Inhibition of human immunodeficiency virus type 1 replication by Z-100, an immunomodulator extracted from human-type tubercle bacilli, in macrophages.
Z-100 is an arabinomannan extracted from Mycobacterium tuberculosis that has various immunomodulatory activities, such as the induction of interleukin 12, interferon gamma (IFN-gamma) and beta-chemokines. The effects of Z-100 on human immunodeficiency virus type 1 (HIV-1) replication in human monocyte-derived macrophages (MDMs) are investigated in this paper. In MDMs, Z-100 markedly suppressed the replication of not only macrophage-tropic (M-tropic) HIV-1 strain (HIV-1JR-CSF), but also HIV-1 pseudotypes that possessed amphotropic Moloney murine leukemia virus or vesicular stomatitis virus G envelopes. Z-100 was found to inhibit HIV-1 expression, even when added 24 h after infection. In addition, it substantially inhibited the expression of the pNL43lucDeltaenv vector (in which the env gene is defective and the nef gene is replaced with the firefly luciferase gene) when this vector was transfected directly into MDMs. These findings suggest that Z-100 inhibits virus replication, mainly at HIV-1 transcription. However, Z-100 also downregulated expression of the cell surface receptors CD4 and CCR5 in MDMs, suggesting some inhibitory effect on HIV-1 entry. Further experiments revealed that Z-100 induced IFN-beta production in these cells, resulting in induction of the 16-kDa CCAAT/enhancer binding protein (C/EBP) beta transcription factor that represses HIV-1 long terminal repeat transcription. These effects were alleviated by SB 203580, a specific inhibitor of p38 mitogen-activated protein kinases (MAPK), indicating that the p38 MAPK signalling pathway was involved in Z-100-induced repression of HIV-1 replication in MDMs. These findings suggest that Z-100 might be a useful immunomodulator for control of HIV-1 infection.
Central Research Laboratories, Zeria Pharmaceutical Co. Ltd, 2512-1 Oshikiri, Kohnan-machi, Ohsato-gun, Saitama 360-0111, Japan.|Department of Immunotherapeutics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Yutaka
Y
Emori
Department of Immunotherapeutics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Tamako
T
Ikeda
Department of Immunotherapeutics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Takashi
T
Ohashi
Department of Immunotherapeutics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Takao
T
Masuda
Central Research Laboratories, Zeria Pharmaceutical Co. Ltd, 2512-1 Oshikiri, Kohnan-machi, Ohsato-gun, Saitama 360-0111, Japan.
Tadashi
T
Kurimoto
Central Research Laboratories, Zeria Pharmaceutical Co. Ltd, 2512-1 Oshikiri, Kohnan-machi, Ohsato-gun, Saitama 360-0111, Japan.
Mineo
M
Takei
Department of Immunotherapeutics, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Mari
M
Kannagi
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D015704:CD4 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D017353:Gene Deletion; D015686:Gene Products, env / Q000172:deficiency; D015754:Genes, nef / Q000235:genetics; D005822:Genetic Vectors; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis; D008055:Lipids / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000821:virology; D008351:Mannans / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000737:chemistry; D019713:Receptors, CCR5 / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects
D000276:Adjuvants, Immunologic; D015704:CD4 Antigens; D015686:Gene Products, env; D008055:Lipids; D008351:Mannans; D019713:Receptors, CCR5; C031208:specific substance maruyama; D016899:Interferon-beta