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

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.

FOXP1 regulates oxidative stress, SIRT1 expression, and resistance to chemotherapies in acute myeloid leukemia cells.

Transcription factor Forkhead box P1 (FOXP1) belongs to the same protein family as the FOXOs that are well-known regulators of murine hematopoietic stem progenitor cell (HSPC) maintenance via dampening oxidative stress. FOXP1 and FOXOs can play opposite, or similar, roles depending on cell context; they can crossregulate each other's expression. In a previous study, we have shown that FOXP1 contributes to healthy human HSPC and acute myeloid leukemia (AML) cell growth. Here, we investigated the role of FOXP1 in HSPCs and AML cell oxidative stress defense in a human context. FOXP1 expression level was associated with an inferior survival outcome in patients with cytogenetically normal AML. FOXP1 knockdown enhanced superoxide anion levels of human-committed CD34+CD38+ cells but not stem cell-enriched CD34+CD38- HSPCs or AML cells in vitro. FOXP1 knockdown triggered enhanced NRF2 activity and increased cell oxidative stress. FOXP1 had no impact on FOXO1/3/4 expression in these cells; genetic and pharmacological inhibition of FOXOs did not change superoxide anion levels of human HSPCs or AML cells. Moreover, FOXP1 antioxidant activity was independent of changes in expression of superoxide dismutase 1 and 2 or catalase. Instead, FOXP1 upregulated expression of the stress sensor SIRT1 by stabilizing SIRT1 protein. FOXP1 loss sensitized AML cells to chemotherapy. Together, this study identified FOXP1 as a new safeguard against myeloid progenitor oxidative stress, which works independently of FOXOs but through SIRT1 and contributes to AML chemoresistance. It proposes FOXP1 expression/activity as a promising target to overcome drug resistance of AML HSPCs.