Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Lara Buscemi, David Ramonet, Jonathan D. Geiger

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

HIV-1 infection causes, with increasing prevalence, neurological disorders characterized in part by neuronal cell death. The HIV-1 protein Tat has been shown to be directly and indirectly neurotoxic. Here, we tested the hypothesis that a non-neurotoxic epitope of Tat can, through actions on immune cells, increase neuronal cell death. Tat1-72 and a mutant Tat1-72 lacking the neurotoxic epitope (TatΔ31-61) concentration-dependently and markedly increased TNF-α production in macrophage-like differentiated human U937 and THP-1 cells, in mouse peritoneal macrophages and in mouse brain microglia. Tat1-72 was but TatΔ31-61 was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat1-72 or TatΔ31-61 were neurotoxic and their immunoneutralization with an anti-TNF-α antibody decreased Tat1-72- and TatΔ31-61-induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat1-72 is different from the epitope that is indirectly neurotoxic following production of TNF-α from immune cells, and suggest that therapeutic interventions against TNF-α might be beneficial against HIV-1 associated neurological disorders.

Original languageEnglish (US)
Pages (from-to)661-670
Number of pages10
JournalNeurobiology of Disease
Volume26
Issue number3
DOIs
StatePublished - Jun 1 2007

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Keywords

  • HIV-1
  • Inflammation
  • Macrophages
  • Microglia
  • Neurotoxicity
  • THP-1 cells
  • TNF-α
  • Tat
  • U937 cells

ASJC Scopus subject areas

  • Neurology

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