Life, death and Tax: role of HTLV-I oncoprotein in genetic instability and cellular transformation

Human T-cell leukemia virus type I (HTLV-I)1 causes adult T-cell leukemia (ATL) (1–3). The virus is also associated with a neuropathy/myelopathy termed HTLV-associated myelopathy and tropical spastic paraparesis. ATL develops in 2–5% of HTLV-I-infected individuals after a long latent period, suggesting a multistage process of immortalization and transformation of T-lymphocytes. Extant data suggest that 8 discrete events likely occur serially in vivo before an HTLV-I-infected cell becomes immortalized and transformed (4). How HTLV-I infection progresses from clinical latency to T-cell malignancy is not well understood but involves the unique viral transactivator/oncoprotein, Tax (Fig. 1). Tax has been shown to be singly sufficient for immortalizing T-lymphocytes (5, 6) and transforming rat fibroblasts (7). Further, transgenic mice expressing Tax (driven by the HTLV-I long terminal repeat (LTR)) develop neurofibroma, a tumor of mesenchymal tissue (8). Finally, large granular lymphocytic leukemia has been found in mice transgenic for Tax expressed from the T-celIt is estimated that cells in the human body divide 1016 times during a lifetime. To control and prevent errors in cell divisions, mammalian cells have evolved “gatekeepers” and “caretakers” to regulate the rate of cell growth and the fidelity by which cellular genetic information is transmitted to progenies (10). Gatekeepers monitor the net proliferative capacity of a cell, whereas caretakers act to eliminate DNA damages. Accordingly, one perspective is that transformation occurs when both gatekeeper and caretaker functions are abrogated. Using HTLV-I as a model, we review in a non-exhaustive fashion current thoughts on how Tax perturbs normal cellular regulation and engenders cellular transformationl specific, granzyme B promoter (9).