Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced tryptophan and increased kynurenine concentrations have been reported in patients with human immunodeficiency virus type 1 (HIV-1) infection. From in vitro data it appears that activated indoleamine 2,3-dioxygenase (IDO) is involved in this metabolic change. IDO is inducible by interferon-(IFN)-gamma. We compared serum concentrations of IFN-gamma and neopterin (the biosynthesis of which is also inducible by IFN-gamma) with serum, tryptophan and kynurenine of 42 patients with HIV-1 infection. IFN-gamma, neopterin and kynurenine levels were significantly increased compared to HIV-1 seronegative controls whereas tryptophan was significantly decreased. Various significant correlations were found between tryptophan, kynurenine, IFN-gamma and neopterin concentrations. Highest degree of correlation was found between neopterin, IFN-gamma and the kynurenine per tryptophan quotient which is the ratio between the product and the substrate concentration of IDO. The data indicate that decreased tryptophan in HIV-1 seropositives may result from chronic immune activation and can be referred to increased activation of IDO.
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PMID:Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection. 190 3

We investigated serum neopterin, tryptophan, and kynurenine concentrations in 23 HIV-1 seropositive patients (Walter Reed Stage 4-6). Ten patients presented with polyneuropathy and three with dementia, one of the patients with dementia also had polyneuropathy and dementia. We found significant associations between lower trytophan concentrations and neurologic/psychiatric symptoms. The negative correlation of tryptophan with kynurenine and neopterin concentrations indicates activity of indoleamine 2,3-dioxygenase (IDO) in patients. IDO can be induced by cytokines such as interferon-gamma and therefore low tryptophan levels may result from chronic immune stimulation in HIV-1 seropositives.
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PMID:Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. 216 83

Increased kynurenine pathway metabolism has been implicated in the aetiology of the AIDS dementia complex (ADC). The rate limiting enzyme for this pathway is indoleamine 2,3-dioxygenase (IDO). We tested the efficacy of different strains of HIV-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 high 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 post-infection. Together, these results indicate that only selected strains of HIV-1 are capable of inducing IDO synthesis and subsequent oxidative tryptophan catabolism in MDM.
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PMID:Induction of indoleamine 2,3-dioxygenase in primary human macrophages by HIV-1. 1093 84

The chronic immune activation state in HIV disease leads to increased activity of the rate-limiting tryptophan-kynurenine pathway enzyme indoleamine 2,3-dioxygenase (2,3-IDO), thereby increasing the formation of neurotoxic tryptophan metabolites such as kynurenine and quinolinic acid. We investigated whether highly active antiretroviral therapy (HAART) (median duration, 100 days; range, 50-188 days) lowers serum levels of these metabolites in HIV-infected individuals and if so, whether this was paralleled by changes in a surrogate marker for immune activation, i.e., soluble tumor necrosis factor receptor p75 (sTNFR p75) concentrations. Baseline quinolinic acid (848 nM, 95% CI 567-1130 vs. 303 nM, 95% CI 267.1-339.5) and kynurenine (4.1 microM, 95% CI 3.3-4.9 vs. 2.7 microM, 95% CI 2.4-2.9) concentrations as well as the mean kynurenine-to-tryptophan ratio (108.2, 95% CI 76.1-140.4 vs. 51.4, 95% CI 47.6-55.3) in 17 HIV-1-infected outpatients (7 with AIDS) were significantly higher than those in 55 healthy age-matched controls (p < 0.01), respectively. Serum quinolinic acid concentrations in 14 of 17 patients decreased (mean, -44.4%) during HAART in comparison with baseline (471.2 nM, 95% CI 288-654.3; p = 0. 022). Thirteen of these 14 patients also had decreases in sTNFR p75 concentrations. Overall, the mean sTNFR p75 concentration decreased by 36.3% (13.5 ng/ml, 95% CI 9.3-17.8 vs. 8.6 ng/ml, 95% CI 5.9-11. 4; p = 0.01, n = 17). Reduction in viral load through HAART and subsequent mitigation of the pathological immune activation state in HIV disease may have reduced 2,3-IDO over activation. This eventually led to a decrease in quinolinic acid formation. The parallel reduction of the immune activation marker sTNFR p75 supports this hypothesis.
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PMID:Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosis factor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 disease. 1095 19

Activated macrophages produce quinolinic acid (QUIN), a neurotoxin, in several inflammatory brain diseases including AIDS dementia complex. We hypothesized that IL1-beta, IL6, transforming growth factor (TGF-beta2 and platelet activating factor could increase macrophage QUIN production. And that the HIV-1 proteins Nef, Tat and gp41 may also increase synthesis of QUIN by macrophages. At 72 h there were significant increases in QUIN production in the cells stimulated with PAF (914 +/- 50 nM) and Nef (2781 +/- 162 nM), with somewhat less production by Tat stimulation (645 +/- 240 nM). The increases in QUIN production approximated in vitro concentrations of QUIN shown to be neurotoxic and correlated closely with indoleamine 2,3-dioxygenase induction. IL1-beta, IL6, TGF-beta2 and gp41 stimulation produced no significant increase in QUIN production. These results suggest that some of the neurotoxicity of PAF, nef and tat may be mediated by QUIN.
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PMID:Quinolinic acid is produced by macrophages stimulated by platelet activating factor, Nef and Tat. 1151 83

