HIV-1通过调控miR-146a逃逸巨噬细胞抗病毒天然免疫的分子机制

艾滋病治疗手段HAART对低水平复制的HIV-1病毒没有效果，成为目前治疗方法的盲区。HIV-1逃逸天然免疫清除、建立慢性感染的机制尚不完全清楚。我们的前期研究发现，在人原代巨噬细胞内miR-146a表达逐步升高，与HIV-1病毒复制水平呈正相关，而与干扰素、TNF-alpha等细胞因子的分泌呈负相关，提示miR-146a可能参与弱化抗HIV-1病毒的天然免疫和炎症反应。我们拟以HIV-1感染的巨噬细胞为模型：研究HIV-1上调miR-146a表达的分子机制；筛查被HIV-1下调的抗病毒因子；确定miR-146a的作用靶点，系统研究miR-146a对巨噬细胞相关抗病毒天然免疫的抑制效应。本项目提出HIV病毒通过调控miR-146a逃逸巨噬细胞抗病毒天然免疫、建立慢性感染新机制，并探索以miR-146a为靶点抑制病毒复制的可能性，为干预艾滋病毒潜伏期治疗提供新思路。

It remains unclear about how Human Immunodeficiency Virus (HIV) escapes from eradication by human innate immunity and establishes persistent infection. It becomes a big challenge that anti-viral treatment fail to clean HIV-1 in low-replicating state. We found in our previous study that, miR-146a was significantly up-regulated while cytokines such as interferon and TNF-alpha were induced in early infection phase but reduced during later phase in human primary macrophage. There are several transcription factor NFkB binding sites in the promoter of miR-146a gene, and the induced expression of miR-146a by LPS, IL-1 band TNF-alpha is NFkB dependent. Therefore, we hypothesize that HIV-1 infection up-regulates miR-146a, the induced miR-146a then down-regulates interferon and TNF-alpha or other antiviral cytokines, and this negative feedback regulation loop helps the virus establishing a persistent or latent infection. We plan to utilize HIV-1 infected human primary macrophage model, to study: (1) how HIV-1 infection up-regulates miR-146a expression in macrophage? (2) effect of miR-146a on HIV-1 infection and replication; (3) targets of miR-146a, especially those target genes of antiviral cytokines and effects of miR-146a on macrophage function. This study aims to discover mechanism of miR-146a contributes to HIV-1 persistent infection, and to give evidence of miR-146a, as a negative regulator, helping HIV-1 to escape from innate immunity. Our study may offer new strategy on HIV-1 latent infection treatment.