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Blood, 15 May 2006, Vol. 107, No. 10, pp. 3933-3939.
Prepublished online as a Blood First Edition Paper on January 10, 2006; DOI 10.1182/blood-2005-06-2567.
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Submitted June 29, 2005
Accepted December 31, 2005
HTLV-1 tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP)
Andreas Krueger, Stefanie C Fas, Marco Giaisi, Marc Bleumink, Anette Merling, Christine Stumpf, Sven Baumann, Denise Holtkotte, Valerie Bosch, Peter H Krammer, and Min Li-Weber*
Tumorimmunology Program, German Cancer Research Center, Heidelberg, Germany
Research Program Infection and Cancer, German Cancer Research Center, Heidelberg, Germany
* Corresponding author; email: m.li-weber{at}dkfz-heidelberg.de.
The HTLV-1 transactivator protein Tax is essential for malignant transformation of CD4 T cells, ultimately leading to adult T cell leukemia (ATL). Malignant transformation may involve development of apoptosis resistance. In this study we investigated the molecular mechanisms by which HTLV-1 Tax confers resistance towards CD95-mediated apoptosis. We show that Tax expressing T cell lines derived from HTLV-1 infected patients express elevated levels of c-FLIPL and c-FLIPS. The levels of c-FLIP correlated with resistance towards CD95-mediated apoptosis. Using an inducible system we demonstrated that both resistance towards CD95-mediated apoptosis and induction of c-FLIP are dependent on Tax. In addition, analysis of early cleavage of the BH3-only Bcl-2 family member Bid, a direct caspase-8 substrate, revealed that apoptosis is inhibited at a CD95 death receptor proximal level in Tax-expressing cells. Finally, using siRNA we directly showed that c-FLIP confers Tax-mediated resistance towards CD95-mediated apoptosis. In conclusion, our data suggest an important mechanism by which expression of HTLV-1 Tax may lead to immune escape of infected T cells and, thus, to persistent infection and transformation.
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