自1981年首次发现AIDS患者以来，虽然历经了30多年的研究，但在HIV-1导致免疫缺陷的细胞和分子机理中，仍有诸多的关键问题有待明晰。CD4+T细胞是HIV-1的主要靶细胞，在自然感染过程和通常的体外实验中，CD4+T细胞的活化和增殖是HIV-1得以大量复制的先决条件。但是Levine等在1996年意外发现，经过包被在磁珠上的CD3/CD28抗体协同刺激后，活化的CD4+T细胞能够逆转对HIV-1的易感性，但是这一现象所包含的调控规律和分子机制，迄今仍无明确答案。
在国家自然科学基金、云南省重点项目和中科院“百人计划”的资助下，中科院昆明动物研究所动物模型和人类疾病机理重点实验室（免疫生物学实验室）博士研究生徐雯雯、韩妙君等在张华堂研究员的指导下，采用生物芯片技术，对能够逆转HIV-1易感性的CD4+T细胞进行了全基因组分析，从中发现了产生逆转效应的mRNA表达谱特征。在对数据进一步的深入发掘和系统分析中，发现137个核心基因在共表达网络中能够调控其他基因的表达，进而影响细胞内与细胞骨架、细胞周期和蛋白酶体等功能相关基因的表达，最终导致逆转效应的发生。该结果为HIV-1易感性研究提供了新的思路，并可能有助于进一步的临床生物标记的研究，已发表在BMC Medical Genomics 。
相关综述和细胞学实验研究分别发表在《国际免疫学杂志》2011年34卷03期169-171页和2011年34卷05期297-301页。（生物谷Bioon.com）
doi:10.1186/1755-8794-6-15
PMC:
PMID:
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
Wen-Wen Xu, Miao-Jun Han, Dai Chen, Ling Chen, Yan Guo, Andrew Willden, Di-Qiu Liu and Hua-Tang Zhang
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.
