Regulation of indoleamine 2,3-dioxygenase expression in simian immunodeficiency virus-infected monkey brains.
The human immunodeficiency virus type 1-associated cognitive-motor disorder, including the AIDS dementia complex, is characterized by brain functional abnormalities that are associated with injury initiated by viral infection of the brain. Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in tryptophan catabolism in extrahepatic tissues, can lead to neurotoxicity through the generation of quinolinic acid and immunosuppression and can alter brain chemistry via depletion of tryptophan. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we demonstrate that cells of the macrophage lineage are the main source for expression of IDO in the SIV-infected monkey brain. Animals with SIV encephalitis have the highest levels of IDO mRNA, and the level of IDO correlates with gamma interferon (IFN-gamma) and viral load levels. In vitro studies on mouse microglia reveal that IFN-gamma is the primary inducer of IDO expression. These findings demonstrate the link between IDO expression, IFN-gamma levels, and brain pathology signs observed in neuro-AIDS.
Burudi
E M E
EM
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Marcondes
M Cecilia G
MC
Watry
Debbie D
DD
Zandonatti
Michelle
M
Taffe
Michael A
MA
Fox
Howard S
HS
D015526:AIDS Dementia Complex / Q000209:etiology; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008253:Macaca mulatta; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D016097:Simian Acquired Immunodeficiency Syndrome / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D014366:Tryptophan Oxygenase / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D014366:Tryptophan Oxygenase