Glutamate production by HIV-1 infected human macrophage is blocked by the inhibition of glutaminase

Nathan Erdmann, Jianxing Zhao, Alicia L. Lopez, Shelley Herek, Norman Curthoys, Terry D. Hexum, Takashi Tsukamoto, Dana Ferraris, Jialin Zheng

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Mononuclear phagocyte (macrophages and microglia) dysfunction plays a significant role in the pathogenesis of human immunodeficiency virus (HIV) associated dementia (HAD) through the production and release of soluble neurotoxic factors including glutamate. The mechanism of glutamate regulation by HIV-1 infection remains unclear. In this report, we investigated whether the enzyme glutaminase is responsible for glutamate generation by HIV-1 infected monocyte-derived macrophages. We tested the functionality of novel small molecule inhibitors designed to specifically block the activity of glutaminase. Glutaminase inhibitors were first characterized in a kinetic assay with crude glutaminase from rat brain revealing an uncompetitive mechanism of inhibition. The inhibitors were then tested in vitro for their ability to prevent glutamate generation by HIV-infected macrophages, their effect upon macrophage viability, and HIV infection. To validate these findings, glutaminase specific siRNA was tested for its ability to prevent glutamate increase during infection. Our results show that both glutaminase specific small molecule inhibitors and glutaminase specific siRNA were effective at preventing increases in glutamate by HIV-1 infected macrophage. These findings support glutaminase as a potential component of the HAD pathogenic process and identify a possible therapeutic avenue for the treatment of neuroinflammatory states such as HAD.

Original languageEnglish (US)
Pages (from-to)539-549
Number of pages11
JournalJournal of Neurochemistry
Volume102
Issue number2
DOIs
StatePublished - Jul 2007

Keywords

  • Glutamate
  • Glutaminase
  • HIV-1-associated dementia
  • Macrophages

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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