Yves Lévy

University of Paris-Est, La Haye-Descartes, Centre, France

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Publications (114)629.24 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated the immunogenicity of a prime/boost vaccine strategy combining 5 lipopeptides (HIV-Lipo-5) and a recombinant modified vaccinia virus Ankara (rMVA-HIV) in cynomolgus macaques. Both of these vaccine components deliver HIV LAI Gag, Pol, and Nef antigens. Systemic and local safety was excellent in all groups. Immunization with HIV-Lipo-5 alone induced significant serum anti-HIV antibody titers which were not modified by rMVA-HIV immunization. However, induction of T-cell responses, as measured by IFNγ and IL-2 producing cells upon short-term stimulation with HIV peptide pools, required combined immunization with rMVA-HIV. Responses were preferentially observed against Gag antigen. Interestingly, HIV-Lipo-5 efficiently primed HIV induced T-cell responses upon the injection of rMVA-HIV, which may help to reduce the required number of vector injections. Our results provide a rationale for the use of a strategy involving HIV-Lipo-5 priming followed by rMVA-HIV booster immunization as a prophylactic or therapeutic vaccine approach against HIV infection and AIDS. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 03/2015; 33(20). DOI:10.1016/j.vaccine.2015.03.032 · 3.49 Impact Factor
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    ABSTRACT: HIV-1 replication depends on the state of cell activation and division. It is established that SAMHD1 restricts HIV-1 infection of resting CD4 T cells. The modulation of SAMHD1 expression during T-cell activation and proliferation, however, remains unclear, as well as a role for SAMHD1 during HIV-1 pathogenesis. SAMHD1 expression was assessed in CD4 T cells after their activation and in-vitro HIV-1 infection. We performed phenotype analyzes using flow cytometry on CD4 T cells from peripheral blood and lymph nodes from cohorts of HIV-1-infected individuals under antiretroviral treatment or not, and controls. We show that SAMHD1 expression decreased during CD4 T-cell proliferation in association with an increased susceptibility to in-vitro HIV-1 infection. Additionally, circulating memory CD4 T cells are enriched in cells with low levels of SAMHD1. These SAMHD1 cells are highly differentiated, exhibit a large proportion of Ki67 cycling cells and are enriched in T-helper 17 cells. Importantly, memory SAMHD1 cells were depleted from peripheral blood of HIV-infected individuals. We also found that follicular helper T cells present in secondary lymphoid organs lacked the expression of SAMHD1, which was accompanied by a higher susceptibility to HIV-1 infection in vitro. We demonstrate that SAMHD1 expression is decreased during CD4 T-cell activation and proliferation. Also, CD4 T-cell subsets known to be more susceptible to HIV-1 infection, for example, T-helper 17 and follicular helper T cells, display lower levels of SAMHD1. These results pin point a role for SAMHD1 expression in HIV-1 infection and the concomitant depletion of CD4 T cells.
    AIDS (London, England) 03/2015; 29(5):519-30. DOI:10.1097/QAD.0000000000000594 · 6.56 Impact Factor
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    ABSTRACT: HIV vaccine strategies are expected to be a crucial component for controlling the HIV epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later -stage (phase IIB and III) development are discussed, taking into account the specificities of both prophylactic and therapeutic HIV vaccine development.
    Human Vaccines and Immunotherapeutics 03/2015; 11(4). DOI:10.1080/21645515.2015.1011974 · 3.64 Impact Factor
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    ABSTRACT: The role of regulatory T cells (Tregs) in vaccination has been poorly investigated. We have reported that vaccination with ex vivo-generated dendritic-cells (DC) loaded with HIV-lipopeptides (LIPO-5-DC vaccine) in HIV-infected patients was well tolerated and highly immunogenic. These responses and their relation to viral replication following analytical treatment interruption (ATI) were variable. Here, we investigated whether the presence of HIV-specific Tregs might explain these differences. Co-expression of CD25, CD134, CD39 and FoxP3 was used to delineate both antigen-specific Tregs and effectors T cells (Teffs). Median LIPO-5 specific-CD25+CD134+ polyfunctional T cells increased from 0.1% (IQR 0-0.3) before vaccination (week -4) to 2.1% (IQR 1.1-3.9) at week 16 following 4 immunizations (p=0.001) and were inversely correlated with maximum viral load following ATI (r=-0.77, p=0.001). Vaccinees who displayed lower levels of HIV-specific CD4+CD134+CD25+CD39+FoxP3+ Tregs responded better to the LIPO-5-DC vaccine. After vaccination, the frequency of HIV-specific Tregs decreased (from 69.3 at week -4 to 31.7% at week 16) and inversely correlated with HIV-specific IFN-γ-producing cells (r=-0.64, p=0.002). We show that therapeutic immunization skewed the HIV-specific response from regulatory to effector phenotype which impacts on the magnitude of viral replication following ATI.
