Nef, an accessory protein of HIV−1, has been shown to be critical for both high viral loads and progression to AIDS. We recently demonstrated that Nef inhibited the bioactivities of M-CSF, a monocytes/macrophages-specific cytokine (

Blood 105: 3230–3237, 2005
). The inhibitory effect of Nef is a likely explanation for dysregulated functions in HIV−1−infected macrophages. Here, we examined the specificity and molecular mechanism of the newly-characterized function of Nef, to clarify its relevance to the pathogenetic activity of Nef. By analyzing cytokine-dependent cell lines expressing the conditionally active Nef, we found that Nef had a profound inhibitory effect on M-CSF signal, but not on IL-4- and GM-CSF signals. We also found that Nef down-regulated the surface expression of M-CSF receptor (M-CSFR) but not of GM-CSF receptors. The M-CSFR down-regulation by Nef was reproducible in 293 cells when co-transfected with Hck, a member of Src kinases. Interestingly, the down-regulation of cell surface M-CSFR in the presence of Nef and Hck correlated with the concomitant increase of the immature form of M-CSFR. These results suggested that Nef perturbed M-CSFR maturation through Hck and thereby selectively inhibited M-CSF signal.

Topics:
hiv-1, macrophage colony-stimulating factor, macrophage colony-stimulating factor receptor, cytokine, acquired immunodeficiency syndrome, granulocyte-macrophage colony-stimulating factor, receptors, granulocyte-macrophage colony-stimulating factor, recombinant granulocyte-macrophage colony-stimulating factors, src-family kinases, viral load result

Disclosures: Supported by Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.

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2006, The American Society of Hematology
2006
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