HIV-1 Nef Interferes with M-CSF Receptor Signalling 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 the disease progression. Here, we show for the first time that Nef interferes with the M-CSF/M-CSF receptor 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 M-CSF receptor complex. The formation of the molecular complex should occur under physiological conditions, i.e., upon M-CSF stimulation. Due to the 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 signalling through Hck activation and thereby inhibits M-CSF functions in monocytes/macrophages.