Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states

Human T-cell leukemia virus type I (HTLV-1) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-1 proviral integration site remains unsolved. We determined the integration sites of HTLV-1 proviruses in ATL cells and HTLV-1-infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-1 provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-1 provirus was prone to integration near the transcriptional start sites in leukemic cells (P =.006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2159; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I-infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression.