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CSF-induced and HIV-1–mediated Distinct Regulation of Hck and C/EBPß Represent a Heterogeneous Susceptibility of Monocyte-derived Macrophages to M-tropic HIV-1 Infection

Iwao Komuro^1,2, Yasuko Yokota¹, Sachiko Yasuda¹, Aikichi Iwamoto² and Kiyoko S. Kagawa¹

¹ Department of Immunology, National Institute of Infectious Disaeses, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan
² Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Shiroganedai 4-6-1, Minato-ku, Tokyo 108-8639, Japan

Address correspondence to K.S. Kagawa, Department of Immunology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan. Phone: 81-3-5285-1111; Fax: 81-3-5285-1150; email: akagawak{at}nih.go.jp

Granulocyte/macrophage colony-stimulating factor (GM-CSF)–induced monocyte-derived macrophages (GM-M) are permissive to M-tropic HIV-1 entry, but inhibit viral replication at posttranscriptional and translational levels, whereas M-CSF-induced macrophages (M-M) produce a large amount of HIV-1. M-M express a high level of Hck and a large isoform of C/EBPß, and HIV-1 infection increases the expression of Hck but not of C/EBPß. GM-M express a high level of C/EBPß and a low level of Hck, and HIV-1 infection drastically increases the expression of a short isoform of C/EBPß but decreases that of Hck.

Treatment of M-M with antisense oligonucleotide for Hck (AS-Hck) not only suppresses the expression of Hck, but also stimulates the induction of the short isoform of C/EBPß and inhibits the viral replication. Treatment of GM-M with a moderate amount of AS-C/EBPß not only inhibits the expression of the small isoform of C/EBPß preferentially, but also stimulates the induction of Hck and stimulates the virus production at a high rate. These results suggest that CSF-induced and HIV-1–mediated distinct regulation of Hck and small isoform of C/EBPß represent the heterogeneous susceptibility of tissue M to HIV-1 infection, and the regulation of Hck and C/EBPß are closely related and these two molecules affect one another.

Key Words: macrophages • HIV-1 • Hck • C/EBPß • CSF

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