FOXO1 transcription factor plays a key role in T cell—HIV-1 interaction

Autor: Roux, Arthur, Leroy, Héloise, De Muylder, Bénédicte, Bracq, Lucie, Oussous, Samia, Dusanter-Fourt, Isabelle, Chougui, Ghina, Tacine, Rachida, Randriamampita, Clotilde, Desjardins, Delphine, Le Grand, Roger, Bouillaud, Frederic, Benichou, Serge, Margottin-Goguet, Florence, Cheynier, Remi, Bismuth, Georges, Mangeney, Marianne
Přispěvatelé: [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), Virus-Host Interactions for Therapeutic Targeting of Human Infection (VirHost), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, This work was supported by INSERM, CNRS, the 'proof of concept program' of Institut Cochin and the 'Agence Nationale de Rercherche sur le SIDA et les Hépatites virales' (ANRS, France)., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bodescot, Myriam
Jazyk: angličtina
Rok vydání: 2019
Předmět:
RNA viruses
CD4-Positive T-Lymphocytes
Male
HIV Infections
Monkeys
Pathology and Laboratory Medicine
Lymphocyte Activation
Virus Replication
Biochemistry
White Blood Cells
Jurkat Cells
Immunodeficiency Viruses
Drug Metabolism
Animal Cells
Medicine and Health Sciences
Cell Cycle and Cell Division
Post-Translational Modification
Phosphorylation
ComputingMilieux_MISCELLANEOUS
Mammals
T Cells
Forkhead Box Protein O1
Cell Cycle
Eukaryota
Virus Latency
Medical Microbiology
Cell Processes
Viral Pathogens
Viruses
Vertebrates
[SDV.IMM]Life Sciences [q-bio]/Immunology
Cellular Types
Pathogens
Macaque
Research Article
Primates
Cell Physiology
endocrine system
Immune Cells
Immunology
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Microbiology
Virology
Retroviruses
Old World monkeys
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Animals
Humans
Pharmacokinetics
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Microbial Pathogens
Pharmacology
Blood Cells
Lentivirus
Organisms
Biology and Life Sciences
HIV
Proteins
Cell Biology
Viral Replication
Cell Metabolism
Macaca fascicularis
Gene Expression Regulation
Amniotes
HIV-1
Virus Activation
Zdroj: PLoS Pathogens
PLoS Pathogens, Public Library of Science, 2019, 15 (5), pp.e1007669. ⟨10.1371/journal.ppat.1007669⟩
PLoS Pathogens, 2019, 15 (5), pp.e1007669. ⟨10.1371/journal.ppat.1007669⟩
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1007669⟩
Popis: HIV-1 is dependent on the host cell for providing the metabolic resources for completion of its viral replication cycle. Thus, HIV-1 replicates efficiently only in activated CD4+ T cells. Barriers preventing HIV-1 replication in resting CD4+ T cells include a block that limits reverse transcription and also the lack of activity of several inducible transcription factors, such as NF-κB and NFAT. Because FOXO1 is a master regulator of T cell functions, we studied the effect of its inhibition on T cell/HIV-1 interactions. By using AS1842856, a FOXO1 pharmacologic inhibitor, we observe that FOXO1 inhibition induces a metabolic activation of T cells with a G0/G1 transition in the absence of any stimulatory signal. One parallel outcome of this change is the inhibition of the activity of the HIV restriction factor SAMHD1 and the activation of the NFAT pathway. FOXO1 inhibition by AS1842856 makes resting T cells permissive to HIV-1 infection. In addition, we found that FOXO1 inhibition by either AS1842856 treatment or upon FOXO1 knockdown induces the reactivation of HIV-1 latent proviruses in T cells. We conclude that FOXO1 has a central role in the HIV-1/T cell interaction and that inhibiting FOXO1 with drugs such as AS1842856 may be a new therapeutic shock-and-kill strategy to eliminate the HIV-1 reservoir in human T cells.
Author summary HIV-1 is controlled by host restriction factors that interfere with its life cycle. However, the virus has equipped itself to counter these strategies. We report a new interplay between HIV-1 and human T lymphocytes through the FOXO1 transcription factor. By using AS1842856, a drug targeting FOXO1, we found that FOXO1 inhibition triggers metabolic activation and G0/G1 transition of resting T cells and also by the inactivation of the SAMHD1 viral restriction factor. FOXO1 inhibition makes resting CD4+ T cells permissive to HIV-1 infection. We finally found that pharmacologic (AS1842856 treatment) or genetic (shRNA) silencing of FOXO1 reactivate HIV-1 latent proviruses. Thus FOXO1 appears as an important player of the HIV-1/T-cell relationship and a new potential therapeutic target for intervention during HIV-1 infection.
Databáze: OpenAIRE
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