Ce projet avait comme but principal d'identifier de nouvelles protéines pouvant réguler le VIH-1 chez les macrophages primaires. Étant l'un des réservoirs viraux persistants chez les personnes infectées, il est important d'étudier l'établissement de l'infection chez ce type cellulaire et de trouver de nouvelles protéines pouvant être une cible thérapeutique potentielle.
Le criblage de petits ARN interférents a très bien fonctionné chez les MDMs. Bien que chaque donneur réagit différemment à l'infection, le knock-down de plusieurs gènes a modulé l'infection virale efficacement. Sur les cinquante gènes testés, cinq protéines ont été identifiées comme des régulateurs négatifs de l'infection, dont trois qui n'étaient pas connues pour intervenir dans le cycle infectieux du VIH-1. Une autre protéine testée a été identifiée comme un régulateur positif et deux autres ont eu des résultats contradictoires dépendamment de la séquence de siRNA utilisée. Cette étude a permis de constater que plusieurs voies bien distinctes influencent la réplication virale chez le macrophage humain, que ce soit des protéines impliquées dans le métabolisme des lipides ou dans la réparation de l'ADN. Bien que certaines protéines ayant ressorti du criblage ont déjà été étudiées dans le contexte du VIH-1 (ex. ADAR1, APOBEC3B, ATM, MDM2 et OAS1), celles-ci ne l'étaient pas nécessairement dans l'environnement cellulaire des macrophages.
Notre attention s'est plutôt portée sur les protéines peu étudiées dans l'infection des MDMs. Nous avons sélectionné quatre gènes pour pousser les études plus loin. Tout d'abord, le gène MDM2 est déjà connu pour réguler l'infection, mais la littérature montre des effets positifs et négatifs sur celle-ci. Étant notre seul gène identifié comme régulateur positif de l'infection, nous avons choisi d'enquêter plus en profondeur sur son rôle exact. Nous avons montré que le siRNA n'avait pas de toxicité sur les cellules et que le knock-down de MDM2 diminuait l'infection. L'expérience a été testée avec plusieurs modèles viraux et l'effet a été remarqué autant au niveau de l'expression du gène rapporteur que pour la production de nouvelles particules virales. Comme nous avons remarqué un effet indirect de MDM2 sur la réplication virale, nous dirigerons nos études futures vers l'identification des protéines intermédiaires interagissant avec le VIH-1 et trouver laquelle des étapes du cycle viral est affectée par celle-ci. Il est probable que ce soit au niveau de l'intégration du génome viral
60
vu l'importance de MDM2 dans le cycle cellulaire, donc l'activité des sentiers de réparation de l'ADN et de régulation du cycle cellulaire en réponse au VIH-1 devra être étudiée plus en détail.
Trois protéines régulant négativement l'infection et qui sont totalement inconnues dans le contexte du VIH-1 vont aussi être les sujets d'études plus poussées. La première est FABP9, une protéine liant les acides gras. Considérant la nature de l'enveloppe virale, il est possible que cette protéine interagisse avec cette composante du virion. La deuxième protéine, GGH, est plutôt impliquée dans le métabolisme de l'acide folique et la disponibilité du glutamate, une molécule présente en grande quantité dans le plasma de patients infectés. Son impact sur la régulation du glutamate sera étudié et possiblement une corrélation avec le taux d'infection sera observée. Finalement, LOXL3 montre aussi une restriction de l'infection. Cette lysyl oxydase pourrait agir à plusieurs étapes du cycle viral et affecte peut-être la stabilité des protéines du VIH-1. Ces trois protéines sont des facteurs de restriction potentiels, mais des études complexes devront être effectuées avant de pouvoir les classer dans cette catégorie, comme prouver que le virus possède une protéine interférant avec l'un de nos facteurs de restriction potentiels ou montrer que l'évolution a favorisé l'activité antivirale du gène.
Ce projet a donc permis de mieux comprendre les facteurs de l'hôte jouant un rôle dans l'infection par le VIH-1 chez les macrophages humains et a réussi son but premier: huit protéines ont été identifiées comme des régulateurs de l'infection et quatre d'entre elles vont être étudiées plus en détail. Par contre, avant d'aller plus loin, il faudra identifier à quelle étape du cycle viral chacune de ces protéines agit pour planifier les expérimentations plus complexes. De plus, chacun de nos gènes testés provient d'une analyse transcriptomique nous ayant montré que ces gènes sont plus ou moins fortement exprimés dans les cellules infectées que dans les cellules ayant résisté à l'infection. Nous devrons donc déterminer si c'est l'infection qui module l'expression du gène ou si le virus infecte préférentiellement les macrophages exprimant un niveau inhabituel de la protéine.
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