Glutaminase dysregulation in HIV-1-infected human microglia mediates neurotoxicity: relevant to HIV-1-associated neurocognitive disorders.
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.
Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5930, USA. yhuan1@unmc.edu
Yunlong
Y
Huang
Lixia
L
Zhao
Beibei
B
Jia
Li
L
Wu
Yuju
Y
Li
Norman
N
Curthoys
Jialin C
JC
Zheng
D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001921:Brain / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D019483:Disintegrins / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000201:enzymology* / Q000821:virology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D019483:Disintegrins; D018691:Excitatory Amino Acid Antagonists; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D013778:Tetrazolium Salts; D013844:Thiazoles; C551792:vicrostatin; D005973:Glutamine; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D053148:Caspase 3; D005972:Glutaminase; C022616:thiazolyl blue