Neopterin is well established as a reliable marker in HIV-1 infection. Neopterin concentrations measured in urine or serum indicate sensitively the course and progression of the disease as well as efficacy of anti-retroviral therapy. The main trigger for neopterin production is Th1-type cytokine interferon-gamma. During acute HIV-1 infection, enhanced formation of neopterin occurs already at a very early time point, before antibody seroconversion takes place. After this stage, neopterin concentrations in serum and urine closely correlate with virus load in the circulation of HIV-1-infected patients. Data provide evidence for an important role of immune activation and Th1-type cytokine interferon-gamma in the pathogenesis of HIV-1 infection. This review subsumes the importance of neopterin as a marker in HIV-1 infection. Further evidence is increasing, that neopterin derivatives might modulate immune response by interfering with the cellular redox balance, activating redox-sensitive transcription factors, or inducing apoptosis in specific cell types. The possible impact of neopterin derivatives and of other biochemical pathways induced by interferon-gamma such as indoleamine 2,3-dioxygenase in chronic diseases like HIV-1 infection is discussed.
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PMID:Neopterin in HIV-1 infection. 1548 7

Inadequate local cell-mediated immunity appears crucial for the establishment of chronic HIV infection. Accumulation of regulatory T cells (Treg) at the site of HIV replication, the lymphoid organs, may influence the outcome of HIV infection. Our data provide the first evidence that chronic HIV infection changes Treg tissue distribution. Several molecules characteristics of Treg (FoxP3, CTLA-4, glucocorticoid-induced TNFR family-related receptor, and CD25) were expressed more in tonsils of untreated patients compared with antiretroviral-treated patients. Importantly, most FoxP3+ cells expressed CTLA-4, but not CD69. Furthermore, a direct correlation between FoxP3 levels and viral load was evident. In contrast, FoxP3 expression was decreased in circulating T cells from untreated patients, but normalized after initiation of treatment. Functional markers of Treg activity (indoleamine 2,3-dioxygenase, TGF-beta, and CD80) were markedly increased in the tonsils of untreated patients. Our data could provide a new basis for immune-based therapies that counteract in vivo Treg and thereby reinforce appropriate antiviral immunity.
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PMID:The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients. 1574 40

The impairment of adaptive immune responses to HIV and abnormalities in the immune regulatory function mechanisms during HIV infection have been regarded as key issues in AIDS pathogenesis since the early years of the pandemic. However, the multiple mechanisms underlying this impairment are still not fully understood. New emerging information shows that alterations in the number and/or function of regulatory T-cells may contribute to HIV pathogenesis. Thus, pharmacologic manipulation of regulatory T-cells as well as blocking the activity of other immunomodulatory molecules, such as indoleamine 2,3-dioxygenase, glucocorticoid-induced tumor necrosis factor receptor and PD1, might provide a valuable approach to redirect the immune system towards an efficient antiviral response.
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PMID:Do regulatory T-cells play a role in AIDS pathogenesis? 1707 84

Infection with the human immunodeficiency virus type 1 (HIV) results in a chronic infection that progressively cripples the host immune defenses. HIV infection is associated with increased tryptophan (trp) catabolism by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO). IDO has powerful immune suppressive activity, which could contribute to the immune dysfunction observed in HIV-infected patients. In this review we discuss the immune mechanisms that could mediate the HIV-induced increase of IDO activity (such as IFN-gamma, IFN-alpha, CTLA-4/B7 and direct viral exposure). We then consider the current knowledge of IDO-mediated immune suppressive mechanisms with regard to different cell types (CD4(+) T cells, CD8(+) T cells, natural killer cells, B cells and regulatory T cells), from the perspective of their potential consequences for the HIV-infected host. HIV-induced, IDO-mediated trp catabolism may contribute to the perpetuation of HIV infection into its chronic phase by dampening efficient immune anti-viral responses. Therapeutic approaches aimed at manipulating this powerful immune suppressive mechanism might be considered in the setting of HIV infection.
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PMID:How does indoleamine 2,3-dioxygenase contribute to HIV-mediated immune dysregulation. 1743 Jan 10

High levels of viral replication occur in gut-associated lymphoid tissue (GALT) and other lymphoid tissues (LT) since the early phase of human/simian immunodeficiency virus (HIV/SIV) infection. Regulatory T cells (T(reg)), a subset of immunosuppressive T cells expressing CTLA-4 and the FoxP3 transcription factor, accumulate in LT during HIV/SIV infection. Here we show that FoxP3 and CTLA-4 mRNA are increased in leukocytes from the spleens, lymph nodes (LN), and mucosal sites of chronically SIV-infected macaques with high viremia (SIV(HI)) compared to animals with low viremia (SIV(LO)). FoxP3 and CTLA-4 correlated with SIV RNA levels in tissues; SIV virus levels in the spleen, inguinal LN, mesenteric LN, colon, and jejunum directly correlated with the plasma virus level. Importantly, CTLA-4 and FoxP3 mRNA were predominantly increased in the CD25(-) subpopulation of leukocytes from SIV(HI), further challenging the classical definition of T(reg) as CD4(+) CD25(+) T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by T(reg) in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIV(HI) compared to SIV(LO) and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIV(HI) compared to SIV(LO) and correlated with plasma viral levels. Increased T(reg) and IDO in LT of SIV-infected macaques may be the consequence of increased tissue inflammation and/or may favor virus replication during the chronic phase of SIV infection.
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PMID:Regulatory T-cell markers, indoleamine 2,3-dioxygenase, and virus levels in spleen and gut during progressive simian immunodeficiency virus infection. 1771 31


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