Jacques Dutrieux

Université René Descartes - Paris 5, Lutetia Parisorum, Île-de-France, France

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Publications (12)53.72 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Epstein-Barr virus (EBV) is associated with several malignancies, including carcinomas, such as nasopharyngeal carcinoma, and lymphomas, such as Burkitt's lymphoma and Hodgkin's lymphoma. The Latent Membrane Protein 1 (LMP1) is the major oncogene protein of EBV as its expression is responsible for the induction of cell transformation, immortalization and proliferation. Arsenic trioxide was shown to induce a cytotoxic effect on nasopharyngeal cancer cells associated with LMP1 down-regulation. However, the effect of arsenic on EBV-associated lymphoproliferative malignancies has been less studied. We investigated the effect of two different arsenical compounds, arsenic trioxide (As2O3) and sodium arsenite (NaAsO2) on the induction of cell death in P3HR1 cells, an Epstein-Barr virus-positive Burkitt lymphoma derived cell line. Both compounds inhibited cell growth and induced cell death. By flow-cytometry and Western blot analysis, we provide evidence that NaAsO2 induced caspase-dependent apoptosis whereas As2O3 triggered autophagic cell death. Furthermore, we show that NaAsO2 treatment led to a dramatic decrease of the expression level of LMP1 and the cellular protein PML. Importantly, this down-regulation was associated with a reactivation of EBV lytic cycle through the induction of immediate-early proteins Zta and Rta. These results are in agreement with a model in which LMP1 maintains EBV in a latent state by stabilizing PML expression. Altogether, our results suggest that NaAsO2 would represent a better therapeutic candidate than As2O3 in EBV-induced B lymphoma for its capacity to promote viral reactivation.
    Biochimie 09/2014; · 3.14 Impact Factor
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    ABSTRACT: Thymus dysfunction characterizes human/simian immunodeficiency virus (SIV) infections and contributes to physiopathology. However, both the mechanisms involved in thymic dysfunction and its precise timing remain unknown. We here analyzed thymic function during acute SIV infection in rhesus macaques. Rhesus macaques were intravenously infected with SIVmac251 and bled every 2/3 days or necropsied at different early time points postinfection. Naive T-cell counts were followed by flow cytometry and their T-cell receptor excision circle content evaluated by qPCR. Thymic chemokines were quantified by reverse transcription-qPCR and localized by in-situ hybridization in thymuses collected at necropsy. Thymic interferon alpha (IFN-α) subtype production was quantified by reverse transcription-qPCR combined to heteroduplex tracking assay. The effect of thymic IFN-α subtypes was tested on sorted triple negative thymocytes cultured on OP9-hDL1 cells. A reduced intrathymic proliferation history characterizes T cells produced during the first weeks of infection. Moreover, we evidenced a profound alteration of both chemokines and IFN-α subtypes transcriptional patterns in SIV-infected thymuses. Finally, we showed that IFN-α subtypes produced in the infected thymuses inhibit thymocyte proliferation, still preserving their differentiation capacity. Thymopoiesis is deeply impacted from the first days of SIV infection. Reduced thymocyte proliferation - a time-consuming process - together with modified chemokine networks is consistent with thymocyte differentiation speed-up. This may transiently enhance thymic output, thus increasing naive T-cell counts and diversity and the immune competence of the host. Nonetheless, long-lasting modification of thymic physiology may lead to thymic exhaustion, as observed in late primary HIV infection.
