Gaardbo Julie C, Trøsied Marius, Stiksrud Birgitte, Midttun Øivind, Ueland Per M, Ullum Henrik, Nielsen Susanne D
*Viro-immunology Research Group, Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; †Department of Clinical Immunology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; ‡Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway; §KG Jebsen Centre of Inflammation Research, University of Oslo, Oslo, Norway; ‖Institute of Clinical Medicine, University of Oslo, Oslo, Norway; and ¶Bevital A/S, Bergen, Norway.
J Acquir Immune Defic Syndr. 2015 Nov 1;70(3):228-35. doi: 10.1097/QAI.0000000000000758.
HIV infection is associated with increased ratio between kynurenine and tryptophan (KTR) in plasma, increased microbial translocation, expansion of regulatory T cells (Tregs), and depletion of Tc17/mucosa-associated invariant T (MAIT) cells. The association between these parameters and the impact of KTR on CD4 T-cell recovery in HIV-infected patients on combination antiretroviral therapy (cART) after 2 years of follow-up was investigated.
Forty-one HIV-infected individuals treated with cART for a minimum of 2 years were included. Tregs, CD161Tc17/MAIT cells, naive cells, immune activation, senescence, and apoptosis were measured using flow cytometry. Soluble CD14 (sCD14), lipopolysaccharide, and tryptophan metabolites in plasma were measured retrospectively before cART and at inclusion initiation using Limulus Amebocyte Lysate colometric assay, enzyme-linked immunosorbent assay, and tandem mass spectrometry, respectively. KTR was calculated, and patients were divided into 2 groups defined by high vs. low KTR. CD4 T-cell count was determined at inclusion and after 2 years of follow-up.
KTR decreased after cART initiation. Patients on cART with high KTR displayed an immunological profile with high sCD14, high percentage Tregs, low percentage CD161Tc17/MAIT cells, low percentage naive cells, low CD4/CD8 ratio, and poor immune reconstitution after 2 years of follow-up compared with patients with low KTR.
Our results support the hypothesis that tryptophan catabolism, indoleamine 2,3-dioxygenase 1 (IDO1) activation, microbial translocation, and perturbed distribution of Tregs and CD161Tc17/MAIT cells are part of a vicious circle that perpetuates exhaustion of the immune system and progression of untreated HIV infection and challenge immune reconstitution in patients on cART.
HIV感染与血浆中犬尿氨酸与色氨酸的比例（KTR）升高、微生物易位增加、调节性T细胞（Tregs）扩增以及Tc17/黏膜相关恒定T细胞（MAIT）耗竭有关。研究了这些参数之间的关联以及KTR对接受联合抗逆转录病毒治疗（cART）的HIV感染患者2年随访后CD4 T细胞恢复的影响。
纳入41例接受cART治疗至少2年的HIV感染者。使用流式细胞术检测Tregs、CD161Tc17/MAIT细胞、幼稚细胞、免疫激活、衰老和凋亡情况。分别采用鲎试剂比色法、酶联免疫吸附测定法和串联质谱法回顾性检测cART前及入组开始时血浆中的可溶性CD14（sCD14）、脂多糖和色氨酸代谢产物。计算KTR，并将患者分为高KTR组和低KTR组。在入组时和随访2年后测定CD4 T细胞计数。
开始cART后KTR降低。与低KTR患者相比，高KTR的cART患者在随访2年后表现出高sCD14、高比例Tregs、低比例CD161Tc17/MAIT细胞、低比例幼稚细胞、低CD4/CD8比值以及免疫重建不良的免疫特征。
我们的结果支持以下假设，即色氨酸分解代谢、吲哚胺2,3-双加氧酶1（IDO1）激活、微生物易位以及Tregs和CD161Tc17/MAIT细胞分布紊乱是恶性循环的一部分，这种恶性循环会使免疫系统持续耗竭、未经治疗的HIV感染进展，并对接受cART的患者的免疫重建构成挑战。
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