Fig. 5.

Model of the development of ATLL. HTLV-1 infection constitutes the first hit that predisposes each infected T-cell to malignant transformation. The probability that a given clone undergoes transformation depends principally on the balance of two opposing forces: negative selection by the host CTL response to HTLV-1 antigens, and persistent or repeated expression of two regulatory genes of HTLV-1, tax and HBZ, whose products prolong the lifespan of the T-cell clone and so increase the chance of accumulation of further genetic or epigenetic hits. These further hits may cause constitutive activation of the pathways initially activated by Tax, after which loss of Tax expression confers a survival advantage on the clone by escape from the strong anti-Tax CTL response. In contrast to the frequent silencing of Tax expression, HBZ expression appears to persist [32]; an effective CTL response to HBZ reduces the proviral load and the risk of HAM/TSP, and may reduce the risk of ATLL.