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Kynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages
S J Kerr1, P J Armati, L A Pemberton
1Centre for Immunology, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Abstract:
The AIDS dementia complex (ADC) is a consequence of excessive immune activation driven at least in part by systemic HIV infection and probably brain infection. Quinolinic acid (QUIN) is a neurotoxic tryptophan metabolite produced by macrophages in response to stimulation with cytokines or infection with HIV-1. Consequently it has been implicated in ADC pathogenesis. However, macrophages infected with HIV-1 synthesize numerous neurotoxic substances. Therefore we conducted experiments using human fetal brain tissue to determine the relative importance of QUIN as a neurotoxin in ADC. Human macrophages were infected with HIV-1 in vitro using a viral isolate from a demented patient. 6-Chloro-D-tryptophan, an inhibitor of QUIN biosynthesis, was added to half the macrophage cultures to block formation of QUIN. Supernatants containing QUIN (SQpos) or in which QUIN biosynthesis had been inhibited (SQneg) were then added to human fetal brain aggregate cultures. Toxicity was evaluated using lactate dehydrogenase efflux, trypan blue exclusion, immunohistochemistry, image analysis, and electron microscopy. Each technique showed a reduction of toxicity in SQneg-treated cultures. These studies confirm the significance of QUIN as a neurotoxin in ADC and suggest that neuroprotective strategies may have a place in the treatment of this disease.
Insights
Quinolinic acid (QUIN), a neurotoxin, significantly contributes to AIDS dementia complex (ADC) neurotoxicity. Inhibiting QUIN biosynthesis reduced neurotoxicity, suggesting neuroprotective strategies for ADC treatment.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- AIDS dementia complex (ADC) involves immune activation and HIV infection.
- Quinolinic acid (QUIN), a tryptophan metabolite, is implicated in ADC pathogenesis.
- Macrophages infected with HIV-1 produce various neurotoxic substances.
Purpose of the Study:
- To determine the relative importance of QUIN as a neurotoxin in ADC.
- To investigate the neuroprotective potential of inhibiting QUIN biosynthesis.
Main Methods:
- Human macrophages infected with HIV-1 in vitro.
- Inhibition of QUIN biosynthesis using 6-Chloro-D-tryptophan.
- Exposure of human fetal brain aggregate cultures to macrophage supernatants with or without QUIN.
- Evaluation of neurotoxicity using LDH efflux, trypan blue exclusion, immunohistochemistry, image analysis, and electron microscopy.
Main Results:
- Macrophage supernatants containing QUIN induced significant neurotoxicity in brain cultures.
- Inhibiting QUIN biosynthesis in macrophages reduced the neurotoxicity of their supernatants.
- Multiple evaluation techniques confirmed reduced toxicity in cultures treated with QUIN-inhibited supernatants.
Conclusions:
- Quinolinic acid (QUIN) is a significant neurotoxin contributing to AIDS dementia complex (ADC).
- Blocking QUIN biosynthesis offers a potential neuroprotective strategy for ADC.
- Further research into neuroprotective agents may benefit ADC treatment.