[Molecular pathomechanism of HTLV-I infectious diseases]

Human T-cell lymphotropic virus type I(HTLV-I) is a type C retrovirus, closely associated with adult T-cell leukemia. In the past few years, studies have revealed an association between the virus and disorders of organ systems including myelopathy, polymyositis, alveolitis, and Sjögren's syndrome. In addition, we have proposed that HTLV-I-associated proliferative changes in nonlymphocyte synovial cells are termed HTLV-I-associated arthropathy(HAAP). To clarify the pathologic association of HTLV-I with this arthropathy, we attempted to detect HTLV-I proviral DNA in synovial tissue. Proviral HTLV-I DNA was detected not only in peripheral blood mononuclear cells but also in fresh synovial tissue cells and lymphocyte-depleted cultured synovial cells. We also detected mRNA for HTLV-I tax/rex in cultured synovial cells by reverse transcription polymerase chain reaction. Moreover, induction of chronic inflammatory arthropathy in mice transgenic for HTLV-I tax gene strongly suggested the pathogenic mechanism of HAAP. Histologic findings of affected joints in mice showed erosions of bones and pannus-like granulomtous change with infiltration of mononuclear cells. Thus, this novel mechanism might explain synovial proliferation caused by HTLV-I. Tax-expressing transgenic mouse lines also demonstrated that tax itself could serve as an oncogne in fibroblastic cells. Tumors occurred in 100% of the mice with reproducible time periods after wounding. We established cell lines, which expressed high levels of c-fos, c-myc, myb, PDGF, TGF-beta, Zif, and IL-6. Antisense ablation of the p65 subunits of NF-kappa B profoundly inhibited tumor growth in vitro with no apparent affect on the growth of normal cells. These studies were successfully extended to tax-transgenic animals. Intraperitoneal injections of NF-kappa B p65 antisense at the 40 micrograms/g weight dose led to growth arrest after 7 days, and apparent involution after 20 days of treatment. We think activation of NF-kappa B by Tax is important for tumor progression. This paper supports the importance of analyzing molecular pathomechanisms.