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Journal of Virology, February 2005, p. 1367-1378, Vol. 79, No. 3
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.3.1367-1378.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Resistance to Apo2 Ligand (Apo2L)/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Mediated Apoptosis and Constitutive Expression of Apo2L/TRAIL in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines

Takehiro Matsuda,^1,2 Alex Almasan,³ Mariko Tomita,¹ Jun-nosuke Uchihara,^1,4 Masato Masuda,⁴ Kazuiku Ohshiro,⁵ Nobuyuki Takasu,⁴ Hideo Yagita,⁶ Takao Ohta,² and Naoki Mori^1*

Division of Molecular Virology and Oncology, Graduate School of Medicine,¹ Division of Child Health and Welfare,² Division of Endocrinology and Metabolism, Faculty of Medicine, University of the Ryukyus, Nishihara,⁴ Department of Internal Medicine, Naha Prefectural Hospital, Naha, Okinawa,⁵ Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan,⁶ Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio³

Received 29 March 2004/ Accepted 7 September 2004

Adult T-cell leukemia (ATL), a CD4⁺-T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1), is difficult to cure, and novel treatments are urgently needed. Apo2 ligand (Apo2L; also tumor necrosis factor-related apoptosis-inducing ligand [TRAIL]) has been implicated in antitumor therapy. We found that HTLV-1-infected T-cell lines and primary ATL cells were more resistant to Apo2L-induced apoptosis than uninfected cells. Interestingly, HTLV-1-infected T-cell lines and primary ATL cells constitutively expressed Apo2L mRNA. Inducible expression of the viral oncoprotein Tax in a T-cell line up-regulated Apo2L mRNA. Analysis of the Apo2L promoter revealed that this gene is activated by Tax via the activation of NF-B. The sensitivity to Apo2L was not correlated with expression levels of Apo2L receptors, intracellular regulators of apoptosis (FLICE-inhibitory protein and active Akt). NF-B plays a crucial role in the pathogenesis and survival of ATL cells. The resistance to Apo2L-induced apoptosis was reversed by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal (LLnL), an NF-B inhibitor. LLnL significantly induced the Apo2L receptors DR4 and DR5. Our results suggest that the constitutive activation of NF-B is essential for Apo2L gene induction and protection against Apo2L-induced apoptosis and that suppression of NF-B may be a useful adjunct in clinical use of Apo2L against ATL.

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* Corresponding author. Mailing address: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. Phone: 81 (98) 895-1130. Fax: 81 (98) 895-1410. E-mail: n-mori{at}med.u-ryukyu.ac.jp.

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Journal of Virology, February 2005, p. 1367-1378, Vol. 79, No. 3
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.3.1367-1378.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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