Contributors: Les Laboratoires Biodim-Mutabilis; Biocitech; Institut Cochin (IC UM3 (UMR 8104 / U1016)); Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Laboratory of Experimental Virology - Department of Medical Microbiology Amsterdam, The Netherlands; Academic Medical Center - Academisch Medisch Centrum Amsterdam (AMC); University of Amsterdam Amsterdam (UvA)-University of Amsterdam Amsterdam (UvA)-Center for Infection and Immunity Amsterdam - CINIMA Amsterdam, The Netherlands; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); AIDS Research Group Barcelona, Spain; Hospital Clinic Barcelona, Spain -August Pi i Sunyer Biomedical Research Institute - IDIBAPS Barcelona, Spain; Immuno-Rhumatologie Moléculaire; Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM); Centre d'Economie de l'Université Paris Nord (CEPN); Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Centre National de la Recherche Scientifique (CNRS); Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS); Institut Cochin (UMR_S567 / UMR 8104); Institut de génétique et biologie moléculaire et cellulaire (IGBMC); Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Center for Infection and Immunity Amsterdam (CINIMA); This work was supported by Biodim Mutabilis under the Authorization Number DUO 2145, assigned by the French Ministry of Research for work with genetically modified organisms, and by Grants from EU FP7 to Biodim, BB, SE and AZ under the HIVINNOV consortium, Grant Agreement No. 305137, from the Eurostar Grant ResistAids to Biodim and BB (Grant Agreement No. E!10239) and by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01, and Instruct as part of the European Strategy Forum on Research Infrastructures (ESFRI). Felipe García team was supported by Grants SAF2015-66193-R, SAF2012-39075, Montserrat Plana by Grant FIS PI15/00480 and Nikki van Bel by NWO-CW (TOP Grant).; ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010); European Project: 305137,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIVINNOV(2012)
نبذة مختصرة : International audience ; BACKGROUND:HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells.RESULTS:Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN-LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non-treated virus. Autologous CD4+ T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable.CONCLUSIONS:Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune ...
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