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

55 Citations (Scopus)

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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Glutaminase
Microglia
HIV-1
Glutamic Acid
HIV
Brain
AIDS Dementia Complex
Neurotoxins
Small Interfering RNA
HIV Infections
Neurocognitive Disorders
Protein Isoforms
Up-Regulation
Macrophages
RNA
Neurons
Enzymes
Serum

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Glutaminase dysregulation in HIV-1-infected human microglia mediates neurotoxicity : Relevant to HIV-1-associated neurocognitive disorders. / Huang, Yunlong; Zhao, Lixia; Jia, Beibei; Wu, Li; Li, Yuju; Curthoys, Norman; Zheng, Jialin C.

In: Journal of Neuroscience, Vol. 31, No. 42, 19.10.2011, p. 15195-15204.

Research output: Contribution to journalArticle

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