Glutaminase dysregulation in HIV-1-infected human microglia mediates neurotoxicity: Relevant to HIV-1-associated neurocognitive disorders

Yunlong Huang, Lixia Zhao, Beibei Jia, Li Wu, Yuju Li, Norman Curthoys, Jialin C. Zheng

Research output: Contribution to journalArticle

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Abstract

Microglia represent the main cellular targets of HIV-1 in the brain. Infected and/or activated microglia play a pathogenic role in HIV-associated neurocognitive disorders (HAND) by instigating primary dysfunction and subsequent death of neurons. Although microglia are known to secrete neurotoxins when infected with HIV-1, the detailed mechanism of neurotoxicity remains unclear. Using a human microglia primary culture system and macrophage-tropic HIV-1 strains, we have now demonstrated that HIV-1 infection of microglia resulted in a significant increase in extracellular glutamate concentrations and elevated levels of neurotoxicity. RNA and protein analysis revealed upregulation of the glutamate-generating enzyme glutaminase isoform glutaminase C in HIV-1-infected microglia. The clinical relevance of these findings was further corroborated with investigation of postmortem brain tissues. The glutaminase C levels in the brain tissues of HIV dementia individuals were significantly higher than HIV serum-negative control and correlated with elevated concentrations of glutamate. When glutaminase was subsequently inhibited by siRNA or by a small molecular inhibitor, the HIV-induced glutamate production and the neuronal loss was diminished. In conclusion, these findings support glutaminase as a potential component of the HAND pathogenic process as well as a novel therapeutic target in their treatment.

Original languageEnglish (US)
Pages (from-to)15195-15204
Number of pages10
JournalJournal of Neuroscience
Volume31
Issue number42
DOIs
StatePublished - Oct 19 2011

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ASJC Scopus subject areas

  • Neuroscience(all)

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