Human T-cell lymphotropic virus type 3: Complete nucleotide sequence and characterization of the human Tax3 protein

We and others have recently uncovered the existence of human T-cell lymphotropic virus type 3 (HTLV-3), the third member of the HTLV family. We have now sequenced the full-length HTLV-3(Py143) provirus. As expected, HTLV-3Py143 contains open reading frames corresponding to the gag, pol, env, tax, and rex genes. Interestingly, its long terminal repeat (LTR) includes only two Tax-responsive elements, as is the case for type 3 simian T-cell lymphotropic viruses (STLV-3). Phylogenetic analyses reveal that HTLV-3Py143 is closely related to central African STLV-3. Unexpectedly, the proximal pX region of HTLV-3(Py143) lacks 366 bp compared to its STLV-3 counterpart. Because of this deletion, the previously described RorfII sequence is lacking. At the amino acid level, Tax3(Py143) displays strong similarities with HTLV-1 Tax, including the sequence of a PDZ class I binding motif. In transient-transfection assays, Tax3(Py143) activates the transcriptions from HTLV-3, HTLV-1, and HTLV-2 LTRs. Mutational analysis indicates that two functional domains (M22 and M47) important for transactivation through the CREB/ATF or NF-kappa B pathway are similar but not identical in Tax1 and Tax3(Py143). We also show that Tax3(Py143) transactivates the human interleukin-8 and Bcl-X-L promoters through the induction of the NF-kappa B pathway. On the other hand, Tax3(Py143) represses the transcriptional activity of the p53 tumor suppressor protein as well as the c-Myb promoter. Altogether, these results demonstrate that although HTLV-3 and HTLV-1 have only 60% identity, Tax3(Py143) is functionally closely related to the transforming protein Tax1 and suggest that HTLV-3, like HTLV-1, might be pathogenic in vivo.