Kynurenine Reduces Memory CD4 T-cell Survival by Interfering with IL-2 Signaling early During HIV-1 Infection.
Résumé
Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we showed that the increased production of kynurenine correlates with defective 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 plasma concentration of kynurenine inhibits IL-2 signaling through the production of reactive oxygen species. We further showed that IL-2 signaling in memory CD4 T-cells was improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored IL-2 response in memory CD4 T-cells by reducing ROS and kynurenine production. Study findings provide a kynurenine-dependant mechanism though IL-2 signaling for the reduced CD4 T cell survival that can be reversed by early treatment initiation in HIV-1 infection. The persistence of functional memory CD4 T-cells represents the basis for a 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 the tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.