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

Arthur Roux,Arthur Roux,Arthur Roux,Arthur Roux,Lucie Bracq,Lucie Bracq,Lucie Bracq,Lucie Bracq,Lucie Bracq,Lucie Bracq,Samia Oussous,Samia Oussous,Samia Oussous,Samia Oussous,Marianne Mangeney,Marianne Mangeney,Marianne Mangeney,Marianne Mangeney,Georges Bismuth,Georges Bismuth,Georges Bismuth,Georges Bismuth,Bénédicte De Muylder,Bénédicte De Muylder,Bénédicte De Muylder,Bénédicte De Muylder,Héloise Leroy,Delphine Desjardins,Delphine Desjardins,Delphine Desjardins,Delphine Desjardins,Delphine Desjardins,Delphine Desjardins,Isabelle Dusanter-Fourt,Isabelle Dusanter-Fourt,Isabelle Dusanter-Fourt,Isabelle Dusanter-Fourt,Serge Benichou,Clotilde Randriamampita,Clotilde Randriamampita,Clotilde Randriamampita,Clotilde Randriamampita,Florence Margottin-Goguet,Florence Margottin-Goguet,Florence Margottin-Goguet,Florence Margottin-Goguet,Frederic Bouillaud,Ghina Chougui,Ghina Chougui,Ghina Chougui,Ghina Chougui,Remi Cheynier,Rachida Tacine,Rachida Tacine,Rachida Tacine,Rachida Tacine,Roger Le Grand,Roger Le Grand,Roger Le Grand,Roger Le Grand,Roger Le Grand,Roger Le Grand

doi:10.1371/journal.ppat.1007669

Abstract

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.

Highlights

As other viruses, HIV-1 is an obligate intracellular pathogen strictly dependent on a suitable host cell machinery for most of the steps of its life cycle, a machinery that is hijacked by the virus to generate its progeny
HIV-1 is controlled by host restriction factors that interfere with its life cycle
We report a new interplay between HIV-1 and human T lymphocytes through the FOXO1 transcription factor

Summary

Introduction

HIV-1 is an obligate intracellular pathogen strictly dependent on a suitable host cell machinery for most of the steps of its life cycle, a machinery that is hijacked by the virus to generate its progeny. Host cell transcription factors such as NF-κB and NFAT, the activity of which is dependent on T cell stimulation, recognize specific target sites in the viral promoter contained in the long terminal repeats (LTRs), and are essential for expression of viral components and HIV-1 genome replication [2]. This transcriptional control is instrumental for the generation of viral reservoirs, defined as cell types where the virus persists during therapy [3,4]. They do not produce virus particles when cells are in a resting state, but can give rise to infectious virions following activation by various stimuli, leading to viral rebound when cART is interrupted

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