    PLoS Pathogens 03/2015; 11(3):e1004752. DOI:10.1371/journal.ppat.1004752 · 8.06 Impact Factor
  • Clinical Microbiology and Infection 12/2014; 21(4). DOI:10.1016/j.cmi.2014.11.029 · 5.20 Impact Factor
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    ABSTRACT: The long-term spontaneous evolution between humans and the human immunodeficiency virus (HIV) is not well characterized; many species, including humans, exhibit remnants of other retroviruses in their genomes that question such possible endogenization of HIV. We investigated two HIV-infected patients with no HIV-related disease and no detection with routine tests of plasma HIV RNA or cell-associated HIV DNA. We used Sanger and deep sequencing to retrieve HIV DNA sequences integrated in the human genome and tested the host humoral and cellular immune responses. We noticed that viruses from both patients were inactivated by the high prevalence of the transformation of tryptophan codons into stop codons (25% overall (3-100% per gene) and 24% overall (0-50% per gene)). In contrast, the humoral and/or cellular responses were strong for one patient and moderate for the other, indicating that a productive infection occurred at one stage of the infection. We speculate that the stimulation of APOBEC, the enzyme group that exchanges G for A in viral nucleic acids and is usually inhibited by the HIV protein Vif, has been amplified and made effective from the initial stage of the infection. Furthermore, we propose that HIV cure may occur through HIV endogenization in humans, as observed for many other retroviruses in mammals, rather than clearance of all traces of HIV from human cells which defines viral eradication.This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 11/2014; 20(12). DOI:10.1111/1469-0691.12807 · 5.20 Impact Factor
  • AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1:A245. DOI:10.1089/aid.2014.5544.abstract · 2.46 Impact Factor
  • AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1:A173-4. DOI:10.1089/aid.2014.5366.abstract · 2.46 Impact Factor
  • AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1:A189-90. DOI:10.1089/aid.2014.5406.abstract · 2.46 Impact Factor
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    ABSTRACT: In the present study, we have investigated the functional profile of CD4 T cells from patients with common variable immunodeficiency (CVID), including production of cytokines and proliferation in response to bacteria and virus-derived antigens. We show that the functional impairment of CD4 T cells, including the reduced capacity to proliferate and to produce IFN-γ and IL-2, was restricted to bacteria-specific and not virus-specific CD4 T cells. High levels of endotoxins were found in the plasma of patients with CVID, suggesting that CD4 T cell dysfunction might be caused by bacterial translocation. Of note, endotoxemia was associated with significantly higher expression of programmed death 1 (PD-1) on CD4 T cells. The blockade of the PD-1-PD-L1/2 axis in vitro restored CD4 T cell proliferation capacity, thus indicating that PD-1 signaling negatively regulates CD4 T cell functions. Finally, we showed that intravenous immunoglobulin G (IVIG) treatment significantly reduced endotoxemia and the percentage of PD-1(+) CD4 T cells, and restored bacteria-specific CD4 T cell cytokine production and proliferation. In conclusion, the present study demonstrates that the CD4 T cell exhaustion and functional impairment observed in CVID patients is associated with bacterial translocation and that IVIG treatment resolves bacterial translocation and restores CD4 T cell functions.
