The HIV-1 Transactivator Factor (Tat) Induces Enterocyte Apoptosis through a Redox-Mediated Mechanism

Buccigrossi, Vittoria; Laudiero, Gabriella; Nicastro, Emanuele; Miele, Erasmo; Esposito, Franca; Guarino, Alfredo

doi:10.1371/journal.pone.0029436

Cited by 56 publications

(45 citation statements)

References 53 publications

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“…Similarly, previous observations showed that oxidative stress is responsible for the induction of apoptosis in several cell types, including natural killer cells, enterocytes, podocytes, and astrocytes, during HIV-1 infection (44,(48)(49)(50). Recent studies, such as those conducted by Kalinowska et al (14) and Trautmann et al (16), also showed that decreased IL-7-induced pSTAT5 levels in CD8 T cells during HIV-1 infection were associated with oxidative stress.…”

Section: Ccr7mentioning

confidence: 62%

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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Section: Ccr7mentioning

confidence: 62%

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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“…Desjardins and MacManus (1995) induced apoptosis in human adenocarcinoma colon cell line (HT29) by teniposide (VM26), Yan and Polk (2002) induced HT29 cell apoptosis by tumor necrosis factor (TNF), and Harnois et al (2004) induced HT29 cell apoptosis by cytochalasin D. However, similar to weaning, most of these apoptosis models are believed to be related to oxidative stress (Zhu et al 2012). Buccigrossi et al used HT29 and Caco-2 cells for a Tat-induced apoptosis study, and 10 mM H 2 O 2 for 5 min was used as the control in the paper by Buccigrossi et al (2011). Nevertheless, HT29 and Caco-2 cells are both tumorigenic cell lines.…”

Section: Discussionmentioning

confidence: 99%

X/XO or H2O2 induced IPEC-J2 cell as a new in vitro model for studying apoptosis in post-weaning piglets

et al. 2014

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We previously demonstrated that intestinal epithelial cell apoptosis in weaned piglets is much more serious than that observed in sucking piglets and is related to oxidative stress during weaning. It is difficult to study the apoptosis mechanisms only using in vivo methods because of the limit of existing research technology. An in vitro cellular system is required for piglet intestinal epithelial cell apoptosis research. In this study, a non-tumorigenic epithelial cell line, IPEC-J2 cells, was employed as a cell model. Hydrogen peroxide and xanthine/xanthine oxidase (X/ XO) were both used and compared for apoptosis modeling. The concentrations of hydrogen peroxide and XO were selected and verified using cell viability analysis, the comet assay and flow cytometry. Intracellular ROS were measured using fluorescent probes. Additionally, the expression levels of the apoptosis-related genes Fas, Bcl-2, P53, Caspase 3, Caspase 8, and Caspase 9 were analyzed using quantitative RT-PCR. The results indicated the optimal modeling method is a final concentration of 0.5 mM H 2 O 2 incubated with IPEC-J2 cells for 1 h at 37°C in 5 % CO 2 for hydrogen peroxide-induced apoptosis modeling, and a final concentration of 250 lM X/50 U/L XO incubated with IPEC-J2 cells for 6 h at 37°C in 5 % CO 2 for X/XO-induced apoptosis modeling. For the apoptotic pathway, the X/XO modeling method is more similar to 21 days weaning piglets. Therefore, we suggest that X/XO modeling with IPEC-J2 cells be used as an in vitro cell culture model for weaning piglet intestinal epithelial cell apoptosis.

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“…Diverse authors have been contributed to the observation that oxidative stress in HIV could drive disulfide CD4 modification, necessary for HIV entry on host, CD4 T lymphocyte depletion and also viral replication increase influencing both aspects on the HIV immunodeficiency condition with unfavorable evolution [9][10][11][12][13][14]. Furthermore, antiretroviral therapy could influence on oxidative stress in HIV infection [15].…”

Section: Multivariate Discriminant Analysis Of Redox and Progression mentioning

confidence: 99%

Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

Valle¹,

Duque-Vizcaino²,

Calás-Hechavarria³

et al. 2017

Oxid Antioxid Med Sci

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Objectives: Infection by human immunodeficiency virus (HIV) generates sustained reactive oxygen species production. An increasing number of studies underline the pathogenic impact of high-grade local and systemic oxidative stress in the activation of Herpesvirus 8 producing Kaposi's sarcoma (KS) co-infection in acquired immunodeficiency syndrome (AIDS) patients. This study aimed to determine the redox status in AIDS-KS Cuban individuals and to explore the relation between redox and progression variables. Methods: Blood samples were drawn from 99 individuals divided into three groups (33 each one; age range 30-50 years): AIDS, AIDS-KS, and presumable healthy subjects. Total peroxide, malondialdehyde, and advanced oxidation protein products as damage indexes and antioxidant responses (glutathione, peroxidation potential, superoxide dismutase, and catalase) were determined from the blood samples. Furthermore, hematological and hemochemical indexes, progression indexes (viral load, CD4 + T lymphocyte absolute count), and tumoral progression indexes were assessed. Different statistical analyses were done. Results: Compared to healthy subjects, both groups of AIDS patients had significant differences in global indices of damage and antioxidant status. The comparison between the groups revealed that AIDS-KS group had a significantly higher damage and lower antioxidant status compared to the healthy control and AIDS groups. Multivariate statistical analysis clearly separated groups according progression indexes and redox profile, obtaining two canonical functions. Conclusions: These results corroborate that substantial oxidative stress occurs in AIDS condition and also during KS-HIV co-infection with different molecular extension and interdependence to progression indexes. Redox indexes diagnosis should be considered in early diagnostics, prevention and treatment of KS-HIV coinfection, which would be worthwhile to conduct a more comprehensive study and manage of infection.

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The HIV-1 Transactivator Factor (Tat) Induces Enterocyte Apoptosis through a Redox-Mediated Mechanism

Cited by 56 publications

References 53 publications

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

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

X/XO or H2O2 induced IPEC-J2 cell as a new in vitro model for studying apoptosis in post-weaning piglets

Multivariate discriminant analysis of redox and progression indexes in Cuban AIDS patients with Kaposis sarcoma

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