Human T-cell Lymphotrophic Virus Type-I (HTLV-I) is the probable etiologic agent in the development of Adult T-cell Leukemia (ATL). The purpose of the proposed study is to evaluate the biological role of the viral determinants of HTLV-I which are likely to play a role in the development of ATL. HTLV-I has several properties uncommon among retroviruses: The ability to immortalize cells in vitro; the ability to encode or in someway induce in trans, the transcriptional activation of its own LTR and perhaps other, cellular genes; it carries an exogenous viral gene (LOR) or genes (pX) in addition to the gag, pol and, env genes found in other retro- viruses; it only infrequently expresses RNA or viral protein at detectable levels in circulating leukemic cells; and, when proviral DNA is introduced into mammalian cells as naked DNA, it is transcriptionally inactive in stably transformed cells even though its LTR alone can be shown to be transcriptionally active when introduced adjacent to foreign genes in transient transcription experiments. To address the function of the pX region and the molecular mechanisms of the biological activities described above, we will introduce molecularly cloned HTLV-I proviral DNA segments into mammalian cells in vitro and into cats in vivo using transcription regulatory elements from other retroviruses, and in the case of the in vivo and certain in vitro experiments, horizontally transmissable Feline Leukemia Virus (FeLV) vectors. Transcriptionally active pX and gag-pX genes will be evaluated for their ability to trans-activate other viral genes and LTR sequences, and to complement EJ-ras in the tumorigenic transformation of rat embryo fibroblasts in a manner analogous to the myc gene. HTLV genes will also be inserted into a rescuable FeLV provirus and transmitted into human and cat cells and into cats in vivo to monitor lymphocyte immortalization, cell transformation and oncogenicity attributable to HTLV segments of these viruses.
