Immunothérapie de l’infection par le VIH par l’utilisation de cytokines : Un état des lieux

Les stratégies d’immunothérapie de l’infection par le VIH utilisant des cytokines ont pour objectifs d’interférer avec les mécanismes de dérégulation de l’homéostasie lymphocytaire T induits par le virus, de potentialiser les effets des antiviraux sur la restauration immunitaire et de mobiliser les réservoirs du virus. Les interleukines 2 et 7 (IL-2 et IL-7) sont les cytokines les plus prometteuses. Un bénéfice clinique potentiel de ces stratégies est l’arrêt des traitements antiviraux, dont la toxicité à long terme est une préoccupation majeure. Par ailleurs, les effets d’une telle immuno-intervention sur la régulation de l’homéostasie lymphocytaire T ou sur les fonctions immunologiques en présence du VIH nous renseignent également sur la physiopathologie de l’infection.The theoretical objectives of cytokine therapies in HIV infection are to impact T cell homeostasis and/or to improve immune functions or the mobilization of the HIV reservoir. Among cytokines, IL-2 and IL-7 are promising agents under clinical evaluation. Intermittent administration of IL-2 is by far the furthest studied strategy in HIV infection. This cytokine increases CD4 T lymphocytes in HIV-infected individuals. Recent clinical data showed that this effect is sustained over years. IL-2 therapy induces a peripheral expansion of T cells as a consequence of prolonged survival of T cells and decreased immune activation. These effects suggest that a cytokine therapy may interfere with critical factors of HIV disease. Recent data provide arguments that IL-2 therapy improves immune functions in HIV-infected patients. Whether these effects may be translated into clinical benefits is under evaluation in ongoing phase III studies. The potential interest of IL-7 in the treatment of HIV-infection is based on its crucial role on T cell homeostasis both in thymic output and peripheral T proliferation and survival. Although no data in human are still available, recent studies provide arguments to assess this cytokine in HIV infection. Phase I studies are ongoing or planned

Role of regulatory T cells in the pathogenesis of HIV-1 infection

International audiencen.

Immunotherapy in HIV infection; current and future challenges

International audiencen.

T-regulatory cells and vaccination “pay attention and do not neglect them”: Lessons from HIV and cancer vaccine trials

Efficient vaccines are characterized by the establishment of long-lived memory T cells, including T-helper (effectors and follicular) and T-regulatory cells (Tregs). While the former induces cytotoxic or antibody responses, the latter regulates immune responses by maintaining homeostasis. The role of Tregs in inflammatory conditions is ambiguous and their systematic monitoring in vaccination along with effector T-cells is not instinctive. Recent studies from the cancer field clearly showed that Tregs suppress vaccine-induced immune responses and correlate with poor clinical benefit. In HIV infection, Tregs are needed during acute infection to preserve tissue integrity from an overwhelmed activation, but are not beneficial in chronic infection as they suppress anti-HIV responses. Current assays used to evaluate vaccine-induced specific responses are limited as they do not take into account antigen-specific Tregs. However, new assays, such as the OX40 assay, which allow for the simultaneous detection of a full range of Th-responses including antigen-specific Tregs responses, can overcome these issues. In this review article we will revise the role of Tregs in vaccination and review the recent work performed in the field, including the available tools to monitor them, from novel assays to humanized mouse models

Construction of continuous functions with prescribed local regularity

International audienceIn this work we investigate both from a theoretical and a practical point of view the following problem: Let s be a function from [0;1] to [0;1]. Under which conditions does there exist a continuous function f from [0;1] to IR such that the regularity of f at x, measured in terms of Hölder exponent, is exactly s(x), for all x [0;1]? We obtain a necessary and sufficient condition on s and give three constructions of the associated function f. We also examine some extensions, as for instance conditions on the box or Tricot dimension or the multifractal spectrum of these functions. Finally we present a result on the "size" of the set of functions with prescribed local regularity

Construction of Continuous Functions with Prescribed Local Regularity

Projet FRACTALESIn this work we investigate both from a theoretical and a practical point of view the following problem¸: Let $s$ be a function from $[0¸;1]$ to $[0¸;1]$. Under which conditions does there exist a continuous function $f$ from $[0¸;1]$ to \RR such that the regularity of $f$ at $x$, measured in terms of Hölder exponent, is exactly $s(x)$, for all $x \in [0¸;1]$¸? \\ We obtain a necessary and sufficient condition on $s$ and give three constructions of the associated function $f$. We also examine some extensions regarding, for instance, the box or Tricot dimension or the multifractal spectrum. Finally we present a result on the «size» of the set of functions with prescribed local regularity

