| 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. |