脂肪酸代谢重塑通过调控免疫应答对HIV感染疾病进展的作用及机制研究

Immunemetabolism plays an important role in revealing the pathogenic mechanism and providing intervention strategy of immune related diseases, but whether it contributes to the rapid progression of HIV infection is unknown. We found for the first time, plasma fatty acid metabolites in the early stage of HIV infection effectively predict disease progression. The expression of fatty acid oxidation enzyme in CD8+T cells from progressors is significantly increased compared with non-progressors. These data suggest that there is a fatty acid metabolism “reprogramming” in HIV infected rapid progressors. We postulated that the enhancement of fatty acid oxidative may weaken the immune response through the insufficient metabolic support of T cell function and the induction of regulatory T cells and PPARγ expression. To prove the hypothesis, this study intends to clarify: 1) The fatty acid metabolism reprogramming in the T cell of rapid progressors; 2) The effect and mechanisms of fatty acid metabolism reprogramming on T cell immune responses; 3) The factors driving T cell fatty acid reprogramming in rapid progressors; 4) The restore of T cell immune responses of rapid progressors by the intervention of fatty acid reprogramming. Our data will clarify the effect and mechanisms of fatty acid metabolism reprogramming on HIV disease rapid progression and provide potential targets for immune therapy.

“免疫代谢”对揭示疾病转归机制及干预具有重要作用，但是否影响HIV感染疾病快速进展尚不可知。我们首次发现，血浆脂肪酸代谢物可在HIV感染早期有效预测疾病快速进展，进展者CD8+T细胞脂肪酸氧化关键酶表达升高，提示脂肪酸代谢“重塑”（Reprogramming），脂肪酸氧化增强。我们推测：早期大量抗原刺激等导致低糖及细胞因子微环境改变，促使快速进展者效应T细胞代谢向脂肪酸氧化重塑，不能有效支撑其功能发挥，并通过促进调节性T细胞分化、诱导PPARγ表达等削弱T细胞效应功能，导致疾病进展。为证实以上假设，本研究拟明确：1）HIV快速进展者T细胞脂肪酸代谢重塑情况；2）脂肪酸代谢重塑对T细胞功能的影响及机制；3）导致快速进展者T细胞脂肪酸代谢重塑的上游因素；4）干预脂肪酸代谢重塑对快速进展者T细胞免疫损伤的恢复，最终明确脂肪酸代谢重塑对HIV感染快速进展的影响，为免疫治疗等提供创新靶点。

HIV感染中免疫系统损伤的复杂机制尚不清楚，“快速进展者”（Rapid progressor，RPs）在HIV感染早期免疫系统损害严重，明确其机制对于揭示疾病转归机制及干预具有重要作用。我们对23名HIV感染RPs(感染1年内CD4+T细胞计数<350个/µl)和21名“正常进展者”(Normal progressors，NPs；感染1年后CD4+T细胞计数>500个细胞/μl)的血浆代谢组进行研究，发现11种差异表达脂质代谢产物可以区分大部分RPs和NPs。其中，长链脂肪酸eicosenoate显著抑制CD4+和CD8+T细胞增殖和IFN-γ等细胞因子分泌，并诱导耗竭标志物TIM-3表达。深入研究显示，eicosenoate增加了T细胞活性氧（ROS）水平，降低线粒体耗氧率(OCR)和线粒体质量，表明其可损伤线粒体功能。机制研究表明，eicosenoate可诱导T细胞p53表达，而抑制p53可有效降低T细胞线粒体ROS表达，采用线粒体靶向抗氧化剂mito-TEMPO，可恢复eicosenoate诱导的T细胞功能损伤。上述研究表明，脂质代谢产物eicosenoate通过诱导p53增加线粒体ROS，从而抑制T细胞功能，为HIV感染疾病快速进展机制解析提供了新线索，为免疫干预提供新手段。