近日,，中科院昆明動(dòng)物所的科研人員發(fā)現(xiàn)能夠逆轉(zhuǎn)艾滋病病毒-1型（HIV-1）易感性的主要靶細(xì)胞的分子機(jī)制。該研究成果發(fā)表在《BMC醫(yī)學(xué)遺傳學(xué)》和《國(guó)際免疫學(xué)雜志》上,。該成果獲得了國(guó)家自然科學(xué)基金、云南省重點(diǎn)項(xiàng)目和中科院“百人計(jì)劃”的資助,。
據(jù)介紹,，自1981年首次發(fā)現(xiàn)HIV以來(lái)，雖然歷經(jīng)30多年的研究,，但在HIV-1導(dǎo)致免疫缺陷的細(xì)胞和分子機(jī)理中,，仍有許多關(guān)鍵問(wèn)題不清楚。CD4+T細(xì)胞是HIV-1的主要靶細(xì)胞,，在自然感染過(guò)程和通常的體外實(shí)驗(yàn)中,，該細(xì)胞的活化和增殖是HIV-1得以大量復(fù)制的先決條件。
1996年,，科學(xué)家意外發(fā)現(xiàn),，經(jīng)過(guò)CD3/CD28抗體協(xié)同刺激后，活化的CD4+T細(xì)胞能夠逆轉(zhuǎn)對(duì)HIV-1的易感性,。易感性是由遺傳基礎(chǔ)所決定的相同環(huán)境下不同個(gè)體患病的風(fēng)險(xiǎn),。但目前，尚不清楚這一現(xiàn)象所包含的調(diào)控規(guī)律和分子機(jī)制,。
在該所研究員張華堂的指導(dǎo)下,，博士研究生徐雯雯、韓妙君等采用生物芯片技術(shù),，對(duì)能夠逆轉(zhuǎn)HIV-1易感性的CD4+T細(xì)胞進(jìn)行了全基因組分析,，從中發(fā)現(xiàn)了產(chǎn)生逆轉(zhuǎn)效應(yīng)的信使核糖核酸（mRNA）表達(dá)譜特征。
在對(duì)數(shù)據(jù)進(jìn)一步展開深入發(fā)掘和系統(tǒng)分析后,，科研人員發(fā)現(xiàn)了137個(gè)核心基因在共表達(dá)網(wǎng)絡(luò)中能夠調(diào)控其他基因的表達(dá),，進(jìn)而影響細(xì)胞內(nèi)與細(xì)胞骨架、細(xì)胞周期和蛋白酶體等功能相關(guān)的基因的表達(dá),，最終導(dǎo)致逆轉(zhuǎn)效應(yīng)的發(fā)生,。
該結(jié)果為HIV-1易感性研究提供了新思路，或?qū)⒂兄谶M(jìn)一步的臨床生物標(biāo)記研究,。(生物谷Bioon.com)
生物谷推薦英文摘要閱讀
BMC Medical Genomics 2013, 6:15 doi:10.1186/1755-8794-6-15
Genome-wide search for the genes accountable for the induced resistance to HIV-1 infection in activated CD4+ T cells: apparent transcriptional signatures, co-expression networks and possible cellular processes
Background
Upon co-stimulation with CD3/CD28 antibodies, activated CD4?+?T cells were found to lose their susceptibility to HIV-1 infection, exhibiting an induced resistant phenotype. This rather unexpected phenomenon has been repeatedly confirmed but the underlying cell and molecular mechanisms are still unknown.
Methods
We first replicated the reported system using the specified Dynal beads with PHA/IL-2-stimulated and un-stimulated cells as controls. Genome-wide expression and analysis were then performed by using Agilent whole genome microarrays and established bioinformatics tools.
Results
We showed that following CD3/CD28 co-stimulation, a homogeneous population emerged with uniform expression of activation markers CD25 and CD69 as well as a memory marker CD45RO at high levels. These cells differentially expressed 7,824 genes when compared with the controls on microarrays. Series-Cluster analysis identified 6 distinct expression profiles containing 1,345 genes as the representative signatures in the permissive and resistant cells. Of them, 245 (101 potentially permissive and 144 potentially resistant) were significant in gene ontology categories related to immune response, cell adhesion and metabolism. Co-expression networks analysis identified 137 “key regulatory” genes (84 potentially permissive and 53 potentially resistant), holding hub positions in the gene interactions. By mapping these genes on KEGG pathways, the predominance of actin cytoskeleton functions, proteasomes, and cell cycle arrest in induced resistance emerged. We also revealed an entire set of previously unreported novel genes for further mining and functional validation.
Conclusions
This initial microarray study will stimulate renewed interest in exploring this system and open new avenues for research into HIV-1 susceptibility and its reversal in target cells, serving as a foundation for the development of novel therapeutic and clinical treatments.
