Tax alters telomerase activity through both quantitative and qualitative hTERT transcriptional dysregulations

In untransformed cells impaired for DNA damage repair such as Tax positive cells, insufficient telomerase activity (TA) triggers tumorigenic telomere dysfunctions. Here we show that in quiescent HTLV-1+ T cells deriving from carriers, hTERT expression paralleled tax expression, suggesting that Tax promotes an immortalized phenotype in quiescent T cells. Interestingly, PHA-stimulation significantly augmented tax expression in CD4+ (2.6 times, p= 0.022) but not in CD8+ T cells (1.3, ns). 48 hours after PHA stimulation, uninfected and HTLV-1+CD8+ cells augmented their TA and hTERT expression (p<0.03 for each). In contrast PHA possessed no significant effect on TA and hTERT in HTLV-1+CD4+ cells. The PHA-induced fold changes in TA and hTERT expression were respectively 22 and 6.9-folds lower in infected than in uninfected CD4+ T cells, indicating that PHA decreased the level of TA more than 3 folds that of hTERT expression in the sole HTLV-1+CD4+ T cells subset. This hiatus between hTERT expression and TA was reproduced in vitro upon ectopic Tax expression in epithelial cells. We thus supposed that upon PHA-dependent Tax expression, a negative post-transcriptional element targeted hTERT for decreasing TA in HTLV-1+CD4+ T cells. Accordingly we next demonstrated that, beside its repressive effect on the hTERT promoter, ectopic Tax expression strongly redistributed hTERT RNA isoforms towards a significantly increased proportion in inactive isoforms and a significantly decreased proportion in the active A+B+ isoform. Thus via Tax expression, naturally HTLV-1 infected CD4+ T cells undergo both transcriptional and post-transcriptional hTERT modifications that significantly decrease TA in vivo.