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Journal of Virology, June 2007, p. 5908-5918, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02811-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Enhanced Replication of Human T-Cell Leukemia Virus Type 1 in T Cells from Transgenic Rats Expressing Human CRM1 That Is Regulated in a Natural Manner

Ryo Takayanagi,¹ Takashi Ohashi,¹ Eizaburo Yamashita,² Yohei Kurosaki,¹ Kumiko Tanaka,¹ Yoshiyuki Hakata,^1, Yasumasa Komoda,³ Satoru Ikeda,³ Yasuko Tsunetsugu-Yokota,⁴ Yuetsu Tanaka,⁵ and Hisatoshi Shida^1*

Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo 060-0815,¹ Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto,² Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka 569-1125,³ Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640,⁴ Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan⁵

Received 20 December 2006/ Accepted 5 March 2007

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL). To develop a better animal model for the investigation of HTLV-1 infection, we established a transgenic (Tg) rat carrying the human CRM1 (hCRM1) gene, which encodes a viral RNA transporter that is a species-specific restriction factor. At first we found that CRM1 expression is elaborately regulated through a pathway involving protein kinase C during lymphocyte activation, initially by posttranscriptional and subsequently by transcriptional mechanisms. This fact led us to use an hCRM1-containing bacterial artificial chromosome clone, which would harbor the entire regulatory and coding regions of the CRM1 gene. The Tg rats expressed hCRM1 protein in a manner similar to expression of intrinsic rat CRM1 in various organs. HTLV-1-infected T-cell lines derived from these Tg rats produced 100- to 10,000-fold more HTLV-1 than did T cells from wild-type rats, and the absolute levels of HTLV-1 were similar to those produced by human T cells. We also observed enhancement of the dissemination of HTLV-1 to the thymus in the Tg rats after intraperitoneal inoculation, although the proviral loads were low in both wild-type and Tg rats. These results support the essential role of hCRM1 in proper HTLV-1 replication and suggest the importance of this Tg rat as an animal model for HTLV-1.

Published ahead of print on 14 March 2007.

Present address: Department of Microbiology, New York University School of Medicine, 522 First Avenue, New York, NY 10016.