HIV-1 Nef interferes with M-CSF receptor signaling through Hck activation and inhibits M-CSF bioactivities.
HIV-1 Nef protein is a major determinant of the pathogenicity of the virus. It has been shown that Nef activates Hck, a member of Src family kinase, in monocytes/macrophages and that the interaction is critical for AIDS-like disease progression in a mouse model. However, it was unclear how the molecular interaction in monocytes/macrophages leads to disease progression. Here, we show for the first time that Nef interferes with the macrophage colony-stimulating factor (M-CSF)/M-CSF receptor signal pathway. In this study, we introduced a conditionally active Nef into myeloid leukemia TF-1-fms cells and analyzed their responsiveness to M-CSF. We found that Nef-activated Hck constitutively associated with the M-CSF receptor complex. The formation of the molecular complex should occur under physiologic conditions, that is, on M-CSF stimulation. Because of aberrant molecular association, the tyrosine-phosphorylation/activation of the receptor in response to M-CSF was markedly diminished in Nef-active cells. Consequently, Nef activation caused the inhibition of M-CSF-mediated proliferation of TF-1-fms cells and macrophage differentiation of the cells induced by M-CSF and 12-O-tetradecanoylphorbol 13-acetate. These results indicate that HIV-1 Nef interferes with M-CSF receptor signaling through Hck activation and thereby inhibits M-CSF functions in monocytes/macrophages.
Suzu
Shinya
S
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Harada
Hideki
H
Matsumoto
Takahiro
T
Okada
Seiji
S
D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000276:immunology; D015693:Gene Products, nef / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007951:Leukemia, Myeloid; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; D011518:Proto-Oncogene Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck