HTLV-1 p12I protein enhances STAT5 activation and decreases the interleukin-2 requirement for proliferation of primary human peripheral blood mononuclear cells

The p12(1) protein, encoded by the pX open reading frame I of the human T-lymphotropic virus type 1 (HTLV-1), Is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi. Although p121 contains 4 minimal proline-rich, src homology 3-binding motifs (PXXP), a characteristic commonly found in proteins involved in signaling pathways, it has not been known whether p121 has a role in modulating intracellular signaling pathways. This study demonstrated that p121 binds to the cytoplasmic domain of the Interleukin-2 receptor (IL-2R) beta chain that is involved in the recruitment of the Jak1 and Jak3 kinases. As a result of this interaction, p121 increases signal transducers and activators of transcription 5 (STAT5) DNA binding and transcriptional activity and this effect depends on the presence of both IL-2R beta and gamma (c). chains and Jak3. Transcluction of primary human peripheral blood mononuclear cells (PB-MCs) with a human immunodeficiency virus type 1-based retroviral vector expressing p121 also resulted in increased STAT5 phosphorylation and DNA binding. However, p121 could increase proliferation of human PBMCs only after stimulation of T-cell receptors by treatment of cells with low concentrations of aCD3 and alpha CD28 antibodies. In addition, the proliferative advantage of p12(1)-transduced PBMCs was evident mainly at low concentrations of IL-2. Together, these data indicate that p121 may confer a proliferative advantage on HTLV-1-infected cells in the presence of suboptimal antigen stimulation and that this event may account for the clonal proliferation of Infected T cells in vivo. (C) 2001 by The American Society of Hematology.