HUMAN T-CELL LEUKEMIA-VIRUS TYPE-I TAX ASSOCIATES WITH AND IS NEGATIVELY REGULATED BY THE NF-KAPPA-B2 P100 GENE-PRODUCT - IMPLICATIONS FOR VIRAL LATENCY

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa prote in termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-medi ated transformation of T cells likely involves the deregulated express ion of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression o r activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular fac tors HEB-1 and p67(SRF). An additional distinguishing characteristic o f HTLV-I infection is the profound state of viral latency that is pres ent in circulating primary leukemic T cells. In this study, we demonst rate that HTLV-I Tax can physically associate with p100, the product o f the Rel-related NF-kappa B2 gene, both in transfected cells and in H TLV-I-infected leukemic T-cell lines. Furthermore, the physical intera ction of Tax with p100 leads to the inhibition of Tax-induced activati on of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the no rmally nuclearly expressed Tax protein. In contrast, a mutant of Tax t hat selectively fails to activate nuclear NF-kappa B expression does n ot associate with p100. Together, these results suggest that the cytop lasmic interplay of Tax and p100 may play an important role in the ini tiation and maintenance of HTLV-I latency observed in adult T-cell leu kemia.