Aude Garcel
Centre national de la recherche scientifique
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Featured researches published by Aude Garcel.
Retrovirology | 2015
Noëlie Campos; Renier Myburgh; Aude Garcel; Audrey Vautrin; Laure Lapasset; Erika Schläpfer Nadal; Florence Mahuteau-Betzer; Romain Najman; Pauline Fornarelli; Katjana Tantale; Eugenia Basyuk; Martial Seveno; Julian P. Venables; Bernard Pau; Edouard Bertrand; Mark A. Wainberg; Roberto F. Speck; Didier Scherrer; Jamal Tazi
BackgroundCurrent therapies have succeeded in controlling AIDS pandemic. However, there is a continuing need for new drugs, in particular those acting through new and as yet unexplored mechanisms of action to achieve HIV infection cure. We took advantage of the unique feature of proviral genome to require both activation and inhibition of splicing of viral transcripts to develop molecules capable of achieving long lasting effect on viral replication in humanized mouse models through inhibition of Rev-mediated viral RNA biogenesis.ResultsCurrent HIV therapies reduce viral load during treatment but titers rebound after treatment is discontinued. We devised a new drug that has a long lasting effect after viral load reduction. We demonstrate here that ABX464 compromises HIV replication of clinical isolates of different subtypes without selecting for drug resistance in PBMCs or macrophages. ABX464 alone, also efficiently compromised viral proliferation in two humanized mouse models infected with HIV that require a combination of 3TC, Raltegravir and Tenofovir (HAART) to achieve viral inhibition in current protocols. Crucially, while viral load increased dramatically just one week after stopping HAART treatment, only slight rebound was observed following treatment cessation with ABX464 and the magnitude of the rebound was maintained below to that of HAART for two months after stopping the treatment. Using a system to visualize single HIV RNA molecules in living cells, we show that ABX464 inhibits viral replication by preventing Rev-mediated export of unspliced HIV-1 transcripts to the cytoplasm and by interacting with the Cap Binding Complex (CBC). Deep sequencing of viral RNA from treated cells established that retained viral RNA is massively spliced but importantly, normal cellular splicing is unaffected by the drug. Consistently ABX464 is non-toxic in humans and therefore represents a promising complement to current HIV therapies.ConclusionsABX464 represents a novel class of anti-HIV molecules with unique properties. ABX464 has a long lasting effect in humanized mice and neutralizes the expression of HIV-1 proviral genome of infected immune cells including reservoirs and it is therefore a promising drug toward a functional cure of HIV.
Vaccine | 2009
Aude Garcel; Julien Perino; Jean-Marc Crance; Robert Drillien; Daniel Garin; Anne-Laure Favier
As an initial step in the development of a second-generation smallpox vaccine derived from the Lister strain, to be prepared for a variola virus threat, diversity of the traditional vaccine was examined by characterizing a series of ten viral clones. In vitro and in vivo phenotypic studies showed that the biological behavior of the clones diverged from each other and in most cases diverged from the vaccinia virus (VACV) Lister parental population. Taken together, these results demonstrate the heterogeneity of the viral population within the smallpox vaccine and highlight the difficulty in choosing one clone which would meet the current requirements for a safe and effective vaccine candidate.
Vaccine | 2012
Aude Garcel; William Fauquette; Marie-Pierre Dehouck; Jean-Marc Crance; Anne-Laure Favier
Smallpox vaccination is the only currently effective mean to combat the threat of variola virus used as a bioterrorism agent, although it is responsible for a rare but serious complication, the postvaccinal encephalitis (PVE). Development of safer vaccines therefore is a high priority as the PVE physiopathology is not well understood to date. If vaccinia virus (VACV) is responsible for PVE by central nervous system (CNS) dissemination, trans-migration of the VACV across the blood-brain barrier (BBB) would be supposed to be essential. Given the complexity of the pathogenesis of vaccinia neurovirulence, an in vitro BBB model was used to explore the mechanism of VACV to induce BBB permeability. Two VACV strains were studied, the neurovirulent Western Reserve strain (VACV-WR) and the vaccine reference Lister strain (VACV-List). A mouse model was also developed to study the ability of these two viral strains to propagate in the brain from the blood compartment, their neurovirulence and their neuropathogenesis. In vitro, the loss of permeability resulted from the tight-junctions disruption was induced by virus replication. The ability of VACV to release infectious particles at the abluminal side suggests the capacity of both VACV strains to migrate across the BBB from the blood to the CNS. In vivo, the virus replication in mice CNS was strain-dependent. The VACV-WR laboratory strain proved to be neuroinvasive and neurovirulent, whereas the VACV-List strain is safe in physiological conditions. Mice PVE was observed only with VACV-WR in the co-infection model, when BBB opening was obtained by lipopolysaccharide (LPS) treatment. This study suggests that VACV is able to cross the BBB but encephalitis occurs only in the presence of a co-infection by bacteria. So, a model of co-infection, mimicked by LPS treatment, could have important implication towards the assessment of neurovirulence of new vaccines.
