title: Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection.
abstract: 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.
  
  
  
  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.
authors.affiliation: Institut National de la Recherche Scientifique (INRS)-Institut Armand-Frappier, Laval, Québec, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dagenais-Lussier
authors.affiliation: Institut National de la Recherche Scientifique (INRS)-Institut Armand-Frappier, Laval, Québec, Canada.
authors.forename: Mouna
authors.initials: M
authors.lastname: Aounallah
authors.affiliation: Chronic Viral Illness Service and Division of Hematology, McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Vikram
authors.initials: V
authors.lastname: Mehraj
authors.affiliation: Centre de Recherche de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Far
authors.affiliation: Centre de Recherche de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Cecile
authors.initials: C
authors.lastname: Tremblay
authors.affiliation: Center for AIDS Research, Proteomics and Systems Biology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sekaly
authors.affiliation: Chronic Viral Illness Service and Division of Hematology, McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Institut National de la Recherche Scientifique (INRS)-Institut Armand-Frappier, Laval, Québec, Canada julien.vangrevenynghe@iaf.inrs.ca.
authors.forename: Julien
authors.identifier: 0000-0002-2952-4081
authors.initials: J
authors.lastname: van Grevenynghe
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism*; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: C508594:IL2 protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D017382:Reactive Oxygen Species; D007737:Kynurenine