HTLV-1 Tax-Mediated Inhibition of FOXO3a Activity Is Critical for the Persistence of Terminally Differentiated CD4⁺ T Cells

<div><p>The mechanisms involved in the persistence of activated CD4⁺ T lymphocytes following primary human T leukemia/lymphoma virus type 1 (HTLV-1) infection remain unclear. Here, we demonstrate that the HTLV-1 Tax oncoprotein modulates phosphorylation and transcriptional activity of the FOXO3a transcription factor, <i>via</i> upstream activation of the AKT pathway. <i>De novo</i> HTLV-1 infection of CD4⁺ T cells or direct lentiviral-mediated introduction of Tax led to AKT activation and AKT-dependent inactivation of FOXO3a, <i>via</i> phosphorylation of residues Ser253 and Thr32. Inhibition of FOXO3a signalling led to the long-term survival of a population of highly activated, terminally differentiated CD4⁺Tax⁺CD27^negCCR7^neg T cells that maintained the capacity to disseminate infectious HTLV-1. CD4⁺ T cell persistence was reversed by chemical inhibition of AKT activity, lentiviral-mediated expression of a dominant-negative form of FOXO3a or by specific small interfering RNA (siRNA)-mediated silencing of FOXO3a. Overall this study provides new mechanistic insight into the strategies used by HTLV-1 to increase long-term maintenance of Tax⁺CD4⁺ T lymphocytes during the early stages of HTLV-1 pathogenesis.</p>