Scientific Reports | 2017
Karim Chebli; Laura Papon; Conception Paul; Aude Garcel; Noëlie Campos; Didier Scherrer; Hartmut J. Ehrlich; Michael Hahne; Jamal Tazi
The progression of human immunodeficiency virus (HIV) is associated with mucosal damage in the gastrointestinal (GI) tract. This damage enables bacterial translocation from the gut and leads to subsequent inflammation. Dextran sulfate sodium (DSS-exposure) is an established animal model for experimental colitis that was recently shown to recapitulate the link between GI-tract damage and pathogenic features of SIV infection. The current study tested the protective properties of ABX464, a first-in-class anti-HIV drug candidate currently in phase II clinical trials. ABX464 treatment strongly attenuated DSS-induced colitis in mice and produced a long-term protection against prolonged DSS-exposure after drug cessation. Consistently, ABX464 reduced the colonic production of the inflammatory cytokines IL-6 and TNFα as well as that of the chemoattractant MCP-1. However, RNA profiling analysis revealed the capacity of ABX464 to induce the expression of IL-22, a cytokine involved in colitis tissue repair, both in DSS-treated mice and in LPS-stimulated bone marrow-derived macrophages. Importantly, anti-IL-22 antibodies significantly reduced the protective effect of ABX464 on colitis in DSS-treated mice. Because reduced IL-22 production in the gut mucosa is an established factor of HIV and DSS-induced immunopathogenesis, our data suggest that the anti-inflammatory properties of ABX464 warrant exploration in both HIV and inflammatory ulcerative colitis (UC) disease.
Scientific Data | 2017
Laurent Manchon; Karim Chebli; Laura Papon; Conception Paul; Aude Garcel; Noëlie Campos; Didier Scherrer; Hartmut J. Ehrlich; Michael Hahne; Jamal Tazi
RNA-Seq enables the generation of extensive transcriptome information providing the capability to characterize transcripts (including alternative isoforms and polymorphism), to quantify expression and to identify differential regulation in a single experiment. To reveal the capacity of new anti-HIV ABX464 candidate in modulating the expression of genes, datasets were generated and validated using RNA-seq approach. This comprehensive dataset will be useful to deepen the comprehensive understanding of the progression of human immunodeficiency virus (HIV) associated with mucosal damage in the gastrointestinal (GI) tract and subsequent inflammation, providing an opportunity to generate new therapies, diagnoses, and preventive strategies.
Archive | 2010
Jamal Tazi; Florence Mahuteau; Romain Najman; Didier Scherrer; Noëlie Campos; Aude Garcel
Journal of General Virology | 2007
Aude Garcel; Jean-Marc Crance; Robert Drillien; Daniel Garin; Anne-Laure Favier
Archive | 2015
Jamal Tazi; Florence Mahuteau-Betzer; Romain Najman; Didier Scherrer; Noëlie Campos; Aude Garcel
Archive | 2014
Jamal Tazi; Didier Scherrer; Aude Garcel; Noëlie Campos; Romain Najman; Florence Mahuteau-beyzer
Archive | 2015
Jamal Tazi; Didier Scherrer; Aude Garcel; Noëlie Campos; Romain Najman; Florence Mahuteau-Betzer