    AIDS (London, England) 03/2014; · 4.91 Impact Factor
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    ABSTRACT: PML/TRIM19, the organizer of nuclear bodies (NBs), has been implicated in the antiviral response to diverse RNA and DNA viruses. Several PML isoforms generated from a single PML gene by alternative splicing, share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. The knockout of PML renders mice more sensitive to vesicular stomatitis virus (VSV). Here we report that among PML isoforms (PMLI to PMLVIIb), only PMLIII and PMLIV confer resistance to VSV. Unlike PMLIII, whose anti-VSV activity is IFN-independent, PMLIV can act at two stages: it confers viral resistance directly in an IFN-independent manner and also specifically enhances IFN-β production via a higher activation of IRF3, thus protecting yet uninfected cells from oncoming infection. PMLIV SUMOylation is required for both activities. This demonstrates for the first time that PMLIV is implicated in innate immune response through enhanced IFN-β synthesis. Depletion of IRF3 further demonstrates the dual activity of PMLIV, since it abrogated PMLIV-induced IFN synthesis but not PMLIV-induced inhibition of viral proteins. Mechanistically, PMLIV enhances IFN-β synthesis by regulating the cellular distribution of Pin1 (peptidyl-prolyl cis/trans isomerase), inducing its recruitment to PML NBs where both proteins colocalize. The interaction of SUMOylated PMLIV with endogenous Pin1 and its recruitment within PML NBs prevents the degradation of activated IRF3, and thus potentiates IRF3-dependent production of IFN-β. Whereas the intrinsic antiviral activity of PMLIV is specific to VSV, its effect on IFN-β synthesis is much broader, since it affects a key actor of innate immune pathways. Our results show that, in addition to its intrinsic anti-VSV activity, PMLIV positively regulates IFN-β synthesis in response to different inducers, thus adding PML/TRIM19 to the growing list of TRIM proteins implicated in both intrinsic and innate immunity.
    PLoS Pathogens 02/2014; 10(2):e1003975. · 8.14 Impact Factor
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    ABSTRACT: IFN-I production is a characteristic of HIV/SIV primary infections. However, acute IFN-I plasma concentrations rapidly decline thereafter. Plasmacytoid dendritic cells (pDC) are key players in this production but primary infection is associated with decreased responsiveness of pDC to TLR 7 and 9 triggering. IFNα production during primary SIV infection contrasts with increased pDC death, renewal and dysfunction. We investigated the contribution of pDC dynamics to both acute IFNα production and the rapid return of IFNα concentrations to pre-infection levels during acute-to-chronic transition. Nine cynomolgus macaques were infected with SIVmac251 and IFNα-producing cells were quantified and characterized. The plasma IFN-I peak was temporally associated with the presence of IFNα(+) pDC in tissues but IFN-I production was not detectable during the acute-to-chronic transition despite persistent immune activation. No IFNα(+) cells other than pDC were detected by intracellular staining. Blood-pDC and peripheral lymph node-pDC both lost IFNα(-) production ability in parallel. In blood, this phenomenon correlated with an increase in the counts of Ki67(+)-pDC precursors with no IFNα production ability. In tissues, it was associated with increase of both activated pDC and KI67(+)-pDC precursors, none of these being IFNα(+) in vivo. Our findings also indicate that activation/death-driven pDC renewal rapidly blunts acute IFNα production in vivo: pDC sub-populations with no IFNα-production ability rapidly increase and shrinkage of IFNα production thus involves both early pDC exhaustion, and increase of pDC precursors.
    PLoS Pathogens 01/2014; 10(1):e1003915. · 8.14 Impact Factor
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    ABSTRACT: Natural Tregs (nTregs), produced by the thymus, are responsible for the control of autoimmune and inflammatory reactions. Their precise determina-tion is important to better understand the immunologic host defence mech-anisms. Our aim is to phenotypically define nTregs recently emigrated from the thymus and to analyse their behaviour in HIV-1 infected patients receiving antiretroviral therapy and patients who are not undergoing therapy. PBMCs from three groups – healthy controls, HIV-1 infected subjects under antiretroviral therapy and non-treated patients – were stained with a combination of antibodies specific for extra – and intracellular molecules – CD3, CD4, CD45RA, CCR7, CD31, CD25, FOXP3 and CD127 – and their expression was evaluated using multicolour flow cytometry. Our results show that the population of nTreg-Recently Emigrated from the Thymus, specifically characterised by the expression of CD3, CD4, CD45RA, CCR7, FOXP3 and CD31 is heterogeneous. It consists of two fractions accord-ing to the expression of CD25. They might be described as CD25 negative and CD25 positive and their distribution differs between healthy individuals and HIV-infected patients. Both fractions contained CD127 + and CD127 − –cells. Their proportion within each particular CD25 fraction varied between study groups.
