Tuning of AKT-pathway by Nef and its blockade by protease inhibitors results in limited recovery in latently HIV infected T-cell line.
Fiche publication
Date publication
avril 2016
Journal
Scientific reports
Auteurs
Membres identifiés du Cancéropôle Est :
Pr HERBEIN Georges, Pr ROHR Olivier
Tous les auteurs :
Kumar A, Abbas W, Colin L, Khan KA, Bouchat S, Varin A, Larbi A, Gatot JS, Kabeya K, Vanhulle C, Delacourt N, Pasquereau S, Coquard L, Borch A, König R, Clumeck N, De Wit S, Rohr O, Rouzioux C, Fulop T, Van Lint C, Herbein G
Lien Pubmed
Résumé
Akt signaling plays a central role in many biological processes, which are key players in human immunodeficiency virus 1 (HIV-1) pathogenesis. We found that Akt interacts with HIV-1 Nef protein. In primary T cells treated with exogenous Nef or acutely infected with Nef-expressing HIV-1 in vitro, Akt became phosphorylated on serine(473) and threonine(308). In vitro, Akt activation mediated by Nef in T-cells was blocked by HIV protease inhibitors (PI), but not by reverse transcriptase inhibitors (RTI). Ex vivo, we found that the Akt pathway is hyperactivated in peripheral blood lymphocytes (PBLs) from cART naïve HIV-1-infected patients. PBLs isolated from PI-treated patients, but not from RTI-treated patients, exhibited decreased Akt activation, T-cell proliferation and IL-2 production. We found that PI but not RTI can block HIV-1 reactivation in latently infected J-Lat lymphoid cells stimulated with various stimuli. Using luciferase measurement, we further confirmed that Nef-mediated reactivation of HIV-1 from latency in 1G5 cells was blocked by PI parallel to decreased Akt activation. Our results indicate that PI-mediated blockade of Akt activation could impact the HIV-1 reservoir and support the need to further assess the therapeutic use of HIV-1 PI in order to curtail latently infected cells in HIV-1-infected patients.
Mots clés
Cells, Cultured, HIV Infections, pathology, HIV-1, physiology, Humans, Phosphorylation, Protein Interaction Mapping, Protein Kinase Inhibitors, metabolism, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, metabolism, Signal Transduction, T-Lymphocytes, physiology, Virus Latency, nef Gene Products, Human Immunodeficiency Virus, metabolism
Référence
Sci Rep. 2016 Apr;6:24090