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Journal of Virology, July 2006, p. 7118-7126, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00409-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Induction of Lactoferrin Gene Expression in Myeloid or Mammary Gland Cells by Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax: Implications for Milk-Borne Transmission of HTLV-1

Masako Moriuchi1 and Hiroyuki Moriuchi1,2*

Division of Medical Virology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,1 Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan2

Received 26 February 2006/ Accepted 23 April 2006

Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia, is transmitted vertically via breastfeeding. We have previously demonstrated that lactoferrin, a major milk protein, enhances HTLV-1 replication, at least in part by upregulating the HTLV-1 long terminal repeat promoter. We now report that HTLV-1 infection can induce lactoferrin gene expression. Coculture with HTLV-1-infected MT-2 cells increased the levels of lactoferrin mRNA in myeloid-differentiated HL-60 cells, as well as MCF-7 cells, models of two probable sources (neutrophils and mammary epithelium) of lactoferrin in breast milk. MT-2 cell coculture could be replaced with cell-free culture supernatants of MT-2 cells to exert the same effect. Furthermore, extracellularly administered Tax protein also induced lactoferrin gene expression at physiologically relevant concentrations. In transient-expression assays, Tax transactivated the lactoferrin gene promoter in HL-60 or MCF-7 cells. Experiments with Tax mutants, as well as site-directed mutants of the lactoferrin promoter reporters, indicated that the NF-{kappa}B transactivation pathway is critical for Tax induction of the lactoferrin gene promoter activity in myeloid-differentiated HL-60 cells, but not in MCF-7 cells. These results suggest that HTLV-1 infection may be able to induce expression of lactoferrin in a paracrine manner in the lactic compartment. Our findings, in conjunction with our previous study, implicate that mutual interaction between HTLV-1 and lactoferrin would benefit milk-borne transmission of this virus.

* Corresponding author. Mailing address: Department of Pediatrics, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Phone: 81-95-849-7297. Fax: 81-95-849-7301. E-mail: hiromori{at}net.nagasaki-u.ac.jp.

Journal of Virology, July 2006, p. 7118-7126, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00409-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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