Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent for adult T-cell leukemia/lymphoma (ATL). 1–3 Only a small proportion of HTLV-1 carriers eventually develop ATL after a long latency. 4 However, the critical events in the leukemogenic process remain unclear. In general, viral load is an important factor affecting the outcome of virus-associated disease. The HTLV-1 proviral DNA load in the peripheral blood mononuclear cells (PBMCs) of carriers exhibits a wide range of values. 5 Enhanced expression of HTLV-1 Tax, which transactivates transcription of viral mRNA and of host genes that control cell proliferation, induces amplification of infected cells (ie, the number of proviral copies). 6 One of the host genes encodes the IL-2 receptor (IL-2R), which is overexpressed on the surface of ATL cells. 7 We have observed that subjects with detectable tax/rex mRNA have a higher number of IL-2R-positive T cells. 8 We also have found a positive association between HTLV-1 proviral load and the level of soluble IL-2R in asymptomatic carriers, 5 as well as the number of morphologically abnormal lymphocytes on a peripheral blood smear among carriers. 9, 10 In addition, the HTLV-1 proviral load within a carrier is stable over many years. 5 It has been postulated that clonal proliferation of HTLV-1-infected cells likely is responsible for maintaining the proviral load level in a carrier. 11, 12 HTLV-1 Tax may contribute to the clonal proliferation of HTLV-1-infected cells by promoting their abnormal growth. 6 Tax also exerts dysregulation of the cell cycle by binding to its inhibitors and inhibiting some tumor-suppressor proteins. 6

The accumulated data support the hypothesis that increased HTLV-1 proviral load and clonal expansion of HTLV-1-infected cells are key to the process of leukemogenesis in HTLV-1 carriers. However, proviral DNA levels and clonality of HTLV-1-infected cells have not been directly evaluated as predictors of the development of ATL in asymptomatic carriers. Given an ATL incidence rate as low as 1 case per 1,000 person-years among HTLV-1 carriers, such a study would require extensive follow-up of a relatively large number of HTLV-1 carriers.