Abstract
Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naïve, Successfully Treated (ST), and elite controllers (EC). In ART-naïve patients, increased IDO activity/expression, together with elevated levels of TNF-α and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-naïve patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression.
Highlights
Chronic HIV-1 infection is characterized by progressive depletion of total CD4+ T-cells and persistent immune activation, events that are only partially controlled by antiretroviral therapy (ART)
Our results provide evidence that IDOinduced Trp catabolism into Kyn induces a harmful effect on the T-helper 17 (Th17)/Treg ratio that may subsequently contribute to enhanced microbial translocation during HIV-1 infection
Levels of the Trp catabolite Kyn were significantly elevated in ART-naïve subjects compared to all other groups (ART-naïve: 2.37±0.76 vs. Successfully Treated (ST): 2.08±0.91, elite controllers (EC): 1.74±0.36, healthy subjects (HS): 1.72±0.44 μmol/L; Figure 1B)
Summary
Chronic HIV-1 infection is characterized by progressive depletion of total CD4+ T-cells and persistent immune activation, events that are only partially controlled by antiretroviral therapy (ART). IDO catabolizes the essential amino acid Tryptophan (Trp) into an immunosuppressive metabolite, Kynurenine (Kyn), that limits immune responses in cancers and chronic viral infections and/or induces immune tolerance during pregnancy[5,6,7,8,9,10,11]. Another enzyme that catabolizes Trp is Tryptophan 2,3-dioxygenase (TDO) which is mainly expressed in the liver as well as other tissues including the brain, uterus and skin [12,13,14,15]. HIV-1 infection is characterized by a rapid Th17 cell depletion associated with an expansion of Tregs owing to cellular immune activation
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