IL-2 immunotherapy in chronically SIV-infected Rhesus Macaques

BACKGROUND: Despite inducing a sustained increase in CD4+ T cell counts, intermittent recombinant IL-2 (rIL-2) therapy did not confer a better clinical outcome in HIV-infected patients enrolled in large phase III clinical trials ESPRIT and SILCAAT. Several hypotheses were evoked to explain these discrepancies. Here, we investigated the impact of low and high doses of IL-2 in Rhesus macaques of Chinese origin infected with SIVmac251 in the absence of antiretroviral therapy (ART). RESULTS: We demonstrated that rIL-2 induced a dose dependent expansion of CD4+ and CD8+ T cells without affecting viral load. rIL-2 increased CD4 and CD8 Treg cells as defined by the expression of CD25(high)FoxP3(+)CD127(low). We also showed that rIL-2 modulated spontaneous and Fas-mediated CD4(+) and CD8(+) T cell apoptosis. The higher dose exhibited a dramatic pro-apoptotic effect on both CD4(+) and CD8(+) T cell populations. Finally, all the animals treated with rIL-2 developed a wasting syndrome in the month following treatment simultaneously to a dramatic decrease of circulating effector T cells. CONCLUSION: These data contribute to the understanding of the homeostatic and dosage effects of IL-2 in the context of SIV/HIV infection

Durable natural killer cell responses after heterologous two-dose Ebola vaccination

Natural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2. Here, in a multicentre, phase 2 clinical trial (EBL2001), we demonstrate durable ex vivo NK cell activation 180 days after dose 2, with responses enriched in CD56(bright) NK cells. In vitro antibody-dependent responses to immobilised Ebola GP increased after dose 1, and remained elevated compared to pre-vaccination levels in serum collected 180 days later. Peak NK cell responses were observed post-dose 2 and NK cell IFN-γ responses remained significantly elevated at 180 days post-dose 2. Individual variation in NK cell responses were influenced by both anti-Ebola GP antibody concentrations and intrinsic interindividual differences in NK cell functional capacity. In summary, this study demonstrates durable NK cell responses after Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccination and could inform the immunological evaluation of future iterations of the vaccine regimen and vaccination schedules

Mission sur l’écosystème de la recherche et de l’innovation 14 propositions pour engager le processus de rénovation et de simplification de l’écosystème national Rapport à Madame la Ministre de l’Enseignement supérieur et de la Recherche

Mme la Ministre Sylvie Retailleau a confié à M. Philippe Gillet cette mission par lettre en date du 1er décembre 2022 (voir annexe). Après une phase de cadrage, les travaux ont été menés par l’ensemble du groupe de travail composé de Mmes Christine Cherbut et Véronique Perdereau et MM. Yves Caristan et Patrick Lévy de janvier à mai 2023. Les membres de la mission ont été appuyés par un inspecteur général de l’éducation, du sport et de la recherche, M. Charles Persoz. Cette mission s’est inscrite dans un contexte évolutif : la LPR a eu des conséquences récentes, plusieurs programmes stratégiques ont été initiés quelques mois ou quelques semaines avant le démarrage de la mission, comme les PEPR, les PUI, le programme de recherche à risque

Sign Reversals of ac Magnetoconductance in Isolated Quantum Dots

We have measured the electromagnetic response of micron-size isolated mesoscopic GaAs/GaAlAs square dots down to temperature T=16mK, by coupling them to an electromagnetic micro-resonator. Both dissipative and non dissipative responses exhibit a large magnetic field dependent quantum correction, with a characteristic flux scale which corresponds to a flux quantum in a dot. The real (dissipative) magnetoconductance changes sign as a function of frequency for low enough density of electrons. The signal observed at frequency below the mean level spacing corresponds to a negative magnetoconductance, which is opposite to the weak localization seen in connected systems, and becomes positive at higher frequency. We propose an interpretation of this phenomenon in relation to fundamental properties of energy level spacing statistics in the dots.Comment: 4 pages, 4 eps figure