    Journal of Experimental Medicine 09/2014; 211(10):2033-45. DOI:10.1084/jem.20140039 · 13.91 Impact Factor
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    ABSTRACT: Efforts aimed at restoring robust immune responses limiting therapeutically human immunodeficiency virus (HIV)-1 replication are warranted. We report that vaccination with dendritic cells (DC) generated ex vivo and loaded with HIV lipopeptides in patients (n = 19) on antiretroviral therapy was well tolerated and immunogenic. Vaccination increased: i) the breadth of the immune response from 1 (1-3) to 4 (2-5) peptide-pool responses/patient (P = 0.009); ii) the frequency of functional T cells (producing at least 2 cytokines among IFN-γ, TNF-α, and IL-2) from 0.026 to 0.32% (P = 0.002) and from 0.26 to 0.35% (P = 0.005) for CD4+ and CD8+ T cells, respectively; and iii) the breadth of cytokines secreted by peripheral blood mononuclear cells (PBMCs) upon antigen exposure, including IL-2, IFN-γ, IL-21, IL-17 and IL-13. Fifty percent of patients experienced a peak of viral load (VL) 1 log10 lower than the other half following antiviral treatment interruption. An inverse correlation was found between the peak of VL and the frequency of polyfunctional CD4+ T cells (P = 0.007), production of IL-2 (P = 0.006,), IFN-γ (P = 0.01), IL-21 (P = 0.006) and IL-13 (P = 0.001). These results suggest an association between vaccine responses and a better control of viral replication. These findings will help in the development of strategies for a functional cure for HIV infection.This article is protected by copyright. All rights reserved
    European Journal of Immunology 09/2014; 44(9). DOI:10.1002/eji.201344433 · 4.52 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) are pivotal in preventing autoimmunity. They play a major but still ambiguous role in cancer and viral infections. Functional studies of human Tregs are often hampered by numerous technical difficulties arising from imperfections in isolating and depleting protocols, together with the usual low cell number available from clinical samples. We standardized a simple procedure (Single Step Method, SSM), based on magnetic beads technology, in which both depletion and isolation of human Tregs with high purities are simultaneously achieved. SSM is suitable when using low cell numbers either fresh or frozen from both patients and healthy individuals. It allows simultaneous Tregs isolation and depletion that can be used for further functional work to monitor suppressive function of isolated Tregs (in vitro suppression assay) and also effector IFN-γ responses of Tregs-depleted cell fraction (OX40 assay). To our knowledge, there is no accurate standardized method for Tregs isolation and depletion in a clinical context. SSM could thus be used and easily standardized across different laboratories.
    Journal of Immunological Methods 09/2014; DOI:10.1016/j.jim.2014.06.003 · 2.01 Impact Factor
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    ABSTRACT: Innate mechanisms are critical for the development of the host immune responses to antigen. Particularly, early interaction between natural killer (NK) cells and dendritic cells (DC) greatly impacts the establishment of both innate and adaptive immune responses. In this study, using an autologous in vitro co-culture system we analyzed the NK cell response against MVAHIV-infected DC as well as the subsequent ability of these MVAHIV-primed NK cells to control HIV-1 infection in autologous DC. We found that NK cells responded early to MVAHIV- or MVAWT-infected DC in terms of degranulation and cytokine production. After a 4-day priming of NK cells by MVAHIV- or MVAWT-infected DC we observed an enhanced proliferation and modulation in the NK cell receptor repertoire expression. Interestingly, we found that MVAHIV-primed NK cells had a significant higher ability to control HIV-1 infection in autologous DC compared to MVAWT-primed NK cells; and this enhanced anti-HIV-1 activity appeared to be HIV-specific as MVAHIV-primed NK cells did not have a better ability to control other viral infections or respond against tumoral cells. Furthermore, we observed that NK cell receptors NKG2D and NKp46 modulate the priming of NK cells. This data provides evidence that in vitro NK cells can be primed by viral vector-infected DC, in the context of a NK/DC culture, to specifically target viral infected cells.
    Vaccine 08/2014; 32(43). DOI:10.1016/j.vaccine.2014.07.094 · 3.49 Impact Factor
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    ABSTRACT: Natural Killer (NK) cells are the major antiviral effector cell population of the innate immune system. It has been demonstrated that NK-cell activity can be modulated by the interaction with dendritic cells (DCs). The HIV-1 vaccine candidate Modified Vaccinia Ankara encoding an HIV polypeptide (MVAHIV ), developed by the French National Agency for Research on AIDS (ANRS), has the ability to prime NK cells to control HIV-1 infection in DCs. However, whether or not MVAHIV -primed NK cells are able to better control HIV-1 infection in CD4(+) T cells, and the mechanism underlying the specific priming, remain undetermined. In this study we show that MVAHIV -primed NK cells display a greater capacity to control HIV-1 infection in autologous CD4(+) T cells. We also highlight the importance of NKG2D engagement on NK cells and DC-produced IL-15 to achieve the anti-HIV-1 specific priming, as blockade of either NKG2D or IL-15 during MVAHIV -priming lead to a subsequent decreased control of HIV-1 infection in autologous CD4(+) T cells. Furthermore we show that the decreased control of HIV-1 infection in CD4(+) T cells might be due, at least in part, to the decreased expression of membrane-bound IL-15 (mbIL-15) on DCs when NKG2D is blocked during MVAHIV -priming of NK cells. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 08/2014; 44(8). DOI:10.1002/eji.201344149 · 4.52 Impact Factor
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    ABSTRACT: Interleukin-7 is a non-redundant growth, differentiation and survival factor for human T lymphocytes. Most circulating, mature T cells express the receptor for IL-7, but not all. Importantly, CD4 Tregs express greatly reduced levels of IL-7R compared to conventional CD4 T cells, presenting an opportunity to selectively target the latter cells with either more IL-7 to boost responses, or to block IL-7 signalling to limit responses. This article reviews what is known about regulation of IL-7R expression, and recent progress in therapeutic approaches related to IL-7 and its receptor.
