Yves Lévy

Hôpital Albert Chenevier – Hôpitaux Universitaires Henri Mondor, Créteil, Île-de-France, France

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Publications (103)556.28 Total impact

  • 12/2014;
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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; · 4.58 Impact Factor
  • AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1:A245. · 2.46 Impact Factor
  • AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1:A173-4. · 2.46 Impact Factor
  • AIDS Research and Human Retroviruses 10/2014; 30 Suppl 1:A189-90. · 2.46 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; · 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;
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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; · 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; · 5.36 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 07/2014; · 4.52 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. · 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. · 3.96 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 04/2014; · 4.52 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. · 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; · 5.85 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) have emerged as critical regulators of gene expression within cells. One particular miRNA, miR-155 is highly expressed within lymphocytes (both B and T cells) and mediates a number of important roles. These include shaping the transcriptome of lymphoid cells that control diverse biological functions vital in adaptive immunity. The use of mice engineered to be deficient in miR-155, as well as the identification of endogenous targets of miR-155 in T-cells by transcriptome-wide analysis, has helped unravel the crucial role this miRNA plays in fine tuning the regulation of lymphocyte subsets such as B cells, CD8(+) and CD4(+) T cells ranging from Th1, Th2, Th17 and regulatory T cells. In this review, we summarize what we have learned about miR-155 in the regulation of lymphocyte responses at the cellular and molecular level and in particular, we focus on the recent findings that demonstrate miR-155 shapes the balance between tolerance and immunity. This article is protected by copyright. All rights reserved.
    Immunology 12/2013; · 3.74 Impact Factor
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    ABSTRACT: The heterogeneity of human regulatory T cells (Tregs) may explain the discrepancies between studies on Tregs in physiology and pathology. Contrasting effects of IL-7 on the expansion and survival of human Tregs were reported. Therefore, we investigated the effects of IL-7 on the phenotype and function of well-characterized populations of human Tregs. We show that IL-7 signals via the CD127 receptor on naive, memory, and activated memory Tregs sorted from the blood of healthy donors, but it does not affect their proliferation. In contrast, IL-7 affects their suppressive capacities differently. This effect was modest on naive Tregs but was dramatic (90%) on memory Tregs. We provide evidence that IL-7 exerts a synergistic effect through downmodulation of the ectoenzyme CD39, which converts ATP to ADP/AMP, and an increase in ATP receptor P2X7. Both effects lead to an increase in the ATP-mediated effect, tipping the balance to favor Th17 conversion. Using an IL-7 therapeutic study, we show that IL-7 exerts the same effects in vitro and in vivo in HIV-infected individuals. Globally, our data show that IL-7 negatively regulates Tregs and contributes to increase the number of tools that may affect Treg function in pathology.
    The Journal of Immunology 08/2013; · 5.36 Impact Factor
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    ABSTRACT: We have shown that the intradermal (ID) administration of an HIV-1 lipopeptide candidate vaccine (LIPO-4) is well tolerated in healthy volunteers, with one fifth the IM dose delivered by this route inducing HIV-1-specific CD8(+) T-cell responses of a magnitude and quality similar to those achieved by IM administration. In this long-term follow-up, we aimed to investigate the sustainability and epitopic breadth of the immune responses induced. In a prospective multicentre trial, 68 healthy volunteers were randomised to receive, at weeks 0, 4 and 12, either a 0.5ml IM (500μg of each lipopeptide; 35 volunteers) dose or a 0.1ml ID (100μg of each lipopeptide; 33 volunteers) dose of the LIPO-4 vaccine, in the deltoid region of the non-dominant arm. All 68 volunteers received the first two vaccinations, and 44 volunteers in the ID group and 22 in the IM group received the third. We describe here the long-term CD8(+) and CD4(+) T-cell immune responses, up to 48 weeks after the first immunisation. Response frequency was highest at week 14 for CD4(+) T cells, at 85% (28/33) for the IM group and 61% (20/33) for the ID group (p=0.027), and at week 48 for CD8(+) T cells, at 36% (12/33) for the ID group and 31% (11/35) for the IM group (p=0.67). Response rates tended to be lower for volunteers receiving the third vaccination boost, whether IM or ID. Finally, we also observed a striking change in the specificity of the CD8(+) T-cell responses induced shortly (2 weeks) or several months (48 weeks) after LIPO-4 vaccination. Lipopeptide vaccines elicited sustainable CD4(+) and CD8(+) T-cell responses, following IM or ID administration. CD8(+) T-cell responses had shifted and expanded to different epitopes after one year of follow-up. These results should facilitate the design of the next generation of prime-boost trials with repeated doses of lipopeptide vaccines.
    Vaccine 07/2013; · 3.49 Impact Factor
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    ABSTRACT: Background: 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 (DC). The 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 infect DC and to prime T cells. However, whether or not MVAHIV-infected DC are able to induce anti-HIV specific NK cell activity remains undetermined. Methods: DC were infected by MVAHIV, or MVAWT vector as control, and co-cultured with autologous NK cells for 4 days. Then, NK cells were transferred to a plate containing recently infected DC or CD4+ T cells, and p24 production was determined at days 7 and 10 post-infection by ELISA test and flow cytometry. The implication of NK cell receptors NKG2D and NKp46, and membrane-bound IL-15 (mbIL-15) on MVA-infected DC, during the priming of NK cells was determined by using blocking mAbs. Results: We found that NK cells primed by MVAHIV-infected DC are significantly better at controlling HIV-1 replication in autologous DC and CD4+ T cells as compared to those primed by MVAWT-infected DC. The specificity of anti-HIV NK cell activity was determined by measuring the NK cell activity against CMV-infected DC and target cells. In depth analysis of the priming showed that blockade of NKG2D and NKp46 during the priming induced decreased and increased anti-HIV-1 NK cell activity, respectively. Blockade of NKG2D during priming of NK cells by MVAHIV-infected DC endowed NK cells with a particular NK cell receptor repertoire, with a marked decreased expression of activating receptors, and resulted in lower expression of mbIL-15 on MVA-infected DC; whereas blockade of NKp46 resulted in increased expression of mbIL-15 on MVA-infected DC. Conclusions: These data demonstrate that the MVAHIV vaccine candidate is able to induce a specific anti-HIV-1 NK cell activity following their interaction with MVAHIV-infected DC, and that the acquisition of such antiviral activity relies on a modulated crosstalk involving NKG2D and NKp46 on NK cells and the regulation of mbIL-15 on infected DC.
    7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 07/2013
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    ABSTRACT: OBJECTIVE:: To dissect the biological mechanisms involved in the cellular responses to a candidate vaccine containing 5 HIV peptides coupled to a palmytoil tail (HIV-LIPO-5) in healthy volunteers, by using extensive immunogenicity assessments with different stimulation durations. DESIGN:: Immunogenicity substudy of a randomized phase II prophylactic HIV vaccine trial (ANRS VAC 18). METHODS:: HIV-LIPO-5 or placebo was administered at W0, W4, W12 and W24. Peripheral blood mononuclear cells from a subset of participants at W0 and W14 were stimulated with HIV-LIPO-5, Gag peptides contained in the vaccine and control peptides. ELISpot, lymphoproliferation, intracellular cytokine staining (ICS), cytokine multiplex and transcriptomic analyses were performed. Different time points and stimulation conditions were compared, controlling for test multiplicity. RESULTS:: Cultured ELISpot and lymphoproliferation responses were detected at W14. Ex-vivo ICS showed mainly interleukin (IL)-2-producing cells. Secretion of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, IL-5 and IL-13 increased significantly after culture and Gag stimulation at W14 compared to W0. Metallothionein genes were consistently overexpressed after HIV-LIPO-5 stimulation at W0 and W14. At W14, significant probes increased substantially, including IFN-γ, CXCL9, IL2RA, TNFAIP6, CCL3L1 and IL-6. Canonical pathway analyses indicated a role of interferon signalling genes in response to HIV-LIPO-5. CONCLUSION:: HIV-LIPO-5 vaccination elicited Th1 and Th2 memory precursor responses and a consistent modulation in gene expression. The response profile before vaccination suggests an adjuvant effect of the lipid tail of HIV-LIPO-5. Our combined immunogenicity analyses allowed to identify a specific signature profile of HIV-LIPO-5 and indicate that HIV-LIPO-5 could be further developed as a prime in heterologous prime-boost strategies.
    AIDS (London, England) 06/2013; 27(9):1421-1431. · 6.56 Impact Factor

