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Hiv-1 Tat Potentiates Tnf-Induced Nf-Kappa-B Activation and Cytotoxicity
Division of Immunogenetics, German Cancer Research Center, Heidelberg..
Division of Immunogenetics, German Cancer Research Center, Heidelberg..
Division of Immunogenetics, German Cancer Research Center, Heidelberg. Germany .
Division of Immunogenetics, German Cancer Research Center, Heidelberg..
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1995 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 14, no 3, 546-554 p.Article in journal (Refereed) Published
Abstract [en]

This study demonstrates that human immunodeficiency virus type 1 (HTV-1) Tat protein amplifies the activity of tumor necrosis factor (TNF), a cytokine that stimulates HTV-1 replication through activation of NF-kappa B. In HeLa cells stably transfected with the HIV-1 tat gene (HeLa-tat cells), expression of the Tat protein enhanced both TNF-induced activation of NF-kappa B and TNF-mediated cytotoxicity. A similar potentiation of TNF effects was observed in Jurkat T cells and HeLa cells treated with soluble Tat protein, TNF-mediated activation of NF-kappa B and cytotoxicity involves the intracellular formation of reactive oxygen intermediates. Therefore, Tat-mediated effects on the cellular redox state were analyzed. In both T cells and HeLa cells HIV-1 Tat suppressed the expression of Mn-dependent superoxide dismutase (Mn-SOD), a mitochondrial enzyme that is part of the cellular defense system against oxidative stress. Thus, Mn-SOD RNA protein levels and activity were markedly reduced in the presence of Tat. Decreased Mn-SOD expression was associated with decreased levels of glutathione and a lower ratio of reduced:oxidized glutathione. A truncated Tat protein (Tat(1-72)), known to transactivate the HIV-1 long terminal repeat (LTR), no longer affected Mn-SOD expression, the cellular redox state or TNF-mediated cytotoxicity. Thus, our experiments demonstrate that the C-terminal region of HIV-1 Tat is required to suppress Mn-SOD expression and to induce pro-oxidative conditions reflected by a drop in reduced glutathione (GSH) and the GSH:oxidized GSH (GSSG) ratio. They further imply a distinct mechanism of Mn-SOD suppression as compared,vith HIV-1 LTR transactivation by Tat. Taken together, our data suggest that Tat expressed in HIV-1-infected cells and Tat taken up by non-infected cells modulates TNF activity by altering the cellular redox state. These findings may be relevant for HIV-1 replication and for T cell depletion in acquired immune deficiency syndrome.

Place, publisher, year, edition, pages
1995. Vol. 14, no 3, 546-554 p.
Keyword [en]
aids patients, cyto-toxicity, cytotoxicity, dna-binding, factor-alpha, human-immunodeficiency-virus, long terminal repeat, mn-sod, nf-kappa-b activation, superoxide-dismutase, tat, TNF, trans-activation, transcription factor, tumor-necrosis-factor
National Category
Biochemistry and Molecular Biology Cell Biology
URN: urn:nbn:se:liu:diva-87081ISI: A1995QF71800014OAI: diva2:584846
Available from: 2013-01-09 Created: 2013-01-09 Last updated: 2013-01-28

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Los, Marek Jan
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