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

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience 2011;31(42):15195-204

PMID: 22016553

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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.

Address: Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5930, USA. [email protected]

DOI: 10.1523/JNEUROSCI.2051-11.2011

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MeSH Terms: Analysis of Variance, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Brain, Caspase 3, Cells, Cultured, Chromatography, High Pressure Liquid, Disintegrins, Dizocilpine Maleate, Enzyme-Linked Immunosorbent Assay, Excitatory Amino Acid Antagonists, Fetus, Gene Expression Regulation, Viral, Glutamic Acid, Glutaminase, Glutamine, HIV Infections, HIV-1, Humans, Microglia, Microtubule-Associated Proteins, RNA, Small Interfering, Receptors, Cell Surface, Tetrazolium Salts, Thiazoles, Time Factors, CD163 Antigen