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

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,via upstream activation of the akt pathway. de novo htlv-1 infection of cd4+ t cells or direct lentiviral-mediated introduction of tax led to akt activation and akt-dependent inactivation of foxo3a,via 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+cd27negccr7neg 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. © 2014 olagnier et al.