HTLV-I is the etiological agent of adult T-cell leukemia (ATL), tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM) and certain other clinical disorders.  However, after infection of human subjects, the virus enters into a latent state, in which very little viral gene expression occurs in the infected T-cells of these individuals, whereas the characteristics of the major HTLV-I related diseases indicate that their genesis requires active virus expression.  TSP/HAM is characterized by high virus expression which account for most features of this syndrome.  In addition, the viral Tax protein is a key element in the initiation of the leukemic process leading to ATL, whereas during the virus latency the intracellular level of Tax is below its leukemogenic level.  Therefore, the vast majority of HTLV-I infected individuals remain asymptomatic carriers for their entire life and only 1-5% of them eventually develop an HTLV-I related disease 20-40 years after infection.  Generation of such diseases in these individuals plausibly results from activation of the latent virus which is needed for increasing Tax to its pathogenic level.  Our own experiments suggest that this activation might be induced by DNA-damaging agents and certain other stress factors.  Most Tax effects are exerted by its nuclear interaction with transcriptional and other regulatory factors.  However, Tax is also involved in the cytoplasmic activation of the NF-κB system which is, otherwise, tightly regulated by exogenous signalling factors.  Tax also interferes with various DNA repair mechanisms.  Finally, although Tax has been shown to elicit anti-apoptotic effects in certain cell systems and pro-apoptotic effects in others, it appears that, at least in HTLV-I infected T-cells, the anti-apoptotic effects override its pro-apoptotic effects.  With these multiple dis-regulatory effects, Tax sets the infected T-cells into uncontrolled continuous replication and genetic instability.  However, it seems that in individuals with certain specific genetic background virus activation remains permanent and leads to TSP/HAM, whereas in individuals with other genetic backgrounds this activation is only temporary.  Therefore, we propose that progression to ATL in such people is possible only if a mutation impairing one or more genes involved in cell cycle arrest or  apoptosis occurs during the time-gap when the virus in still active, i.e when Tax level is still high and the cells are susceptible to mutagenesis.  Such mutations can set the  cells into uncontrolled replication and genetic instability also in the absence of Tax.  Since Tax is a major factor in HTLV-I pathogenesis we are presently working on  developing a negative trans-dominant Tax mutant with a capacity to neutralize all of the w.t. Tax functions.