持续抗病毒治疗5年以上人类免疫缺陷病毒感染者代谢特征研究

Metabolic characteristics of HIV-infected patients on antiretroviral therapy for more than 5 years

目的检测人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染者持续抗反转录病毒治疗(anti-retroviral therapy,ART)后体内代谢物变化,分析长期接受ART的HIV感染者的代谢特征,为改善和优化ART提供数据支持。方法2022年7月在新疆伊宁市招募持续接受ART 5年以上的HIV感染者23例(治疗组)、从未接受ART的HIV感染者20例(未治疗组)及健康对照组24例。收集3组人群外周静脉血样本,进行CD4+T淋巴细胞(CD4+T细胞)计数和病毒载量(viral load,VL)检测,通过液质联用技术对血浆样本进行非靶向代谢组学检测,采用主成分分析(principal component analysis,PCA)、偏最小二乘法判别分析(partial least squares discriminant analysis,PLS-DA)筛选差异代谢物,比较3组人群间代谢物的差异。结果在治疗组、未治组及健康对照组血浆样本中共鉴定代谢物1028种,按照投影重要度(variable importance for the projection,VIP)>1.0,差异倍数(fold change,FC)>1.2或FC<0.833且P<0.05的标准筛选差异代谢物,发现126种代谢物显著改变并参与HIV感染者代谢的病理生理过程。结果显示,与健康对照组比较,治疗组甘氨鹅脱氧胆酸等42种代谢物表达上调,褪黑素、雌三醇、前列腺素E2等84种代谢物表达下调,涉及多不饱和脂肪酸代谢等多种代谢通路的改变;未治疗组37种代谢物显著上调,73种代谢物显著下调,并在初级胆汁酸代谢通路富集,提示可能存在胆汁酸累积造成的肝毒性。治疗组与未治疗组比较,细辛醛等11种代谢物显著上调,犬尿喹啉酸等19种代谢物显著下调,表明色氨酸代谢通路在其中发挥重要作用。结论长期ART引起的褪黑素、前列腺素E2等代谢物的改变提示持续ART有助于维持HIV感染者的免疫重建。因此,密切关注HIV感染者和艾滋病患者的代谢特征变化,及时调整其用药方案,具有重要意义。

Objective To detect metabolite changes in people living with HIV(PLWH)after continuous antiretroviral therapy(ART)and to analyse the metabolic profiles of long-term ART,in order to provide data to support the improvement and optimization of ART.Methods In July 2022,23 PLWH who had been on ART for more than five years,20 PLWH who had never received ART,and 24 healthy controls were recruited in Yining city,Xinjiang.Blood samples from the three groups were collected for CD4+T-lymphoid count(CD4)and viral load(VL)testing,and plasma samples were subjected to non-targeted metabolomics testing by LC-MS technology.Differential metabolites were screened using principal component analysis(PCA),and partial least squares-discriminant analysis(PLSDA),and differences in metabolites among the three groups were compared.Result A total of 1028 metabolites were identified in plasma samples from the treated,untreated,and healthy control groups,and 126 metabolites were found to be significantly altered and involved in the pathophysiological processes of PLWH metabolism when screened for differential metabolites according to the criteria of VIP>1.0,FC>1.2 or FC<0.833 with a P-value<0.05.The results showed that compared with the healthy control group,the expression of 42 metabolites was up-regulated,and 84 metabolites were down-regulated in the treatment group,involving the changes of various metabolic pathways such as polyunsaturated fatty acid metabolism.In the untreated group,37 metabolites were significantly up-regulated,and 73 were significantly down-regulated.They were enriched in the primary bile acid metabolic pathway,suggesting the possibility of hepatotoxicity caused by bile acid accumulation.In the treatment group compared with untreatment group,11 kinds of metabolites significantly raised,and 19 kinds of metabolites were significantly down-regulated,in which the tryptophan metabolism pathway played an important role.Conclusions Long-term treatment may lead to metabolic diseases in HIV/AIDS patients.The changes in metabolites such as melatonin and PGE2 induced by long-term ART suggest that continuous treatment is helpful to maintain the immune reconstitution of patients.Therefore,it is of great significance to pay close attention to the changes in metabolic characteristics of HIV patients and adjust their drug regimens in time.