Figure 3.

Regulation of Tax expression by viral and cellular mechanisms. The CD8+ T cells specific for Tax antigens are impaired by activated Tregs via the secretion of IL-10 through Tax-mediated NF-κB activation. However, levels of IL-10 are maintained by a positive feedback loop of signal transducer and activator of transcription 3 (STAT3) to maintain the pool of anti-apoptotic genes even in the absence of Tax. As Tax is highly immunogenic, human T-cell lymphotropic virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) suppresses Tax-mediated transcription (1), and HTLV-1 p30 (2) also blocks Tax trans-activation of the viral LTR by competitive binding to CBP/300 and sequestering doubly spliced viral RNA in the nucleus. However, Tax expression can be induced by hypoxia and oxidative stress. In Tax-negative cells, HBZ is constitutively expressed, and chronic activation of NF-κB signaling is maintained by aberrant expression of NF-κB-inducing kinase (NIK) to transcribe anti-apoptotic genes for sustained lymphoproliferation. It is also possible that activated interferon-stimulated genes (ISGs)/pattern recognition receptors (PRRs) triggered by sensing of anti-sense RNA containing the HTLV-1 LTR may contribute to NF-κB activation.