Effective Antiretroviral Therapy Reduces Degradation of Tryptophan in Patients with HIV-1 Infection

Zangerle, Robert; Widner, Bernhard; Quirchmair, Gisela; Neurauter, Gabriele; Sarcletti, Mario; Fuchs, Dietmar

doi:10.1006/clim.2002.5231

Cited by 88 publications

(84 citation statements)

References 27 publications

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“…The rate of IDO-mediated Trp catabolism is increased during HIV disease progression (16,49). We observed higher IDO expression in the mesenteric LN, jejuna, colons, and spleens of SIV HI animals compared to the same compartments of SIV LO animals.…”

Section: It Is Believed That An Early Loss Of Cd4mentioning

confidence: 58%

Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection

Boasso

Vaccari

Hryniewicz

et al. 2007

J Virol

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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 (Treg), 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 (SIVHI) compared to animals with low viremia (SIVLO). 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 SIVHI, further challenging the classical definition of Treg as CD4+ CD25+ T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by Treg in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIVHI compared to SIVLO and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIVHI compared to SIVLO and correlated with plasma viral levels. Increased Treg 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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Section: It Is Believed That An Early Loss Of Cd4mentioning

confidence: 58%

Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection

Boasso

Vaccari

Hryniewicz

et al. 2007

J Virol

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“…The variations of plasma Neo levels also support a rebound in type 1 Th cell responses associated with IFN-␥ production (16). It is well described that Neo production in humans correlates with T cell activation (37,38), and the observed changes in Neo and Kyn/ Trp may both reflect swings in immune activation. Thus, although we cannot exclude that D-1mT administration affected Trp plasma levels by mechanisms not directly related to IDO inhibition, the changes in Neo, IDO, and IFN-␥, as well as the observed increase in plasma Kyn, suggest that D-1mT may have favored the activation of compensating immunosuppressive mechanisms, probably triggered by T cell-derived cytokines.…”

Section: Discussionmentioning

confidence: 88%

Combined Effect of Antiretroviral Therapy and Blockade of IDO in SIV-Infected Rhesus Macaques

Boasso

Vaccari

Fuchs

et al. 2009

The Journal of Immunology

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“…In addition to improving the life expectancy of treated patients by controlling HIV-1 replication, ART inhibits the immunosuppressive tryptophan catabolism (22,34,45,46). To test whether ART could restore the ability of memory CD4 T cells from PHI subjects to respond to IL-2, we collected plasma and PBMCs from HIV-1-infected subjects before treatment (pre-ART) and after 1 year of effective treatment (on ART).…”

Section: Ros Inhibits Il-2 Signaling In Memory Cd4 T Cells During Hivmentioning

confidence: 99%

“…Despite relatively low HIV-1-specific CD8 T-cell responses, recent observations demonstrate a beneficial effect of early initiation of ART in preserving mucosal CD4 T cells, possibly limiting the release of microbial products associated with immune activation (68)(69)(70). It is important to note that the complete reestablishment of IDO-1 activity occurs only when ART is initiated early, in contrast to the partial normalization that occurs when ART is initiated during the chronic phase of infection (34,45,46). Accordingly, we also found a drastic suppression of the Kyn-dependent inhibition of the IL-2 response in memory CD4 T cells after 1 year of ART when ART was initiated during the first months of HIV-1 infection (initiation at 124.6 Ϯ 106.4 days postinfection) (Fig.…”

Section: Ccr7mentioning

confidence: 99%

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

Dagenais-Lussier

Aounallah

Mehraj

et al. 2016

J Virol

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Early HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidant N-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection. IMPORTANCE The persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.P rogressive depletion of CD4 T cells by pyroptosis and activation-related apoptosis is the hallmark of HIV-1 infection (1-4). The loss of memory CD4 T cells and, in particular, central memory CD4 T cells (T CM cells), which are critical to ensure longlasting immune protection, occurs from the onset of infection and independently predicts disease progression (5-8). Memory T-cell survival depends on signals provided by the gamma-chain-receptor cytokines, such as interleukin-2 (IL-2) and IL-7 (9-12). Previous data showed an impaired response to these cytokines in T cells during HIV-1 infection (13-16). However, our knowledge of the molecular mechanisms responsible for these immune defects is still incomplete.CD4 T-cell depletion is also linked with persistent inflammation, which takes place in the gut and lymphoid tissues early after infection and in the bloodstream later after infection (17-19). This inflammation is clinically relevant, since it has not been fully abrogated by long-term antiretroviral therapy (ART) (20)(21)(22)(23). Persistent inflammation during HIV-1 infection is associated with enhanced metabolic activity, which drives a Warburg-like effect on lipid, glucose, and amino acid pathways (22,(24)(25)(26)(27). The catabolism of an essential amino acid like tryptoph...

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Effective Antiretroviral Therapy Reduces Degradation of Tryptophan in Patients with HIV-1 Infection

Cited by 88 publications

References 27 publications

Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection

Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection

Combined Effect of Antiretroviral Therapy and Blockade of IDO in SIV-Infected Rhesus Macaques

Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

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