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

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.
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Submitted on : Wednesday, June 26, 2019 - 10:03:05 AM
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Arthur Roux, Héloise Leroy, Bénédicte de Muylder, Lucie Bracq, Samia Oussous, et al.. FOXO1 transcription factor plays a key role in T cell—HIV-1 interaction. PLoS Pathogens, Public Library of Science, 2019, 15 (5), pp.e1007669. ⟨10.1371/journal.ppat.1007669⟩. ⟨inserm-02165676⟩

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