    Comptes rendus de l'Académie bulgare des sciences: sciences mathématiques et naturelles 01/2014; 67(7):1011-1018. · 0.21 Impact Factor
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    ABSTRACT: Forkhead box N1 (FOXN1) is a transcription factor crucial for thymic epithelium development and prevention of its involution. Investigation of a patient with a rare homozygous FOXN1 mutation (R255X), leading to alopecia universalis and thymus aplasia, unexpectedly revealed non-maternal circulating T-cells, and, strikingly, large numbers of aberrant double-negative αβ T-cells (CD4negCD8neg, DN) and regulatory-like T-cells. These data raise the possibility that a thymic rudiment persisted, allowing T-cell development, albeit with disturbances in positive/negative selection, as suggested by DN and FoxP3+ cell expansions. Although regulatory-like T-cell numbers normalized following HLA-mismatched thymic transplantation, the αβDN subset persisted 5 years post-transplantation. Involution of thymus allograft likely occurred 3 years post-transplantation based on sj/βTREC ratio, which estimates intrathymic precursor T-cell divisions and, consequently, thymic explant output. Nevertheless, functional immune-competence was sustained, providing new insights for the design of immunological reconstitution strategies based on thymic transplantation, with potential applications in other clinical settings.
    PLoS ONE 01/2012; 7(5):e37042. · 3.53 Impact Factor
  • Cytokine 10/2011; 56(1):25–26. · 2.52 Impact Factor
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    ABSTRACT: The contribution of naive CD4⁺ T cells to the pool of HIV-infected cells remains poorly described. This study aimed at evaluating HIV infection in naive T-cell subsets in viremic and HAART-treated patients, together with various parameters implicated in naive T-cell homeostasis, in order to better understand infection in these subsets. HIV provirus was quantified in various FACS-sorted CD4/CD8 T-cell subsets [recent thymic emigrants (RTEs), non-RTE naives and memory T cells] purified from peripheral blood cells of untreated viremic and HAART-treated aviremic HIV-infected patients. HIV proviral DNA was quantified using a highly sensitive real-time PCR assay allowing detection of one HIV copy in 10⁵ cells. Intrathymic precursor T-cell proliferation and circulating T-cell cycling were, respectively, evaluated through measurement of the sj/βTREC ratio (signal joint T-Cell Receptor Excision Circle frequency divided by DβJβTREC frequency) and Ki-67 expression. Plasma interleukin (IL)-7 concentrations were measured by ELISA. RTEs and non-RTEs were equally HIV infected. Altogether, naive CD4⁺ T cells represented 0.24%-60% of the infected cells. In contrast, HIV DNA was undetectable in naive CD8⁺ T cells. RTE infection rate directly correlated with IL-7 plasma levels (r = 0.607, P = 0.0035) but was independent from plasma viral load, peripheral T-cell cycling and intrathymic precursor T-cell proliferation. We demonstrated that RTEs are effectively HIV infected. The similar infection rate observed in RTEs and other naive T cells, its relationship with plasma IL-7 levels, together with the lack of correlation between RTE infection and either thymic or peripheral proliferation, strongly suggests that RTE infection occurs either late during thymopoiesis or early on during their extrathymic maturation.
