Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone

The human T-cell leukemia virus type 1 (HTLV-1) transcriptional trans-activ ator Tax has been demonstrated to have transforming activity in multiple ce ll culture and transgenic-mouse models. In addition to activating transcrip tion from the viral long terminal repeat (LTR) through the cyclic AMP respo nse element binding protein/activating transcription factor (CREB/ATF) fami ly of transcription factors, Tax activates the expression of multiple cellu lar promoters through the NF-kappa B pathway of transcriptional activation. The Tax mutants M22 and M47 have preciously been demonstrated to selective ly abrogate the ability of Tax to activate transcription through the NF-kap pa B or CREB/ATF pathway, respectively. These mutations were introduced in the tax gene of the ACH functional molecular clone of HTLV-1, and virus pro duced from the mutant ACH clones was examined for the ability to replicate and immortalize primary human lymphocytes. While virus derived from the clo ne containing the M47 mutation retained the ability to immortalize T lympho cytes, the M22 mutant lost the ability to immortalize infected cells. These results indicate that activation of the CREB/ATF pathway by Tax is dispens able for the immortalization of T cells by HTLV-1, whereas activation of th e NF-kappa B pathway may be critical.