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Journal of Virology, April 2004, p. 3827-3836, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.3827-3836.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Repression of Tax Expression Is Associated both with Resistance of Human T-Cell Leukemia Virus Type 1-Infected T Cells to Killing by Tax-Specific Cytotoxic T Lymphocytes and with Impaired Tumorigenicity in a Rat Model

Machiko Nomura,¹ Takashi Ohashi,^1* Keiko Nishikawa,¹ Hironori Nishitsuji,¹ Kiyoshi Kurihara,¹ Atsuhiko Hasegawa,¹ Rika A. Furuta,² Jun-ichi Fujisawa,² Yuetsu Tanaka,³ Shino Hanabuchi,¹ Nanae Harashima,¹ Takao Masuda,¹ and Mari Kannagi¹

Department of Immunotherapeutics, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Tokyo 113-8519,¹ Department of Microbiology and Transplantation Center, Kansai Medical University, Osaka 570-8506,² Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan³

Received 7 August 2003/ Accepted 6 January 2004

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Although the viral transactivation factor, Tax, has been known to have apparent transforming ability, the exact function of Tax in ATL development is still not clear. To understand the role of Tax in ATL development, we introduced short-interfering RNAs (siRNAs) against Tax in a rat HTLV-1-infected T-cell line. Our results demonstrated that expression of siRNA targeting Tax successfully downregulated Tax expression. Repression of Tax expression was associated with resistance of the HTLV-1-infected T cells to Tax-specific cytotoxic-T-lymphocyte killing. This may be due to the direct effect of decreased Tax expression, because the Tax siRNA did not alter the expression of MHC-I, CD80, or CD86. Furthermore, T cells with Tax downregulation appeared to lose the ability to develop tumors in T-cell-deficient nude rats, in which the parental HTLV-1-infected cells induce ATL-like lymphoproliferative disease. These results indicated the importance of Tax both for activating host immune response against the virus and for maintaining the growth ability of infected cells in vivo. Our results provide insights into the mechanisms how the host immune system can survey and inhibit the growth of HTLV-1-infected cells during the long latent period before the onset of ATL.

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* Corresponding author. Mailing address: Department of Immunotherapeutics, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: 81(3)5803-5798. Fax: 81(3)5803-0235. E-mail: toha.impt{at}tmd.ac.jp.

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Journal of Virology, April 2004, p. 3827-3836, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.3827-3836.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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