Publication Stats

2k Citations
556.28 Total Impact Points


  • 2012–2014
    • Hôpital Albert Chenevier – Hôpitaux Universitaires Henri Mondor
      Créteil, Île-de-France, France
  • 2010–2014
    • University of Paris-Est
      Centre, France
  • 2009–2014
    • Université Paris-Est Créteil Val de Marne - Université Paris 12
      Créteil, Île-de-France, France
    • Université de Vincennes - Paris 8
      Saint-Denis, Île-de-France, France
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2008–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2013
    • Armed Forces Biomedical Research Institute, France
      Bretigny, Île-de-France, France
    • 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
  • 2005–2012
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      Créteil, Île-de-France, France
  • 2011
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France
  • 2009–2010
    • Centre Hospitalier Universitaire de Nice
      Nice, Provence-Alpes-Côte d'Azur, France
    • Institut de Génétique Moléculaire de Montpellier
      Montpelhièr, Languedoc-Roussillon, France
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
  • 2000–2010
    • French Institute of Health and Medical Research
      • Centre de Recherche des Cordeliers U872
      Lutetia Parisorum, Île-de-France, France
  • 2004–2005
    • Pierre and Marie Curie University - Paris 6
      • Centre de recherche des Cordeliers - UMR_S 872
      Lutetia Parisorum, Île-de-France, France