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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3230-3237.
Prepublished online as a Blood First Edition Paper on December 30, 2004; DOI 10.1182/blood-2004-06-2084.
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Submitted June 3, 2004
Accepted December 21, 2004
HIV-1 Nef interferes with M-CSF receptor signalling through Hck activation and inhibits M-CSF bioactivities
Shinya Suzu, Hideki Harada, Takahiro Matsumoto, and Seiji Okada*
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan
* Corresponding author; email: okadas{at}kaiju.medic.kumamoto-u.ac.jp.
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.
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