    Cytokine & Growth Factor Reviews 07/2014; 25(4). DOI:10.1016/j.cytogfr.2014.07.012 · 6.54 Impact Factor
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    ABSTRACT: Dendritic cells are major APCs that can efficiently prime immune responses. However, the roles of skin-resident Langerhans cells (LCs) in eliciting immune responses have not been fully understood. In this study, we demonstrate for the first time, to our knowledge, that LCs in cynomolgus macaque skin are capable of inducing antiviral-specific immune responses in vivo. Targeting HIV-Gag or influenza hemagglutinin Ags to skin LCs using recombinant fusion proteins of anti-Langerin Ab and Ags resulted in the induction of the viral Ag-specific responses. We further demonstrated that such Ag-specific immune responses elicited by skin LCs were greatly enhanced by TLR ligands, polyriboinosinic polyribocytidylic acid, and R848. These enhancements were not due to the direct actions of TLR ligands on LCs, but mainly dependent on TNF-α secreted from macrophages and neutrophils recruited to local tissues. Skin LC activation and migration out of the epidermis are associated with macrophage and neutrophil infiltration into the tissues. More importantly, blocking TNF-α abrogated the activation and migration of skin LCs. This study highlights that the cross-talk between innate immune cells in local tissues is an important component for the establishment of adaptive immunity. Understanding the importance of local immune networks will help us to design new and effective vaccines against microbial pathogens.
    The Journal of Immunology 07/2014; 193(5). DOI:10.4049/jimmunol.1303339 · 5.36 Impact Factor
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    ABSTRACT: Exogenous Interleukin-7 (IL-7), in supplement to antiretroviral therapy, leads to a substantial increase of all CD4+ T cell subsets in HIV-1 infected patients. However, the quantitative contribution of the several potential mechanisms of action of IL-7 is unknown. We have performed a mathematical analysis of repeated measurements of total and naive CD4+ T cells and their Ki67 expression from HIV-1 infected patients involved in three phase I/II studies (N = 53 patients). We show that, besides a transient increase of peripheral proliferation, IL-7 exerts additional effects that play a significant role in CD4+ T cell dynamics up to 52 weeks. A decrease of the loss rate of the total CD4+ T cell is the most probable explanation. If this effect could be maintained during repeated administration of IL-7, our simulation study shows that such a strategy may allow maintaining CD4+ T cell counts above 500 cells/µL with 4 cycles or fewer over a period of two years. This in-depth analysis of clinical data revealed the potential for IL-7 to achieve sustained CD4+ T cell restoration with limited IL-7 exposure in HIV-1 infected patients with immune failure despite antiretroviral therapy.
    PLoS Computational Biology 05/2014; 10(5):e1003630. DOI:10.1371/journal.pcbi.1003630 · 4.87 Impact Factor
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    ABSTRACT: The pathophysiologic mechanisms classically involved in sickle-cell nephropathy include endothelial dysfunction and vascular occlusion. Arguments demonstrating that ischemia-reperfusion injury-related kidney damage might coincide with vaso-occlusive crisis (VOC) are lacking. In this prospective study, we sought to determine whether tubular cells and glomerular permeability might be altered during VOC. Urine neutrophil gelatinase-associated lipocalin (NGAL) levels and albumin-excretion rates (AER) of 25 patients were evaluated prospectively during 25 VOC episodes and compared to their steady state (ST) values. During VOC, white blood-cell counts (WBC) and C-reactive protein (CRP) were significantly higher than at ST but creatinine levels were comparable. Urine NGAL levels were significantly increased during VOC vs ST (P = 0.007) and remained significant when normalized to urine creatinine (P = 0.004), while AER did not change significantly. The higher urine NGAL concentration was not associated with subsequent (24-48 hour) acute kidney injury. Univariate analysis identified no significant correlations between urine NGAL levels and laboratory parameters during VOC. These results demonstrated that subclinical ischemia-reperfusion tubular injury is common during VOC and highlight the importance of hydroelectrolyte monitoring and correction during VOC.
