIV-1感染的DC向未感染的T細(xì)胞播散病毒時(shí)，降低T細(xì)胞中ADAP的表達(dá)或阻止SLP76-ADAP信號(hào)復(fù)合體,，通過抑制整合素LFA-1介導(dǎo)的病毒突觸（Virological Synapse）的形成,，進(jìn)而阻止HIV-1在免疫細(xì)胞間的傳播；（2）T細(xì)胞的活化能促進(jìn)HIV-1的感染,。當(dāng)T細(xì)胞接受來自共刺激分子CD28的信號(hào)后,，利用SLP76-ADAP信號(hào)復(fù)合體，活化轉(zhuǎn)錄因子NF-κB,，促進(jìn)HIV-1的轉(zhuǎn)錄,。但此轉(zhuǎn)錄過程不依賴整合素LFA-1的活化。該研究從宿主免疫細(xì)胞的角度出發(fā),，首次揭示免疫銜接蛋白ADAP利用不同信號(hào)通路,，多環(huán)節(jié)參與HIV-1轉(zhuǎn)錄、HIV-1在細(xì)胞間播散的感染過程,。這項(xiàng)研究提示靶向宿主免疫細(xì)胞中的SLP76-ADAP信號(hào)復(fù)合體,，可能作為控制HIV-1感染的新靶點(diǎn)。
該研究課題與英國劍橋大學(xué)Christopher E Rudd教授合作共同完成,，并獲得中科院上海巴斯德所王建華研究組的大力幫助,。
該課題得到國家科技部、國家自然科學(xué)基金委,、浦江人才計(jì)劃和中國科學(xué)院分子病毒與免疫重點(diǎn)實(shí)驗(yàn)室的經(jīng)費(fèi)支持（生物谷Bioon.com）,。
生物谷推薦的英文摘要
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.
