Increased Tryptophan Catabolism Is Associated With Increased Frequency of CD161+Tc17/MAIT Cells and Lower CD4+ T-Cell Count in HIV-1 Infected Patients on cART After 2 Years of Follow-Up.

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.