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Human herpesvirus-6 (HHV-6) DNA and high antibody titers have been detected in some human malignancies. To understand the role of HHV-6 in human cancer, the ability of these DNA sequences to convert nontumorigenic human epidermal keratinocytes (RHEK-1) to the tumorigenic phenotype was examined. Of the three HHV-6 clones tested, pZVH14 (8.7-kb insert) and pZVB70 (21-kb insert) exhibited transforming activity in RHEK-1 cells, whereas the other clone pZVE50 (6-kb insert) did not show any activity. Transformed cells were morphologically altered, forming bundles or islets, and produced tumors when injected into nude mice. Southern blot analysis of the pZVH14 DNA-transformed and tumor cells revealed multiple bands hybridizing to the 8.7-kb DNA insert of pZVH14. Karyotype analysis identified the mouse tumor cells to be of human origin and these cells exhibited some chromosomal aberration compared to untransfected RHEK-1 cells. This study demonstrates that pZVH14 DNA detected in some human tumors, and pZVB70 DNA can transform human cells in vitro to tumorigenic phenotype. These data are consistent with the possibility that HHV-6 DNA sequences may have some role in the development of some human cancers.