Human T cell leukemia virus type 1 Tax‐induced signals in cell survival, proliferation, and transformation

Abstract

Human T cell leukemia virus type 1 (HTLV-1), a delta-retrovirus, causes an aggressive malignancy of T lymphocytes called adult T cell leukemia/lymphoma and stimulates permanent cell growth in culture. The virus encodes a nonstructural regulatory protein, Tax, which is both transforming in cell culture and oncogenic in vivo. This multifunctional protein controls viral transcription and in multiple ways interferes with cellular control of survival, proliferation, and genomic stability. Tax, by activation of NF-κB, AP-1, and other transcriptional pathways, enhances expression of cellular genes encoding cytokines (e.g. IL-13, IL-15), cytokine receptors (e.g. IL-2Rα), and antiapoptotic factors (Hiap-1, Bcl-xL, OX40), leading to altered signal transduction (e. g. Jak/Stat, PI3K, Caspase 3/7). Cellular proliferation is stimulated by direct targeting of the cell cycle kinase (Cdk4, Cdk6) holoenzymes, repression of Cdk inhibitors, and the functional inactivation of the tumor suppressor p53. Finally, Tax, by promoting genomic instability through interference with DNA-damage signaling, checkpoint control (G2/M, mitotic spindle assembly), chromosome segregation, and cellular DNA repair pathways could contribute to malignant conversion of infected cells.