A HUMAN T-CELL LEUKEMIA-VIRUS TAX VARIANT INCAPABLE OF ACTIVATING NF-KB RETAINS ITS IMMORTALIZING POTENTIAL FOR PRIMARY T-LYMPHOCYTES

The human T-cell leukemia virus type 1 (HTLV-1) transactivator (Tax) h as been shown to interfere with regulated cellular proliferation. Many studies have focused on the ability of Tax to transform rodent fibrob lasts; however, none has defined the molecular requirements for Tax tr ansformation of human lymphoid cells, We show here that tax induces pe rmanent growth of human primary T-lymphocytes by using a transformatio n/immortalization defective rhadinovirus vector, The cells phenotypica lly resemble HTLV-immortalized lymphocytes and contain episomally pers isting recombinant rhadinoviral sequences, which stably express functi onal Tax protein. As Tax can activate major cellular signal transducin g pathways including NF-kappa B and cAMP-responsive element binding pr otein (CREB), we asked for the relevance of these routes in the immort alization of human lymphocytes. By using Tax mutants that either activ ate exclusively CREB/activating transcription factor or are defective in activating this signaling pathway, we delineated that Tax can induc e immortalization of primary human T-lymphocytes through a mechanism i ndependent of NF-kappa B activation.