The regulation of quinolinic acid in human immunodeficiency virus-infected monocytes.
Quinolinic acid (Quin) is thought to underlie cognitive and motor dysfunctions for a variety of neurological disorders. Specifically, in human immunodeficiency virus (HIV)-associated dementia, Quin levels correlate with the degree of neurological dysfunction observed in affected individuals. Since recent data from our laboratories suggest that both HIV-1 infection and activation of brain macrophages are required for the development of neurotoxicity we examined Quin production during virus infection and immune activation. HIV-1 infection of monocytes induced low levels of Quin while lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) activation of the virus-infected cells elicited 10-fold higher levels. The combined effects of LPS and IFN-gamma for Quin production in HIV-infected monocytes was identical to each factor added alone. Little or no Quin was detected in unstimulated uninfected monocytes. LPS or IFN-gamma activation of uninfected monocytes produced substantially higher levels of Quin than found in similarly stimulated HIV-1-infected monocytes. These results were at variance to the production of tumor necrosis factor-alpha (TNF-alpha). Here, a 2-to 5-fold increase in TNF-alpha levels were observed in culture fluids of LPS-activated HIV-infected cells when compared to similarly stimulated uninfected monocytes. The effect of LPS-induced Quin production by HIV-infected monocytes was not altered by primary human astrocytes. These data suggest that Quin levels seen in HIV dementia are a reflection of macrophage/ microglial activation seen during advanced clinical disease. These findings could help explain, in part, why few HIV-1-infected brain macrophages can give rise to significant neurological impairments.
Nottet
H S
HS
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-5215, USA.
Flanagan
E M
EM
Flanagan
C R
CR
Gelbard
H A
HA
Gendelman
H E
HE
Reinhard
J F
JF
D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000821:virology; D001253:Astrocytes / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000166:cytology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000378:metabolism* / Q000821:virology*; D017378:Quinolinic Acid / Q000378:metabolism*; D013997:Time Factors
D017378:Quinolinic Acid