Kynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages.
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.
Kerr
S J
SJ
Centre for Immunology, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Armati
P J
PJ
Pemberton
L A
LA
Smythe
G
G
Tattam
B
B
Brew
B J
BJ
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000648:ultrastructure; D002449:Cell Aggregation / Q000502:physiology; D002478:Cells, Cultured; D004396:Coloring Agents / Q000493:pharmacokinetics; D005333:Fetus / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D007150:Immunohistochemistry; D007737:Kynurenine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D008854:Microscopy, Electron; D017378:Quinolinic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014343:Trypan Blue / Q000493:pharmacokinetics; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
D004396:Coloring Agents; C026380:6-chlorotryptophan; D007737:Kynurenine; D014364:Tryptophan; D007770:L-Lactate Dehydrogenase; D017378:Quinolinic Acid; D014343:Trypan Blue