title: Tuning of AKT-pathway by Nef and its blockade by protease inhibitors results in limited recovery in latently HIV infected T-cell line.
abstract: 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.
authors.affiliation: Department of Virology, Pathogens &Inflammation Laboratory, University of Franche-Comté and COMUE Bourgogne Franche-Comté University, UPRES EA4266, SFR FED 4234, CHRU Besançon, Besançon, France.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Virology, Pathogens &Inflammation Laboratory, University of Franche-Comté and COMUE Bourgogne Franche-Comté University, UPRES EA4266, SFR FED 4234, CHRU Besançon, Besançon, France.
authors.forename: Wasim
authors.initials: W
authors.lastname: Abbas
authors.affiliation: Laboratory of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colin
authors.affiliation: Department of Virology, Pathogens &Inflammation Laboratory, University of Franche-Comté and COMUE Bourgogne Franche-Comté University, UPRES EA4266, SFR FED 4234, CHRU Besançon, Besançon, France.
authors.forename: Kashif Aziz
authors.initials: KA
authors.lastname: Khan
authors.affiliation: Laboratory of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bouchat
authors.affiliation: Department of Virology, Pathogens &Inflammation Laboratory, University of Franche-Comté and COMUE Bourgogne Franche-Comté University, UPRES EA4266, SFR FED 4234, CHRU Besançon, Besançon, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Varin
authors.affiliation: Department of Medicine, University of Sherbrooke, Sherbrooke, Canada.
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.affiliation: Laboratory of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Jean-Stéphane
authors.initials: JS
authors.lastname: Gatot
authors.affiliation: Department of Infectious Diseases, CHU St-Pierre, ULB, Bruxelles, Belgium.
authors.forename: Kabamba
authors.initials: K
authors.lastname: Kabeya
authors.affiliation: Laboratory of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Vanhulle
authors.affiliation: Laboratory of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Nadège
authors.initials: N
authors.lastname: Delacourt
authors.affiliation: Department of Virology, Pathogens &Inflammation Laboratory, University of Franche-Comté and COMUE Bourgogne Franche-Comté University, UPRES EA4266, SFR FED 4234, CHRU Besançon, Besançon, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pasquereau
authors.affiliation: Department of Virology, Pathogens &Inflammation Laboratory, University of Franche-Comté and COMUE Bourgogne Franche-Comté University, UPRES EA4266, SFR FED 4234, CHRU Besançon, Besançon, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Coquard
authors.affiliation: Research Group "Host-Pathogen Interactions", Paul-Ehrlich-Institute, Langen, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Borch
authors.affiliation: Research Group "Host-Pathogen Interactions", Paul-Ehrlich-Institute, Langen, Germany.|Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA; German Center for Infection Research (DZIF), Langen, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.affiliation: Department of Infectious Diseases, CHU St-Pierre, ULB, Bruxelles, Belgium.
authors.forename: Nathan
authors.initials: N
authors.lastname: Clumeck
authors.affiliation: Department of Infectious Diseases, CHU St-Pierre, ULB, Bruxelles, Belgium.
authors.forename: Stephane
authors.initials: S
authors.lastname: De Wit
authors.affiliation: Institut de Parasitologie et Pathologie Tropicale, University of Strasbourg, Strasbourg, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rohr
authors.affiliation: Department of Virology, Paris University, EA7327 Paris Descartes, APHP Necker Hospital, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Rouzioux
authors.affiliation: Department of Medicine, University of Sherbrooke, Sherbrooke, Canada.
authors.forename: Tamas
authors.initials: T
authors.lastname: Fulop
authors.affiliation: Laboratory of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.affiliation: Department of Virology, Pathogens &Inflammation Laboratory, University of Franche-Comté and COMUE Bourgogne Franche-Comté University, UPRES EA4266, SFR FED 4234, CHRU Besançon, Besançon, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Herbein
mesh_terms: D002478:Cells, Cultured; D015658:HIV Infections / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology / Q000821:virology*; D017735:Virus Latency; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D051057:Proto-Oncogene Proteins c-akt