    AIDS (London, England) 06/2011; 25(9):1153-62. · 4.91 Impact Factor
  • Cytokine 01/2011; 56(1):44-45. · 2.52 Impact Factor
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    ABSTRACT: Interferon-α (IFN-α)-based therapy is presently the standard treatment for hepatitis C virus (HCV)-infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus-infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-α-induced lymphopenia. We showed that low-dose IFN-α treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high-dose IFN-α treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-α. Indeed, the association of both cytokines resulted in increased circulating T-cell counts, in particular in the naive compartments, as a consequence of central and peripheral homeostatic functions of the IL-7. Finally, reduced PD-1 expression by memory CD8(+) T cells and transient T-cell repertoire diversification were observed under IL-7 therapy. Our data strongly suggest that IL-7 immunotherapy will be of substantial benefit in the treatment of HIV/HCV coinfection and should enhance the likelihood of HCV eradication in poorly responding patients.
    Blood 12/2010; 116(25):5589-99. · 9.78 Impact Factor
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    ABSTRACT: Long-term immune recovery in older patients given hematopoietic cell transplantation after non-myeloablative conditioning remains poorly understood. This prompted us to investigate long-term lymphocyte reconstitution and thymic function in 80 patients given allogeneic peripheral blood stem cells after non-myeloablative conditioning. Median age at transplant was 57 years (range 10-71). Conditioning regimen consisted of 2 Gy total body irradiation (TBI) with (n=46) or without (n=20) added fludarabine, 4 Gy TBI with fludarabine (n=6), or cyclophosphamide plus fludarabine (n=8). Stem cell sources were unmanipulated (n=56), CD8-depleted (n=19), or CD34-selected (n=5) peripheral blood stem cells. Immune recovery was assessed by signal-joint T-cell receptor excision circle quantification and flow cytometry. Signal-joint T-cell receptor excision circle levels increased from day 100 to one and two years after transplantation in patients under 50 years of age (n=23; P=0.02 and P=0.04, respectively), and in those aged 51-60 years (n=35; P=0.17 and P=0.06, respectively), but not in patients aged over 60 (n=22; P=0.3 and P=0.3, respectively). Similarly, CD4(+)CD45RA(+) (naïve) T-cell counts increased from day 100 to one and two years after transplantation in patients aged 50 years and under 50 (P=0.002 and P=0.02, respectively), and in those aged 51-60 (P=0.4 and P=0.001, respectively), but less so in patients aged over 60 (P=0.3 and P=0.06, respectively). In multivariate analyses, older patient age (P<0.001), extensive chronic GVHD (P<0.001), and prior (resolved) extensive chronic graft-versus-host disease (P=0.008) were associated with low signal-joint T-cell receptor excision circle levels one year or more after HCT. In summary, our data suggest that thymic neo-generation of T cells occurred from day 100 onwards in patients under 60 while signal-joint T-cell receptor excision circle levels remained low for patients aged over 60. Further, chronic graft-versus-host disease had a dramatic impact on thymic function, as observed previously in patients given grafts after myeloablative conditioning.
    Haematologica 10/2010; 96(2):298-306. · 5.94 Impact Factor
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    ABSTRACT: PML/TRIM19 is the organizer of PML nuclear bodies (NB), large multiprotein structures associated to the nuclear matrix, which recruit a great number of proteins and which are implicated in various cellular processes including antiviral defense. The conjugation of PML to SUMO is required for the formation and function of PML NB. Alternative splicing from a single PML gene generates several PML isoforms (PMLI to PMLVIIb), each harboring a specific carboxy-terminal region. This variability allows each isoform to recruit different partners and thus confers them specific functions. PML gene is directly induced by interferon and certain PML isoforms are implicated in its antiviral properties, as they display intrinsic antiviral activities against RNA or DNA viruses. One isoform, PMLIV, is also implicated in innate immunity by enhancing IFN-β production during a viral infection. Here we review recent findings on PML/TRIM19 implication in interferon response and antiviral defense, at the interface between intrinsic and innate immunity.
    Medecine sciences : M/S. 30(8-9):765-771.

Publication Stats

58 Citations
53.72 Total Impact Points

Institutions

  • 2014
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Institut Pasteur International Network
      • Département de Virologie de Paris
      Paris, Ile-de-France, France