SIV感染猕猴的早期抗病毒治疗对肠道微生物组影响研究

Now, AIDS is also one of biggest risks for public health, and cART is also major strategy to AIDS therapy. Early therapy with cART which can make 5%-15% of HIV-1 patients to post treatment controller is most potential approach to achieve functional cure, and now the mechanism of its is still unknown. Gut microbiota plays an important role in remodeling host immune system and the latter strictly controls gut micro biota. The appropriate interaction between host immune system and gut microbiome is rigorous to maintain normal physiological function. HIV-1 infection alters the gut microenviroment and microbiota which associate with progression of AIDS and non-AIDS defining diseases. It was reported that cART has few effects on gut microbiota in HIV-1 chronic infected patients. However, there is no report about alteration of gut microbiota during or after early treatment. In our early study, we found similar to HIV-1 chronic infection, SIVmac239 chronic infection also caused significant alteration of gut microbiota and microbe network. In this study, we hypothesize that the gut microbiota may be properly maintained in individuals who successfully control the virus replication after early cART and alterations of gut microbiota may relate to therapeutic effects. Then we use SIVmac239-infected and cART early treated-Chinese rhesus macaque model to study the effects of early treatment on gut microbiota and correlations between therapy of cART and gut microbiota through metagenome sequencing of 16s RNA genes, flow cytometry, ELISA and qPCR in order to provide theoretical basis for new HIV-1 therapy strategies.

联合抗逆转录病毒治疗(cART)是目前AIDS防治的主要手段。早期cART是最有望实现功能性治愈的方法，但其实现治疗后控制的机制尚不完全清楚。肠道微生物与宿主免疫系统相互作用，维持机体正常生理功能。HIV-1感染引起肠道微环境及微生物组显著改变，而肠道微生物组变化与疾病进程及非AIDS综合征相关。cART对HIV-1感染慢性期病人肠道微生物组的作用有限，早期治疗对肠道微生物组有何影响国内外还未见报道。我们前期研究发现SIV慢性感染也导致中国猕猴肠道微生物组及微生物网络显著改变。本研究拟在已建立的SIV感染早期治疗猕猴模型基础上，应用宏基因组测序检测肠道微生物组变化，采用流式细胞术、ELISA、qPCR技术检测免疫学、病毒学及生化指标，分析早期治疗对肠道微生物组的影响及肠道微生物组与治疗效果的关联性，从肠道微生物组方面解析早期治疗的功效，阐释微生物组对疗效的影响，为AIDS治疗策略提供依据。

免疫系统与肠道广泛互作维持机体稳定。HIV-1/SIV感染导致肠道微环境和微生物组显著变化，肠道微生物组影响HIV-1/SIV疾病进程。cART对HIV-1慢性感染者肠道微生物组的影响有限，而早期治疗对肠道微生物组有何影响国内外尚无相关报道。本研究我们在SIVmac239感染早期治疗动物模型的基础上，研究早期治疗对肠道微生物组的影响。研究结果表明：1）本研究囊括的实验动物，雌、雄个体肠道菌群差异显著；2）感染和治疗对肠道菌群有一定的影响，不同阶段影响作用各不相同，且雌雄个体受到的影响各不相同，雄性收到影响重于雌性；3）不同治疗状态具有特有的微生物；4）Prevotella属细菌与治疗效果具有一定的关联性。该研究结果提示药物治疗、性别以及治疗效果与肠道菌群具有关联性，Prevotella属细菌可做为治疗效果的指示细菌，也可作为治疗干预的靶标。