Journal
JOURNAL OF NEUROSCIENCE
Volume 31, Issue 42, Pages 15195-15204Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2051-11.2011
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Funding
- National Institutes of Health [R01 NS 41858-01, R01 NS 061642-01, 3R01NS61642-2S1, R21MH083525-01, P01 NS043985, P20 RR15635-01]
- National Natural Science Foundation of China [81028007]
- Kristin Leland
- Agnes Constantino
- Colorado State University
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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.
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