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, 1% SDS) puis transférées sur une membrane PVDF (Immunobilon-P, Millipore) dans un tampon de transfert (25 mM Tris, 192 nM de glycine, SDS pH 8,3 complété avec 0,1% SDS et 20% d'éthanol) pendant 2h à 150 V ou pendant la nuit à 20 V. Les membranes sont, vol.20
, contenant 5% de lait pendant 1h sous agitation puis incubées avec l'anticorps primaire dilué dans du TBS 0,05% Tween 20 5% de lait environ 2h à température ambiante ou pendant la nuit à 4°C. Les membranes subissent 4 lavages de 10 mins dans du TBS 0,05% Tween, p.20
, puis elles sont incubées avec l'anticorps secondaire couplé à la peroxydase HRP correspondant, également dilué dans du TBS 0,05% Tween 20 5% de lait, pendant 45 mins à température ambiante
, Les anticorps primaires suivant ont été utilisés en western blot pour reconnaitre les épitopes viraux du VIH-1 : anticorps monoclonal de souris anti-CAp24 VIH-1 Gag (ARP366 ; National Institute for Biotechnology), anticorps de lapin anti-RT VIH-1 (NIH), anticorps monoclonal de souris anti-IN VIH-1
, anticorps monoclonal de souris anti-Env TMgp41 (41A, Hybridolab) et anticorps monoclonal de souris anti-Env VIH-1
, SUgp120 (110H ; Hybridolab)
, Pour reconnaitre les épitopes du SIV nous avons utilisés : anticorps monoclonal de souris anti-CAp27 SIV Gag (KK64 ; NIH), anticorps monoclonal de souris anti-gp120 SIV
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, Les anticorps secondaires contre les immunoglobulines G couplées à l'HRP de souris (Polyclonal Rabbit anti-Mouse Immunoglobulins/HRP) ou de lapin (Polyclonal Swine antiRabbit Immunoglobulins/HRP) de chez Dako sont utilisés pour les western blot
, La protéine GST-LEDGF a été produite et purifiée à l'IGBMC (Marc Ruff)
, Le plasmide codant pour la protéine recombinante His-IN VIH
, Le plasmide codant pour la protéine IN-His SIVmac 239 nous a été donné par P
, nous tentons de développer des virus SIV porteurs de mutations « humanisées » sur l'IN afin d'étudier si le phénotype des INLAIs sur le VIH-1 peut ainsi être restauré contre le SIV. Pour l'instant, aucun des mutants que nous avons produits n'est assez infectieux pour envisager ce type d'étude. Une autre possibilité serait d'utiliser un virus chimérique SHIV (Simiain/Human immunodeficiency virus) contenant uniquement l'IN du VIH-1 comme contrôle positif, Nous avons réalisé des expériences préliminaires en produisant un stock de virus chimérique SHIV contenant les gènes codants pour la RT et l'IN du VIH-1 insérés dans un génome viral SIV
, Sachant que la liaison de l'IN à l'ARNv génomique décrite par Kessl et al. affiche une haute sélectivité pour des éléments de structure d'ARN spécifiques sur l'ensemble du génome viral dont les séquences TAR et RRE [442], nous pourrions essayer de déterminer si ces régions sur l'ARNv simien peuvent permettre son interaction avec l'IN SIV. En effet, le SIV est plus proche génétiquement du VIH-2 qui possède une structure TAR très différente de celle du VIH-1 ainsi la fixation de l'IN sur la séquence TAR de l'ARNv pourrait donc être différente selon les lentivirus. La comparaison des éléments structurels d'ARN sur le génome viral VIH-1 et SIV et de leur affinité pour l, Par la suite, il serait donc intéressant de chercher à caractériser l'activité réduite des INLAIs sur les étapes tardives de la réplication du SIV
, ARNv ont pu être identifiés [442] et leur mutation compromet l'interaction IN-ARNv sans affecter d'autres fonctions connues de l'IN ce qui induit la production de virions eccentriques non infectieux. En addition de la comparaison des résidus impliqués dans la fixation des INLAIs sur le dimère CCD-CCD IN, il serait donc intéressant d'étudier les différences de séquences entre IN VIH-1 et, De plus, certains résidus sur le domaine CTD de l'IN du VIH-1 impliqués dans son interaction avec l
, Ainsi l'analyse de l'effet des INLAIs sur SIV
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, Les inhibiteurs catalytiques d'IN (INSTIs) utilisés dans les ART ciblent le site actif de l'enzyme et empêchent ainsi la réaction de transfert de brin de l'intégration du VIH-1. La protéine cellulaire Lens Epithelium-Derived Growth Factor (LEDGF/p75), liée à la chromatine, est l'un des principaux cofacteurs de IN. En permettant le ciblage de l'intégration dans des régions actives du génome de l'hôte, l'interaction IN-LEDGF joue un rôle crucial pour la réplication effective du VIH-1 ce qui, L'émergence et la transmission de virus multirésistants à l'ensemble des ARV illustrent la nécessité de développer de nouveaux mécanismes thérapeutiques
, En effet les INLAIs ciblent l'intégration mais possèdent également une seconde activité plus efficace sur les étapes tardives de la réplication du VIH-1. Celle-ci se traduit par la production de virions présentant un défaut d'infectivité. Mon projet de thèse, réalisé en partenariat avec la société biopharmaceutique Mutabilis, s'est intéressé à la caractérisation de l'activité antirétrovirale d'une nouvelle classe d'INLAIs selon deux axes: (1) l'approfondissement des mécanismes d'action de ces INLAIs sur les étapes tardives de la réplication du VIH-1, Au cours de ces dernières années, des inhibiteurs allostériques de l'interaction IN-LEDGF (INLAIs encore appelés LEDGINs ou ALLINIs) ont été développés afin d'inhiber l'étape d'intégration
, Nous avons également évalué l'effet des INLAIs sur la réplication du SIV. Des expérimentations in vitro ont permis de montrer que certaines INLAIs inhibent efficacement l'interaction IN-LEDGF mais n'induisent pas la multimérisation anormale de IN SIV contrairement à ce que nous observons pour IN VIH-1. Ces résultats ont été confirmés in vivo et indiquent que si certaines INLAIs de seconde génération montrent une activité antirétrovirale au cours des étapes précoces, elles ne sont pas capables d'inhiber efficacement les étapes tardives de la réplication du SIV, J'ai pu montrer que les virions produits en présence d'INLAIs développées par Mutabilis présentent un défaut de transcription inverse lors de l'infection des cellules cibles, qui les rend non infectieux. Ces molécules n'influencent pas les étapes tardives de maturation protéique et d'empaquetage de l'ARN du VIH-1 dans les virions
, Mes travaux ont donc permis de mettre en évidence que les virions "inactivés" par ces INLAIs pourraient représenter un nouveau type d'immunogènes pour l'établissement d'une réponse immunitaire anti VIH-1. Cependant l'étude du spectre d'activité suggère que bien que la capacité de certaines INLAIs à inhiber l'interaction IN-LEDGF/p75 semble relativement bien conservée entre le VIH-1 et SIV