Proviral status of HTLV-1 integrated into the host genomic DNA of adult T-cell leukemia cells

Abstract

Human T‐cell leukemia virus type‐1 (HTLV‐1) is the etiological agent of adult T‐cell leukemia (ATL), and leukemic cells always carry the proviral genome monoclonally integrated into their host genomes at the same sequence site, designated as the monoclonal integration. Using Southern blot hybridization (SBH) and sequenced tagged site polymerase chain reaction assays, we examined the proviral status in 558 clinical specimens from 350 patients who are suspected to have ATL. A total of 321 specimens (57.5%) from 241 patients showed positive results for the monoclonal integration according to SBH, using EcoR1 and Pst1. The 241 patients consisted of 136 patients (56.4%) with the complete provirus (C‐type), 62 patients (25.7%) with a defective provirus (D‐type), and 43 patients (17.8%) with multibands (M‐type). The incidence of the D‐ and M‐types were in the order of smoldering, chronic, and acute subtypes of ATL, suggesting that such an aberrant proviral status is generated on the way to multistep carcinogenesis and is subsequently clinically important for the malignant behavior of the disease. Moreover, our data showed that the partial deletion of the proviral genome is initiated first at the site of the gag region and spreads into the sites of the pol and env regions, whereas the long terminal repeats and pX regions are almost always conserved. These results suggest that analysis of the proviral status provides useful diagnostic and virologic–oncological information about ATL and HTLV‐1 pathology, especially the important role of pX gene in tumorigenesis.