ACTIVATION OF THE HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I ENHANCER IS MEDIATED BY BINDING-SITES FOR ELF-1 AND THE PETS FACTOR

Infection with human T-cell leukemia virus type I (HTLV-1) is associat ed with adult T-cell lymphoma/leukemia. This disease occurs in only a small minority of people infected with HTLV-I and manifests itself man y years after infection. Therefore, it appears that a fine balance exi sts between HTLV-I and the host T-cell factors with which it interacts . HTLV-I encodes a transactivating protein, Tax, which activates viral transcription via cellular mechanisms which are incompletely understo od. As viral gene expression is negligible during latency, it is doubt ful that Tax controls the initial transition to the replicative state. Tax-independent cellular factors which control HTLV-I transcription, and presumably latency, have received little study. Recently, the prod uct of the chicken proto-oncogene ets-1 has been shown to bind to the HTLV-I enhancer and modestly activate transcription in certain cell ty pes (S. C. Gitlin, R. Bosselut, A. Gegonne, J. Ghysdael, and J. N. Bra dy, J. Virol. 65:5513-5523, 1991). However, the functional significanc e of the ets-binding site in the intact enhancer has not previously be en shown. We now demonstrate that site-specific mutation of the purine -rich ets-binding site significantly diminishes inducible enhancer fun ction, but not Tax response, in the human Jurkat T-cell line. Similarl y, mutation of the peri-ets (pets) site, not previously noted in the H TLV-I enhancer, markedly inhibits inducible enhancer function but not Tax response. Further, we show that the predominant protein binding th e purine-rich HTLV-I enhancer element in human T cells is not ets-I bu t Elf-I, a member of the ets family which is very similar to the Droso phila morphogen E74. Regulation of HTLV-1 through Elf-1/pets enhancer motifs resembles that seen with human immunodeficiency virus type 2 (D . M. Markovitz, M. Smith, J. Hilfinger, M. C. Hannibal, B. Petryniak, and G. J. Nabel, J. Virol. 66:5479-5484, 1992; J. M. Leiden, C.-W. Wan g, B. Petryniak, M. Smith, D. M. Markovitz, G. J. Nabel, and C. B. Tho mpson, J. Virol. 66:5890-5897, 1992), another human pathogenic retrovi rus with a relatively long incubation period.