    Orphanet Journal of Rare Diseases 04/2014; 9(1):67. DOI:10.1186/1750-1172-9-67 · 3.96 Impact Factor
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    ABSTRACT: Many candidate vaccine strategies against human immunodeficiency virus (HIV) infection are under study, but their clinical development is lengthy and iterative. To accelerate HIV vaccine development optimised trial designs are needed. We propose a randomised multi-arm phase I/II design for early stage development of several vaccine strategies, aiming at rapidly discarding those that are unsafe or non-immunogenic. We explored early stage designs to evaluate both the safety and the immunogenicity of four heterologous prime-boost HIV vaccine strategies in parallel. One of the vaccines used as a prime and boost in the different strategies (vaccine 1) has yet to be tested in humans, thus requiring a phase I safety evaluation. However, its toxicity risk is considered minimal based on data from similar vaccines. We newly adapted a randomised phase II trial by integrating an early safety decision rule, emulating that of a phase I study. We evaluated the operating characteristics of the proposed design in simulation studies with either a fixed-sample frequentist or a continuous Bayesian safety decision rule and projected timelines for the trial. We propose a randomised four-arm phase I/II design with two independent binary endpoints for safety and immunogenicity. Immunogenicity evaluation at trial end is based on a single-stage Fleming design per arm, comparing the observed proportion of responders in an immunogenicity screening assay to an unacceptably low proportion, without direct comparisons between arms. Randomisation limits heterogeneity in volunteer characteristics between arms. To avoid exposure of additional participants to an unsafe vaccine during the vaccine boost phase, an early safety decision rule is imposed on the arm starting with vaccine 1 injections. In simulations of the design with either decision rule, the risks of erroneous conclusions were controlled <15%. Flexibility in trial conduct is greater with the continuous Bayesian rule. A 12-month gain in timelines is expected by this optimised design. Other existing designs such as bivariate or seamless phase I/II designs did not offer a clear-cut alternative. By combining phase I and phase II evaluations in a multi-arm trial, the proposed optimised design allows for accelerating early stage clinical development of HIV vaccine strategies.
    Trials 02/2014; 15(1):68. DOI:10.1186/1745-6215-15-68 · 2.12 Impact Factor
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    ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) infection is characterized by chronic immune activation and suppressed T-lymphocyte functions. Here we report that CD73, both a coactivator molecule of T cells and an immunosuppressive ecto-enzyme through adenosine production, is only weakly expressed by CD8(+) T cells of HIV-infected patients and only partially restored after successful antiviral treatment. CD73 expression on CD8(+) T cells correlates inversely with cell activation both ex vivo and in vitro. However, CD8(+) T cells from HIV controllers (HICs), which spontaneously control HIV replication, express CD73 strongly, despite residual immune activation. Finally, we demonstrate that CD73 is involved in the HIV-specific CD8(+) T-cell expansion. Thus, we show that CD73 is central to the functionality of HIV-specific CD8(+) T cells and that the preservation of HIV-specific CD73(+)CD8(+) T cells is a characteristic of HICs. These observations reveal a novel mechanism involved in the control of viral replication.
    The Journal of Infectious Diseases 12/2013; DOI:10.1093/infdis/jit643 · 5.78 Impact Factor

Publication Stats

2k Citations
629.24 Total Impact Points


  • 2010–2015
    • University of Paris-Est
      La Haye-Descartes, Centre, France
  • 2008–2015
    • Université Paris-Est Créteil Val de Marne - Université Paris 12
      • Faculty of medicine
      Créteil, Île-de-France, France
  • 2010–2014
    • Hôpital Albert Chenevier – Hôpitaux Universitaires Henri Mondor
      Créteil, Île-de-France, France
  • 2013
    • University of Lausanne
      • Department of Medicine
      Lausanne, Vaud, Switzerland
  • 2012
    • ANRS - Agence Nationale de Recherche sur le Sida et les hépatites virales
      Lutetia Parisorum, Île-de-France, France
  • 2009–2012
    • Conservatoire National des Arts et Métiers
      Lutetia Parisorum, Île-de-France, France
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Université de Vincennes - Paris 8
      Saint-Denis, Île-de-France, France
    • Centre Hospitalier Universitaire de Nice
      Nice, Provence-Alpes-Côte d'Azur, France
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2005–2012
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      • Service de Neuroradiologie
      Créteil, Île-de-France, France
  • 2000–2012
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France
  • 2006–2009
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2006–2007
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      Lutetia Parisorum, Île-de-France, France
  • 2004
    • Pierre and Marie Curie University - Paris 6
      • Centre de recherche des Cordeliers - UMR_S 872
      Lutetia Parisorum, Île-de-France, France