HIV type 1 nef gene inhibits tumor necrosis factor alpha-induced apoptosisand promotes cell proliferation through the action of MAPK and JNK in human glial cells

In neurodegenerative diseases associated with AIDS, reactive astrocytosis p lays a central role in the neurotoxicity of the brain parenchyma. Whereas t he HIV-1 nef gene is overexpressed during restricted HIV-1 infection of hum an astrocytes, our previous results have demonstrated that nef expressed in human U251MG glial cells activates the sphingomyelin pathway triggered by TNF-alpha, increasing ceramide production. Since ceramide is an important r egulatory molecule of programmed cell death induced by TNF-alpha, we examin ed whether nef could alter TNF-alpha -induced apoptosis in the U251MG human astrocytoma cell line. Transfection studies indicated that nef could both prevent apoptosis and promote cell proliferation in response to TNF-alpha s timulation. MAPK and JNK activities were further analyzed in order to eluci date signaling cascades subsequent to the upregulation of ceramide producti on. After TNF-alpha treatment, both kinases were shown to be preferentially activated in the presence of nef. These experiments strongly suggest that the HIV-1 Nef protein might modulate the sensitivity of astrocytes to infla mmatory molecules, thus contributing to the development of neurodegenerativ e diseases associated with AIDS.