肠道普通拟杆菌通过NLRP12调控HIV-1感染早期CD4+T细胞凋亡及病毒复制的作用及机制研究

HIV-1感染早期伴随肠道菌群失衡和CD4+T细胞的大量凋亡。我们前期证实了该现象并发现肠道普通拟杆菌的丰度在急性期HIV-1感染者中显著下调，同时该菌代谢产物及细胞相关NOD样受体（NLRP12）也显著下调。NLRP12可以通过调控NF-κB通路抑制细胞凋亡，且NF-κB是HIV-1转录的促进因子。因此我们认为普通拟杆菌可激活NLRP12，进而调控CD4+T细胞凋亡，抑制HIV-1复制，延缓急性期HIV-1感染进程。本项目拟通过人群队列研究和体外细胞实验，采用鸟枪法宏基因组学测序、靶向代谢组学GC-MS等技术，阐释普通拟杆菌调控NLRP12-经典/非经典NF-κB信号轴抑制病毒感染所致CD4+T细胞凋亡及病毒复制的作用和机制。本项目首次从肠道菌群的角度阐释HIV-1感染急性期细胞凋亡、病毒复制的部分作用机制，有助于发现新的辅助治疗策略，对于实现艾滋病“功能性治愈”具有重要的启示意义。

Early HIV-1 infection is accompanied by a gut microbiome imbalance and a large number of CD4+T cell apoptosis. We confirmed this phenomenon and found that the abundance of Bacteroides plebeius was significantly down-regulated in the individuals with acute HIV-1 infection, and its metabolites and cell-associated NOD-like receptors (NLRP12) were also significantly down-regulated. NLRP12 can inhibit apoptosis by regulating the NF-κB pathway, and NF-κB is a promoter of HIV-1 transcription. Therefore, we believe that Bacteroides plebeius can activate NLRP12, and then regulate CD4+T cell apoptosis, inhibit HIV-1 replication, and delay the HIV-1 infection in the acute phase. This project intends to elucidate the role and mechanism of Bacteroides plebeius-NLRP12-classical/non-classical NF-κB signaling axis in inhibiting CD4+T cell apoptosis and virus replication caused by HIV infection through cohort studies and vitro cell experiments, using shotgun metagenomic sequencing and targeted metabolomics GC-MS and other technologies. This project, for the first time, explains part of the mechanism of CD4+T cells apoptosis and viral replication in the acute HIV-1 infection from the perspective of the gut microbiome. It contributes to discover novel adjuvant treatment strategies and has important implications for achieving "functional cure" for AIDS.