ICE-PROTEASES MEDIATE HTLV-I TAX-INDUCED APOPTOTIC T-CELL DEATH

The Tax protein of Human T-cell leukemia virus type 1 (HTLV-1) is impo rtant for the T-cell immortalizing properties of this virus in vitro a nd is considered to be responsible for the early stages of leukemogene sis in infected hosts, Tax can upregulate expression of TNF-alpha and TNF-beta, as well as potentiate apoptosis in activated T-cells and in serum starved murine fibroblasts. To examine the role of CD95 (APO-1/F as) and ICE-proteases in Tax-mediated active T-cell death, Jurkat T ce lls expressing (APO(S)) or lacking (APO(R)) cell surface expression of CD95 (APO-1/Fas) were genetically modified to express hormone-inducib le HTLV-1 Tax constructs, Hormone-inducible action of Tax alone was su fficient to promote programmed cell death in CD95-expressing Jurkat T- cell clones, In contrast, clones lacking CD95 surface expression were resistant to the antiproliferative action of Tax, Both APOS and APOR c lones exhibited Tax-dependent upregulation of CD95 ligand and TNF-alph a. Blocking experiments suggested that while the apoptotic action of T ax critically required ICE-protease function it was largely independen t of cell surface interaction of CD95 Ligand or TNF-alpha with their c orresponding receptors, These observations strongly implicate ICE-prot eases in Tax-induced T-cell death, and suggest a possible involvement of CD95 in this process.