Overall, our findings suggest that both HBZ and Tax1 are negative regulators of immediate early IFN-β innate immune responses, while HBZ but not Tax1 positively regulates the induction of IFN-α and downstream IFN-α signaling.<b>IMPORTANCE</b> Type I interferons are powerful antiviral cytokines and are used extensively in the treatment of HTLV-1-induced adult T cell leukemia (ATL).
At the incipient stages of the development of adult T-cell leukemia, T-cells infected with human T-cell leukemia virus type 1 (HTLV-1) suffer disregulation in cell growth caused by aberrant expression of host genes by the HTLV-1 transactivator protein Tax (Tax1).
Pin1 is highly expressed in adult T-cell leukemia (ATL) cells expressing Tax protein and forced expression of Pin1 in turn increases the Tax protein expression.
Retroviral Tax proteins from human T cell leukemia virus type 1 and type 2 (HTLV-1 and -2) are capable of activating IKK, yet only HTLV-1 infection causes T cell leukemia, which correlates with persistent activation of NF-kappaB induced by Tax1.
The pathogenic potential of human T-cell leukemia virus type 1 (HTLV-1) Tax protein is partly ascribed to its capacity to constitutively activate NF-kappaB factors because constitutive activity of these factors play an important role in the pathophysiology of adult T-cell leukemia (ATL) and tropical spastic paraparesis-HTLV-1 associated myelopathy (TSP-HAM).
However, tax gene expression in ATL cells is disrupted by several mechanisms, including genetic changes in the tax gene and DNA methylation/deletion of the 5' long terminal repeat (LTR).
The premature stop codon in tax gene existed in many non-ATL HTLV-I carriers as a minor population but not in the commonest HTLV-I sequence of the individual.
These findings indicate that Tax-targeted vaccines may be effective for prophylaxis of ATL in a high-risk group, and also for therapy of ATL in at least half the cases.
Since the development of both TSP/HAM and ATL seems to depend on the viral Tax protein, we describe a possible system for anti Tax gene-therapy approach based on a negative transdominant mutant Tax gene.
First, a premature stop codon in the 5' half of the tax gene that looses transactivation activity on the viral enhancer was observed in 3 patients with acute and 1 patient with chronic ATL.
These results strongly suggest that HTLV-I tax gene may transactivate IL-6 gene through kappa B site in HTLV-I-positive T-cell lines and activation of NF-kappa B may be crucial in HTLV-I-induced IL-6 gene activation in ATL.
Because clustering occurs with HTLV-I and ATL, members of ATL families were examined for antibodies to the tax protein and compared with matched HTLV-I-positive blood donors.