Induction of indolamine 2,3-dioxygenase in primary human macrophages by human immunodeficiency virus type 1 is strain dependent.
Increased kynurenine pathway metabolism has been implicated in the etiology of AIDS dementia complex (ADC). The rate-limiting enzyme for this pathway is indolamine 2,3-dioxygenase (IDO). We tested the efficacy of different strains of human immunodeficiency virus type 1 (HIV1-BaL, HIV1-JRFL, and HIV1-631) to induce IDO in cultured human monocyte-derived macrophages (MDM). A significant increase in both IDO protein and kynurenine synthesis was observed after 48 h in MDM infected with the brain-derived HIV-1 isolates, laboratory-adapted (LA) HIV1-JRFL, and primary isolate HIV1-631. In contrast, almost no kynurenine production or IDO protein was evident in MDM infected with the highly replicating macrophage-tropic LA strain HIV1-BaL. The induction of IDO and kynurenine synthesis by HIV1-JRFL and HIV1-631 declined to baseline levels by day 8 postinfection. Abundant HIV-1 replication did not reduce the ability of exogenous gamma interferon (IFN-gamma) to induce IDO and kynurenine synthesis in HIV-infected MDM. The addition of anti-IFN-gamma antibody to MDM infected with HIV1-JRFL resulted in an absence of detectable IDO protein after 48 h and a decrease of 64% +/- 1% in supernatant kynurenine concentration. Together, these results indicate that only selected strains of HIV-1 are capable of inducing IDO synthesis and subsequent kynurenine metabolism in MDM. The induction of IDO, while apparently independent of replication capacity, appears to be mediated by a transient production of IFN-gamma in MDM responding to the initial infection with selected strains of HIV-1.
Grant
R S
RS
School of Physiology and Pharmacology, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia.
Naif
H
H
Thuruthyil
S J
SJ
Nasr
N
N
Littlejohn
T
T
Takikawa
O
O
Kapoor
V
V
D002478:Cells, Cultured; D003470:Culture Media; D049308:Dioxygenases; D004790:Enzyme Induction; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007737:Kynurenine / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000821:virology*; D010105:Oxygenases / Q000096:biosynthesis*; D013045:Species Specificity; D014779:Virus Replication
D003470:Culture Media; D016655:HIV Core Protein p24; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D007371:Interferon-gamma; D010105:Oxygenases; D049308:Dioxygenases