Regulation of Indoleamine 2,3-Dioxygenase Expression in Simian Immunodeficiency Virus-Infected Monkey Brains

Burudi, E.M.E.; Marcondes, Maria Cecília Garibaldi; Watry, Debbie D.; Zandonatti, Michelle; Taffe, Michael A.; Fox, Howard S.

doi:10.1128/jvi.76.23.12233-12241.2002

Cited by 42 publications

(31 citation statements)

References 40 publications

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“…Our findings that perivascular macrophages and microglial nodules are the source of IDO production in the brains of patients with HIVE are in concordance with reports on the source of IDO expression in SIV-infected monkey brains. 56,57 Our ex vivo human brain data are further supported by in vitro experiments demonstrating IDO upregulation of HIV-1 infection and IFN-␥ stimulation in human MDMs. CD8 ϩ lymphocytes attracted by alpha-chemokines 46 may be a source of chronic immune stimulation and a pathogenic force for HAD.…”

Section: Discussionsupporting

confidence: 59%

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis

Potula

Poluektova

Knipe

et al. 2005

Blood

145

141

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IntroductionThe pathogenesis of HIV-1 infection is linked to dysfunction and depletion of CD4 ϩ T lymphocytes. [1][2][3] The virus persists and disseminates over years, despite an apparently intact host immune response. The inability to eliminate HIV-1 suggests that negativeregulatory (tolerogenic) signals may shield HIV-1 from adaptive immune clearance. 4,5 However, the specific mechanisms by which the virus might protect itself from clearance remain unresolved.HIV-1 is known to persist at low levels within the central nervous system (CNS) during most of the disease course. 6 Significant productive HIV-1 replication occurs in brain mononuclear phagocytes (MPs; perivascular macrophages and microglia) during late stages of infection only in a subset of individuals with severe immune suppression and high peripheral viral loads. Secretory viral and cellular products from HIV-1-infected and immune competent brain MPs are known to induce neuronal dysfunction and injury. [7][8][9] These include virotoxins such as Tat, Nef, and gp120 and cellular toxins such as proinflammatory cytokines, chemokines, arachidonic acid and its metabolites, platelet activating factor, nitric oxide, and quinolinic acid. Indoleamine 2,3-dioxygenase (IDO) is the first and the rate-limiting enzyme in the generation of quinolinic acid from tryptophan via the kynurenine pathway. 10 An increase of functional IDO enzymatic activity in the brain could lead to enhanced production of neurotoxins, resulting in neurocognitive dysfunction and HIV-1-associated dementia (HAD). 11-13 Signs of increased IDO activity correlate with tryptophan depletion, progression of systemic and brain HIV-1 infection, and HAD. 14,15 Accumulating evidence suggests that IDO serves immunoregulatory and tolerogenic functions. [16][17][18][19][20][21] It appears that certain antigen presenting cells (APCs) may regulate T-cell responses through the expression of IDO. 22 A number of studies indicate that IDO overexpression by APCs may result in immune suppression and reduced T-cell responses. 17,18,20,[23][24][25] Therefore, HIV-induced IDO activity in the brain may participate not only in local neurotoxicity, but also in the failure of the immune system to clear HIV from this reservoir.A strong association between HAD and profound immunodeficiency supports the notion that a lack of effective adaptive immune responses is associated with ongoing viral replication in the brain. One plausible explanation is that circulating HIV-1-specific CD8 ϩ cells could be partially anergic and may be unable to eliminate HIV-1-infected cells in vivo in the setting of functionally impaired helper CD4 ϩ T cells during late stages of infection. 26,27 Based on these observations, we hypothesize that IDOexpressing APCs (specifically, HIV-1-infected macrophages) might help to create a protected reservoir for HIV-1 persistence in the brain. To test this idea we used a mouse model of HIV-1 For personal use only. on June 19, 2019. by guest www.bloodjournal.org From encephalitis (HIVE) in which nonobese di...

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Section: Discussionsupporting

confidence: 59%

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis

Potula

Poluektova

Knipe

et al. 2005

Blood

145

141

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“…In several brain disorders, such as HIV/SIV encephalitis, there is an increase of IDO in the brain, which is linked to increased levels of IFN-γ, likely expressed in infiltrating T lymphocytes (Burudi et al 2002). IL-4 and IL-13 expression has been found to be present in the normal brain (Szczepanik et al 2001), and IL-4 has been found to have a role in the CNS and other pathologies induced by SHIV infection in macaques (Buch et al 2004;Dhillon et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…As tryptophan is the precursor for the neurotransmitter serotonin, its IDO-induced depletion can cause untoward psychological/psychiatric consequences leading to depression (Widner et al 2000). During HIV infection, which also has CNS consequences due to the presence of the virus-host interaction in the CNS, the IDO-mediated increased accumulation of tryptophan catabolites such as quinolinic acid (QUIN), has been proposed to have a pathogenic role in inducing neuronal death (Bara et al 2000;Burudi et al 2002;Grant et al 2000;Heyes et al 1989;Heyes et al 1992;Stone 2001). In addition to IDO's potential role in HIV-associated dementia, in Alzheimer's disease (AD) it has been shown that the inflammatory cytokines and the amyloid β protein Aβ 1-42 induce IDO expression and production of QUIN in neurotoxic concentrations by human macrophages and microglia, leading to neuronal death (Guillemin and Brew 2002;Guillemin et al 2003).…”

Section: Introductionmentioning

confidence: 99%

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Yadav

Burudi

Alirezaei

et al. 2007

Glia

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-γ and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-γ in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-γ induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-γ, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-γ induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.

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“…In the CNS, IDO has been shown to be induced in brain macrophages in simian immunodeficiency virus encephalitis (SIVE) in macaques, and its expression correlates with that of IFN-␥ (8,19). Consistent with a role for IDO in T-cell suppression, the IDO inhibitor 1-methyl tryptophan has recently been shown to increase viral clearance in a murine model of human immunodeficiency virus encephalitis (HIVE) (62).…”

mentioning

confidence: 81%

Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

Suh

Zhao

Rivieccio

et al. 2007

J Virol

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Regulation of Indoleamine 2,3-Dioxygenase Expression in Simian Immunodeficiency Virus-Infected Monkey Brains

Cited by 42 publications

References 40 publications

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis

IFN‐γ‐induced IDO and WRS expression in microglia is differentially regulated by IL‐4

Astrocyte Indoleamine 2,3-Dioxygenase Is Induced by the TLR3 Ligand Poly(I:C): Mechanism of Induction and Role in Antiviral Response

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