Distinct Tryptophan Catabolism and Th17/Treg Balance in HIV Progressors and Elite Controllers

Jenabian, Mohammad-Ali; Patel, M.H.; Kema, Ido P.; Kanagaratham, Cynthia; Radzioch, Danuta; Thébault, Paméla; Lapointe, Réjean; Tremblay, Cécile; Gilmore, Norbert; Ancuța, Petronela; Routy, Jean‐Pierre

doi:10.1371/journal.pone.0078146

Cited by 92 publications

(112 citation statements)

References 55 publications

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“…In agreement with findings reported in the literature, we demonstrated that the diminished STAT5 phosphorylation found during the early phase of HIV-1 infection correlated not only with enhanced ROS and Kyn levels but also with enhanced levels of several inflammation mark-ers, such as IL-6, sCD14, and IP-10 ( Fig. 3A to C) (22,25,29). Therefore, we cannot exclude the possibility that other mechanisms, which could involve the release of intermediate molecules such as IFN type I and other proinflammatory markers by monocyte/macrophages and DCs, are at play in our observations.…”

Section: Ccr7supporting

confidence: 92%

“…This state is characterized by the decrease of tryptophan availability and the increased production of the immunosuppressive compound Kyn. Enhanced tryptophan/kynurenine catabolism leads to the loss of Th 17 and Th 22 cells, which play key protective roles in the gut for microbial defense (36), the generation of regulatory T cells (25,29,32), and the inhibition of T-cell proliferation (37,38).…”

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

“…Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptophan into kynurenine (Kyn), which is mediated by the indoleamine 2,3-dioxygenase 1 (IDO-1) expressed in dendritic cells (DCs) and monocytes, is increased in HIV-1-infected subjects (22,(28)(29)(30). The enhanced tryptophan catabolism detected early during HIV-1 infection correlates with proinflammatory molecules like IL-6, soluble CD40 (sCD40), and gamma interferon (IFN-␥)-inducible protein 10 (IP-10) (22,25,31,32) and is associated with CD4 T-cell decay (33)(34)(35).…”

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

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Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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Section: Ccr7supporting

confidence: 92%

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

Section: The Persistence Of Functional Memory Cd4 T Cells Represents mentioning

confidence: 99%

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Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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“…In addition, they observed an inverse correlation between the CD4:CD8 ratio and hs-CRP, IL-6, and markers of myeloid cell activation such as sCD14 and indoleamine 2,3-dioxygenase (IDO). IDO is an immune-modulatory enzyme, which breaks down tryptophan into kynurenine and can be considered as a myeloid cell marker of immune suppression [40,41]. For patients with CD4 T cell counts >500/mm 3 , only the tryptophan/kynurenine (KT ratio), a marker of IDO activity, remained significantly correlated with the CD4:CD8 ratio and was able to predict non-AIDS events.…”

Section: Resultsmentioning

confidence: 99%

CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV‐positive patients

Lü¹,

Mehraj²,

Vyboh³

et al. 2015

Journal of the International AIDS Society

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185

129

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IntroductionAbsolute CD4 T cell count and plasma viral load have been established as predictors of HIV disease progression, and CD4 T cell count is used as an indicator for initiation of antiretroviral therapy. Following long-term therapy, patients generally present with significant CD4 T cell recovery contrasting with persistently elevated CD8 T cell counts, which leads to a partial restoration of CD4:CD8 ratio. This review focuses on the relevance of the CD4:CD8 ratio on clinical outcomes, immune dysfunction and HIV reservoir size in long-term treated patients.MethodWe conducted a comprehensive literature review of publications in English language using major electronic databases. Our search was focused on factors contributing to CD4:CD8 T cell ratio and clinical outcome in adult HIV-positive patients in the context of treated infection.DiscussionLow CD4:CD8 ratio has been linked to ageing and acts as a predictor of mortality in the general population. This ratio may represent the combined effects of inflammation and immunological changes called “inflammaging.” Although the mechanisms underlying partial correction of the CD4:CD8 ratio and persistently elevated CD8 T cell count in long-term treated patients remain poorly understood, it has been recently indicated that patients with optimal CD4 T cell recovery and low CD4:CD8 ratio still harbour increased immune activation, an immune senescent phenotype and have a higher risk of non-AIDS morbidity and mortality. This review reconsiders CD4:CD8 ratio in the light of advances in the understanding of immune dysfunction and examines its pathophysiological features and implications on clinical outcome and HIV reservoir size in long-term treated HIV-positive adults.ConclusionThe CD4:CD8 ratio can contribute to the immunological evaluation of treated patients in a long-term follow-up and may be applied for monitoring both immune dysfunction and viral reservoir size in immune-based clinical trials.

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“…The latter can cause the death of effector T cells due to the toxicity of its downstream product. Moreover, kynurenine can bind to aryl hydrocarbon receptor, which is involved in the regulation of Treg and inhibits TH17 cell differentiation, suppressing the immune system [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme catalyzing the initial and rate-limiting steps in the kynurenine pathway, which converts tryptophan into kynurenine. Upregulation of IDO1 decreases tryptophan levels and increases the accumulation of kynurenine and its metabolites. These metabolites can affect the proliferation of T cells. Increasing evidence has shown that IDO1 is highly expressed in various cancer types and associated with poor prognosis of cancer patients. However, the results were inconsistent. Methods: We searched the Web of Science, PubMed, Embase and Cochrane library databases to identify studies evaluating the prognostic value of IDO1 in cancer patients. Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by using fixed-effects/random-effects models. Results: This systematic review and meta-analysis included 2706 patients from 24 articles. The results indicated a shorter overall survival in patients with high expression of IDO1 (hazard ratio [HR] = 2.03, 95% confidence interval [CI]: 1.56-2.63). Furthermore, disease-free survival was worse in patients with high expression of IDO1 (HR = 2.47, 95% CI: 1.46-4.20). Additionally, the pooled odds ratios (ORs) showed that increased IDO1 was significantly associated with tumor differentiation (OR = 1.81, 95% CI: 1.05-3.12), distant metastasis (OR = 1.45, 95% CI: 1.02-2.06), and poor clinical stage (OR = 1.89, 95% CI: 1.13-3.17). However, no significant correlation was observed of increased IDO1 expression with age, sex, lymph node metastasis, and tumor size. Conclusion: High expression of IDO1 is associated with poor clinical outcomes. IDO1 could serve as a biomarker of prognosis and a potential predictive factor of clinicopathology in various cancers. Further studies should be performed to verify the clinical utility of IDO1 in human solid tumors.

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Distinct Tryptophan Catabolism and Th17/Treg Balance in HIV Progressors and Elite Controllers

Cited by 92 publications

References 55 publications

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV‐positive patients

The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis

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