HTLV-1 proviruses encoding non-functional TAX in adult T-cell leukemia

Adult T-cell leukemia (ATL) is associated with prior infection with human T -cell leukemia virus type 1 (HTLV-1). TAX, the major transactivator of HTLV -1, has been implicated in the immortalization of infected T-cells, but mol ecular mechanisms of in vivo malignant cell transformation induced by HTLV- 1 remain unclear. To investigate the role of TAX in the monoclonal prolifer ation of ATL cells, we determined the nucleotide sequence of tax DNA clones obtained from 6 ATL patients and analysed the biological function of their products. We found that ATL cells from 2 of these patients possessed tax w ith a nonsense or frame-shift mutation resulting in the premature terminati on of its protein product, which was no longer functional. This strongly ar gued against an indispensable role of TAX for the maintenance of ATL cells in vivo. On the other hand, the frequency of nucleotide substitutions found in non-functional tax DNA clones from these patients was significantly low er than those in functional tax DNA clones from the others, suggesting a ro le for TAX in the genome instability of infected cells. Although mismatch r epair defects in the microsatellite markers, including those in hMSH3, hMSH 6, BAX, TGF-beta RII, and E2F4 genes, were infrequent, we found an increase in the number of CAG repeats of the E2F4 microsatellite marker in 1 patien t. These findings indicate that while TAX may be a necessary prerequisite f or malignant transformation of infected cells, it is not essential for the maintenance of ATL cells in vivo.