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Journal of Virology, May 2009, p. 5101-5108, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02564-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon{triangledown}

Shuichi Kinpara,1 Atsuhiko Hasegawa,1 Atae Utsunomiya,2 Hironori Nishitsuji,1 Hiroyuki Furukawa,1 Takao Masuda,1 and Mari Kannagi1*

Department of Immunotherapeutics, Tokyo Medical and Dental University, Graduate School, Tokyo 113-8519,1 Department of Hematology, Imamura Bun-in Hospital, Kagoshima 890-0064, Japan2

Received 12 December 2008/ Accepted 13 February 2009

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL), HTLV-1-associated myelopathy/tropical spastic paraparesis, and other inflammatory diseases. Despite such severe outcomes of HTLV-1 infection, the level of HTLV-1 expression in vivo is very low and rapidly increases after transfer of cells to culture conditions. The mechanisms of this phenomenon have remained obscure. In the present study, we found that human and mouse stromal cells, such as epithelial cells and fibroblasts, suppressed HTLV-1 expression in ATL and non-ATL HTLV-1-infected cells. HTLV-1 mRNA and proteins in HTLV-1-infected cells markedly decreased upon coculture with human epithelial-like cells (HEK293T) or mouse embryo fibroblasts (NIH 3T3). When infected cells were reisolated from the cocultures, viral expression was restored to the original level over the following 48 h. Spontaneous induction of HTLV-1 expression in primary ATL cells in the first 24 h of culture was also inhibited by coculture with HEK293T cells. Coculture of HTLV-1-infected cells and HEK293T cells induced type I interferon responses, as detected by beta interferon (IFN-β) promoter activation and IFN-stimulated gene upregulation. HEK293T-mediated suppression of HTLV-1 expression was partly inhibited by antibodies to human IFN-{alpha}/β receptor. NIH 3T3-mediated suppression was markedly abrogated by neutralizing antibodies to mouse IFN-β. Furthermore, viral expression in HTLV-1-infected cells was significantly suppressed when the infected cells were intraperitoneally injected into wild-type mice but not IFN regulatory factor 7 knockout mice that are deficient of type I IFN responses. These findings indicate that the innate immune system suppresses HTLV-1 expression in vivo, at least through type I IFN.

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

{triangledown} Published ahead of print on 4 March 2009.

Journal of Virology, May 2009, p. 5101-5108, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02564-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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