Tax gene expression and cell cycling but not cell death are selected during HTLV-1 infection in vivo

BACKGROUND: Adult T cell leukemia results from the malignant transformation of a CD4(+ )lymphoid clone carrying an integrated HTLV-1 provirus that has undergone several oncogenic events over a 30-60 year period of persistent clonal expansion. Both CD4(+ )and CD8(+ )lymphocytes are infected in vivo; their expansion relies on CD4(+ )cell cycling and on the prevention of CD8(+ )cell death. Cloned infected CD4(+ )but not CD8(+ )T cells from patients without malignancy also add up nuclear and mitotic defects typical of genetic instability related to theexpression of the virus-encoded oncogene tax. HTLV-1 expression is cancer-prone in vitro, but in vivo numerous selection forces act to maintain T cell homeostasis and are possibly involved in clonal selection. RESULTS: Here we demonstrate that the HTLV-1 associated CD4(+ )preleukemic phenotype and the specific patterns of CD4(+ )and CD8(+ )clonal expansion are in vivo selected processes. By comparing the effects of recent (1 month) experimental infections performed in vitro and those observed in cloned T cells from patients infected for >6-26 years, we found that in chronically HTLV-1 infected individuals, HTLV-1 positive clones are selected for tax expression. In vivo, infected CD4(+ )cells are positively selected for cell cycling whereas infected CD8(+ )cells and uninfected CD4(+ )cells are negatively selected for the same processes. In contrast, the known HTLV-1-dependent prevention of CD8(+ )T cell death pertains to both in vivo and in vitro infected cells. CONCLUSIONS: Therefore, virus-cell interactions alone are not sufficient to initiate early leukemogenesis in vivo.