NF-κB hyper-activation by HTLV-1 tax induces cellular senescence,but can be alleviated by the viral anti-sense protein HBZ

Activation of i-κb kinases (ikks) and nf-κb by the human t lymphotropic virus type 1 (htlv-1) trans-activator/oncoprotein,tax,is thought to promote cell proliferation and transformation. paradoxically,expression of tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors,p21cip1/waf1 and p27kip1,which cause p53-/prb-independent cellular senescence. here we demonstrate that p21cip1/waf1-/p27kip1-mediated senescence constitutes a checkpoint against ikk/nf-κb hyper-activation. senescence induced by tax in hela cells is attenuated by mutations in tax that reduce ikk/nf-κb activation and prevented by blocking nf-κb using a degradation-resistant mutant of i-κbα despite constitutive ikk activation. small hairpin rna-mediated knockdown indicates that rela induces this senescence program by acting upstream of the anaphase promoting complex and relb to stabilize p27kip1 protein and p21cip1/waf1 mrna respectively. finally,we show that down-regulation of nf-κb by the htlv-1 anti-sense protein,hbz,delay or prevent the onset of tax-induced senescence. we propose that the balance between tax and hbz expression determines the outcome of htlv-1 infection. robust htlv-1 replication and elevated tax expression drive ikk/nf-κb hyper-activation and trigger senescence. hbz,however,modulates tax-mediated viral replication and nf-κb activation,thus allowing htlv-1-infected cells to proliferate,persist,and evolve. finally,inactivation of the senescence checkpoint can facilitate persistent nf-κb activation and leukemogenesis.