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AIDS Res Hum Retroviruses. 2000 Dec 10;16(18):1959-65.

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

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1
Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Québec, Canada G1V 4G2.

Abstract

In neurodegenerative diseases associated with AIDS, reactive astrocytosis plays a central role in the neurotoxicity of the brain parenchyma. Whereas the HIV-1 nef gene is overexpressed during restricted HIV-1 infection of human 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 regulatory molecule of programmed cell death induced by TNF-alpha, we examined 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 stimulation. MAPK and JNK activities were further analyzed in order to elucidate signaling cascades subsequent to the upregulation of ceramide production. 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 inflammatory molecules, thus contributing to the development of neurodegenerative diseases associated with AIDS.

PMID:
11153078
DOI:
10.1089/088922200750054684
[Indexed for MEDLINE]

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