Multihit model for selection of HTLV-1–infected cells to become ATLL cells as a result of multiple intrinsic and extrinsic forces. Virus infection of CD4⁺ lymphocytes initially results in polyclonal infection (indicated by cells of different color with provirus shown in the nucleus). Expression of HTLV-1 Tax promotes oligoclonal expansion of infected T cells and genetic instability. Immune responses select for T cells with low levels of Tax expression. Driver mutations result in further selection resulting in ATLL in those individuals in which multiple “hits” have occurred to produce a lymphoproliferative malignancy.