METTL3介导的SOCS3 m6A修饰调控T细胞分化在HIV感染长期不进展中的作用机制

HIV-1感染长期不进展者（LTNP）CD4+T细胞维持正常功能的机制尚未清楚。我们前期发现LTNP的CD4+T细胞分化特异并受SOCS3影响，且调控T细胞分化的METTL3呈高表达。而SOCS3存在m6A修饰位点，可被METTL3调控。据此假设：METTL3介导的SOCS3 m6A修饰调控T细胞分化在HIV感染长期不进展中发挥作用。本研究通过分析人群中METTL3的m6A修饰水平和SOCS3通路与CD4+T细胞分化的关系，并在体外敲降METTL3、SOCS3等关键基因，明确METTL3对SOCS3的m6A修饰作用，同时检测被SCOS3调控的IL-12/STAT4信号通路和CD4+T细胞分化水平，阐明METTL3介导SOCS3的m6A修饰调控T细胞分化和免疫平衡在LTNP中的作用机制。本研究首次从m6A表观遗传学角度探讨LTNP的分子机制，有望为艾滋病功能性治愈提供新策略。

The mechanism of long-term non-progressors (LTNP) maintaining CD4+T cells normal function remains unclear. Our previous results have shown that CD4+T cells in LTNP are specifically differentiated and influenced by the expression of SOCS3. And METTL3, which regulates T cell differentiation, was highly expressed in LTNP. SOCS3 has m6A modification site, which can be regulated by METTL3. Therefore, we hypothesize that METTL3-mediated SOCS3 m6A modification regulates T cell differentiation plays a role in LTNP. In this study, we analyzed the relationship between METTL3 m6A and SOCS3 pathway with T cell differentiation, and knocked down some key genes such as METTL3 and SOCS3 in vitro, to investigate the regulation of METTL3-mediated SOCS3 m6A. We also examined the IL-12/STAT4 signaling pathway regulated by SCOS3 and CD4+T cell differentiation levels, to elucidate the mechanism of T cell differentiation and immune homeostasis were regulated by METTL3-mediated SOCS3 m6A modification in LTNP. For the first time, from an epigenetic perspective of m6A, to explore the molecular mechanism of long-term non-progression of HIV-1 infection, which is expected to provide a new strategy for functional cure of AIDS.