Liver fibrosis is strongly associated with an enhanced level of immunosuppressive tryptophan catabolism independently of HCV viremia in ART-treated HIV/HCV co-infected patients

  • Mohammad-Ali Jenabian
  • Ido Kema
  • Robert Paulino Ramirez
  • Sahar Saeed
  • Kathleen Rollet
  • Kishanda Vyboh
  • Jean-Carlos Tejada
  • Norbert Gilmore
  • Marina B Klein
  • Jean-Pierre Routy
Open Access
Oral presentation

Keywords

Liver Fibrosis Sustained Virological Response Kynurenine Healthy Subject APRI Score 

Background

HCV infection induces hepatic and extra-hepatic damage that includes kidney and neurocognitive dysfunction. Tryptophan (Trp) is catabolized into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3 dioxegenase (TDO). Increased Trp catabolism measured by Kyn/Trp ratio has been associated with neurocognitive impairment and immune dysfunction in HIV mono-infection. Here, we assessed the contribution of Trp catabolism in HCV/HIV co-infected patients.

Methods

Plasma samples were collected from ART-treated (HIV RNA <40 copies/ml) HCV/HIV co-infected patients with or without liver fibrosis (n=20 per group), HBV/HIV co-infected patients (n=25), ART-treated and untreated HIV-mono-infected patients and 30 healthy subjects (HS), (n=30 per group). Furthermore, 17 additional HCV/HIV INF-α/ribavirin treated patients were longitudinally assessed before and 6 months after sustained virological response (SVR). IDO and TDO enzymatic activity (Kyn/Trp ratio) was measured by isotope dilution tandem mass spectrometry. Statistical analyses were performed using Anova, unpaired or paired t-tests and Spearman correlation tests.

Results

Among HCV/HIV patients, those having fibrosis compared with non-fibrosis had higher APRI scores (2.48±0.23 vs 0.36±0.018, p<0.0001) and elevated Kyn levels (2.6±0.24 vs. 1.97±0.15 µmol/L, p=0.038). For HBV/HIV co-infected, Kyn level was also elevated (2.1±0.16 µmol/L). The Kyn/Trp ratio was equally elevated in all HCV and HBV co-infected groups, similar to the untreated mono-infected HIV group. Importantly, HCV/HIV fibrotic and HBV/HIV groups but not the non-fibrotic group had higher Kyn/Trp ratios compared to the ART-treated and HS groups. Unlike HIV viremia, HCV viremia was not correlated with the Kyn/Trp ratio. However, in all HCV/HIV co-infected patients, Kyn/Trp ratio was correlated with the APRI score (p=0.027). Successful HCV treatment improved APRI score (0.89±0.13 vs. 0.4±0.04, p=0.001), contrasting with unchanged elevated Kyn/Trp ratios six months after SVR.

Conclusion

ART-treated HCV/HIV and HBV/HIV co-infected patients presented with elevated immunosuppressive Kyn/Trp ratios when compared to mono-infected HIV-treated patients and reached a ratio similar to the untreated HIV mono-infected patients. In ART-treated patients, liver fibrosis on its own, but not HCV viremia, was associated with an enhanced level of immunosuppressive Tryptophan catabolism. These findings suggest that a necrotico-inflammatory liver syndrome persists even after SVR, and subsequently induces a systemic immune activation by increasing tryptophan catabolism.

Copyright information

© Jenabian et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Mohammad-Ali Jenabian
    • 1
    • 2
  • Ido Kema
    • 3
  • Robert Paulino Ramirez
    • 4
  • Sahar Saeed
    • 5
  • Kathleen Rollet
    • 1
  • Kishanda Vyboh
    • 1
  • Jean-Carlos Tejada
    • 6
  • Norbert Gilmore
    • 1
    • 2
  • Marina B Klein
    • 1
    • 2
  • Jean-Pierre Routy
    • 1
    • 2
  1. 1.Chronic Viral Illnesses Service of the McGill University Health CenterMontrealCanada
  2. 2.Research Institute of the McGill University Health CenterMontrealCanada
  3. 3.Department of Laboratory Medicine, University Medical CenterUniversity of GroningenGroningenThe Netherlands
  4. 4.School of Medicine, Research DepartmentUniversidad IberoamericanaSanto DomingoDominican Republic
  5. 5.Clinical Research Solutions, Montreal, Quebec, Canada Division of HematologyMcGill University Health CenterMontrealCanada
  6. 6.Instituto Dominicano de Estudios VirologicosSanto DomingoDominican Republic

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