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. 2013 Oct 16;8(10):e78146.
doi: 10.1371/journal.pone.0078146. eCollection 2013.

VSports在线直播 - Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers

Mohammad-Ali Jenabian  1 , Mital Patel, Ido Kema, Cynthia Kanagaratham, Danuta Radzioch, Paméla Thébault, Réjean Lapointe, Cécile Tremblay, Norbert Gilmore, Petronela Ancuta, Jean-Pierre Routy
Affiliations

Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers

Mohammad-Ali Jenabian et al. PLoS One. .

Erratum in

  • PLoS One. 2014;9(1). doi:10.1371/annotation/11698dd2-0bc1-4fe0-ad92-b161b5594e81

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. VSports手机版.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Tryptophan catabolism is elevated in HIV-infected subjects with disease progression but not elite controllers.
Plasma levels of (A) tryptophan (Trp), (B) kynurenine (Kyn), (C) and 3 -hydroxykynurenine were measured by XLC-MS/MS in ART-successfully treated (ST, n=88), ART-naïve (n=96), elite controllers (EC, n=19), and healthy subjects (HS, n=50), (D) IDO activity in shown, defined as the Kyn/Trp ratio. Statistical analysis was provided by ANOVA tests followed by unpaired t-tests used for comparison of two variables.
Figure 2
Figure 2. Tryptophan catabolites are associated with higher HIV-1 viral load (VL) and lower CD4+ T-cell counts in ART-naïve patients.
Association between plasmatic HIV-1 viral load and plasmatic (A) tryptophan (Trp) (B) kynurenine (Kyn) (C) 3-hydroxykynurenine (3OH-Kyn) and (D) IDO activity as defined by Kyn/Trp and CD4+ T-cell counts and plasmatic (E) tryptophan (F) kynurenine (G) 3-hydroxykynurenine and (H) IDO activity (Kyn/Trp ratio) in ART-naïve patients (n=96). Pearson rank correlation was used for statistical analysis.
Figure 3
Figure 3. Th17/Treg imbalance in HIV-1 infection correlates with IDO enzyme activity.
(A) Th17 cells (CD4+IL-17+) frequency in study groups following PMA/Ionomycine in vitro Stimulation (B) Frequency of Treg (CD4+CD25highCD127lowFoxP3high cells) in study groups ex vivo . (C) Th17/Treg ratio in study groups. (C) Th17/Treg ratio in study groups. (D) Correlation between IDO enzymatic activity defined by Trp/Kyn ratio and Th17/Treg ratio in study groups. (E) Association between IDO enzymatic activity and Treg frequency in study groups. (F) Correlation between bacterial translocation marker sCD14 and Th17/Treg ratio in study groups. ST: ART-successfully treated, ART-naïve, EC: elite controllers, and HS: healthy subjects. n=14 per study group. Statistical analysis was provided by Kruskal-Wallis test followed by Mann-Whitney U test for comparison of two variables.
Figure 4
Figure 4. Trp catabolizing enzyme IDO-1 mRNA expression is associated with Treg frequency in HIV-1 infected patients with different clinical outcomes.
(A) Real-time quantitative RT-PCR was used to quantify IDO-1 mRNA and (B) TDO expression relative to the 18s ribosomal RNA from PBMCs of study groups. (C) Association between IDO enzymatic activity and Treg frequency in study groups. ST: ART-successfully treated, ART-naïve, EC: elite controllers, and HS: healthy subjects. N=14 per study group. Statistical analysis was provided by Kruskal-Wallis test followed by Mann-Whitney U test for comparison of two variables. Pearson rank test was used for the correlation.
Figure 5
Figure 5. Correlations between IDO enzymatic activity and levels of inflammatory soluble factors implicated in IDO induction.
Associations between IDO activity (Kyn/Trp ratio) and plasmatic levels of (A) IL-1β (B) IFNγ (C) sCD40L (D) TNF-α and (E) IL-6 in ST: ART-successfully treated, ART-naïve, EC: elite controllers, and HS: healthy subjects. n=14 per study group. Pearson rank correlation was used for statistical analysis.
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