肠道微生物易位对HIV感染慢性免疫激活的调控机制研究

Chronic immune activation is a key factor for HIV disease progression. Bacterial products, a consequence of microbial translocation from the gut, are likely causes of systemic immune activation, yet the mechanism(s) remain largely unknown. Our pilot studies documented that III interferon and CD56 + T cells in innnate immunity played an important role in anti-HIV infection and replication (supported by National Natural Science Fund,and see joint publication [4], [5]). To take the advantage of the experiences in our collaborative research on HIV and resources for the proposed studies, this investigation will examine the plasma and PBMC levels of microbial components, systemic antibodies to microbial antigens, cell-surface signal transducer molecules, chronic immune activation markers and Th17 cell populations as well as miRNA expression profiles in Chinese HIV-infected patients, and determine the in vitro and in vivo impact of different microbial components on the expression of chronic immune activation markers and on the intracellular innate immunity. In addition, we will examine the effects of the microbial products on HIV replication in the target cells. These proposed studies aim at the understanding of mechanism(s) by which microbial translocation facilitates chronic immune activation, thus providing a theoretical basis for the development of new anti-HIV drugs that target microbial translocation.

慢性免疫激活是促进HIV疾病进展的关键因素，而肠道细菌易位的产物可导致慢性免疫激活，但作用机制尚未阐明。前期研究发现并证实天然免疫中III型干扰素和CD56+T细胞具有抗HIV感染与复制的作用（受国家自然科学基金资助并已结题，见附件[4]和[5]）。本研究拟借助在HIV感染免疫领域的研究优势和资源，通过检测HIV感染者（慢性及进展期）外周血中不同细菌成分及相应抗体、细胞表面信号转导分子、慢性免疫激活标志物和Th17细胞数等表达水平以及miRNA的调节变化，运用体内和体外实验明确不同细菌成分（肽聚糖，脂多糖，鞭毛蛋白）对HIV感染者PBMC中慢性免疫激活标志物的调控以及对细胞内天然免疫的影响，并研究细菌成分对HIV在靶细胞内复制的作用。这些研究旨在了解不同细菌成分通过增强机体慢性免疫激活而加速HIV感染病程的作用机制，为研发以易位细菌成分为靶点的抗HIV新药物提供理论依据。

慢性免疫激活是促进HIV疾病进展的关键因素，而肠道细菌易位的产物可导致慢性免疫激活，但作用机制尚未阐明。本研究发现作为细菌主要成分的鞭毛蛋白能够抑制HIV的感染与复制，通过介导TLR5信号通路及调控炎症因子IL-6、IL-8、TNF-α、IL-1β等，进而促进胞内抗病毒因子IFN-α、IFN-β、APOBEC3G/3F等表达，最终阐明鞭毛蛋白介导的体外抗HIV-1的天然免疫机制；此外通过检测HIV感染者（慢性及进展期）外周血中细菌成分鞭毛蛋白及相应抗体、细胞表面信号转导分子、慢性免疫激活标志物等变化，再次验证了鞭毛蛋白对HIV感染者PBMC中慢性免疫激活标志物有调控作用以及对细胞内天然免疫的影响。同时我们还发现无能CD4+T细胞易于HIV感染。这些研究旨在了解不同细菌成分通过增强机体慢性免疫激活而加速HIV感染病程的作用机制，为研发以易位细菌成分为靶点的抗HIV新药物提供理论依据。