HIV-1 Tat-mediated apoptosis in human brain microvascular endothelial cells

Tae Aug Kim, Hava Karsenty Avraham, Young Ho Koh, Shuxian Jiang, In Woo Park, Shalom Avraham

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Abstract

The integrity of the blood-brain barrier (BBB) is critical for normal brain function. Neuropathological abnormalities in AIDS patients have been associated with perivascular HIV-infected macrophages, gliosis, and abnormalities in the permeability of the BBB. The processes by which HIV causes these pathological conditions are not well understood. To characterize the mechanism by which HIV-1 Tat protein modulates human brain microvascular endothelial cell (HBMEC) functions, we studied the effects of HIV-1 Tat in modulating HBMEC apoptosis and permeability. Treatment of HBMEC with HIV-1 Tat led to Flk-1/KDR and Flt-4 receptor activation and the release of NO. The protein levels of endothelial NO synthase (NOS) and inducible NOS were increased by HIV-1 Tat stimulation. Importantly, HIV-1 Tat caused apoptosis of HBMEC, as evidenced by changes in the cleavage of poly(A)DP-ribose polymerase, DNA laddering, and incorporation of fluorescein into the nicked chromosomal DNA (TUNEL assay). HIV-1 Tat-mediated apoptosis in HBMEC was significantly inhibited in the presence of N-nitro-L-arginine methyl ester (an inhibitor of NOS) and wortmannin (a phosphoinositol 3-kinase inhibitor). Furthermore, HIV-1 Tat treatment significantly increased HBMEC permeability, and pretreatment with both N-nitro-L-arginine methyl ester and wortmannin inhibited the Tat-induced permeability. Taken together, these results indicate that dysregulated production of NO by HIV-1 Tat plays a pivotal role in brain endothelial injury, resulting in the irreversible loss of BBB integrity, which may lead to enhanced infiltration of viruscarrying cells across the BBB.

Original languageEnglish
Pages (from-to)2629-2637
Number of pages9
JournalJournal of Immunology
Volume170
Issue number5
DOIs
StatePublished - 1 Mar 2003

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    Kim, T. A., Karsenty Avraham, H., Koh, Y. H., Jiang, S., Park, I. W., & Avraham, S. (2003). HIV-1 Tat-mediated apoptosis in human brain microvascular endothelial cells. Journal of Immunology, 170(5), 2629-2637. https://doi.org/10.4049/jimmunol.170.5.2629