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Overexpression of interleukin-15 prevents the development of murine retrovirus-induced acquired immunodeficiency syndrome

MASAYUKI UMEMURA^*, HITOSHI NISHIMURA^*, TOSHIKI YAJIMA, WORAWID WAJJWALK^*, TESTUYA MATSUGUCHI^*, MASAHIDE TAKAHASHI, YUKIHIRO NISHIYAMA^#, MASAHIKO MAKINO^¶, YOSHIYUKI NAGAI and YASUNOBU YOSHIKAI¹

^* Laboratory of Host Defense, Research Institute for Disease Mechanism and Control, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
Center of Excellence, Department of Pathology II, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
^# Laboratory of Virology, Research Institute for Disease Mechanism and Control, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
^¶ Leprosy Research Center, National Institute Infectious Disease, Tokyo 189-0002, Japan; and
Toyama Institute of Health, Toyama, 939-0363, Japan

¹Correspondence: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3–1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail: yoshikai{at}bioreg.kyushu-u.ac.jp

LP-BM5 murine leukemia virus (MuLV) infection causes murine acquired immunodeficiency syndrome (MAIDS), a disease characterized by varied functional abnormalities of immunocompetent cells. We found that MAIDS progression was severely retarded in IL-15 transgenic (Tg) mice constructed with cDNA encoding secretable IL-15 under the control of an MHC class I promoter. Several immune defects, including impaired natural killer activity, depressed IFN- production by T cells stimulated with anti-T cell receptor cross-linking, and increased susceptibility to Mycobacteium bovis infection, were prevented in IL-15 Tg mice inoculated with LP-BM5 MuLV. Cytotoxic T lymphocyte response to a highly antigenic 10-mer peptide encoded by LP-BM5-defective virus gag p12 gene was detected in the spleen and peritoneal exudate cells from IL-15 Tg mice infected with LP-BM5 MuLV. Intramuscular injection of cDNA encoding secretable IL-15 also prevented the development of MAIDS. These results indicate that IL-15 prevents the progression of MAIDS and may provide insight into an immunotherapeutic approach using the IL-15 gene for controlling retrovirus-induced immunodeficiency.—Umemura, M., Nishimura, H., Yajima, T., Wajjwalk, W., Matsuguchi, T., Takahashi, M., Nishiyama, Y., Makino, M., Nagai, Y., Yoshikai, Y. Overexpression of interleukin-15 prevents the development of murine retrovirus-induced acquired immunodeficiency syndrome.

Key Words: IL-15 • transgenic mice • murine AIDS • CD8⁺ CTL • NK cells • gene therapy

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