Conclusion et Perspectives

Au cours de ce travail, nous avons pu étudier la résistance du VHC à des CBA in vitro. La sélection positive induite par les lectines a engendré une modification de l’organisation des N-glycanes, en ciblant deux sites de N-glycosylation. Puisqu’aucune mutation de résistance aux CBA n’a pu être identifiée, la barrière génétique de résistance à une telle stratégie thérapeutique semble forte pour le VHC. Contrairement au VIH, les N-glycanes du VHC sont fortement conservés et les décalages des sites de N-glycosylation sont rarement retrouvés. En outre, la majorité des N-glycanes portés par les protéines d’enveloppe joue un rôle important pour la survie du virus. Par conséquent, l’adaptation du VHC à une pression de sélection exercée par des CBA pourrait être plus difficile que dans le cas du VIH.

A notre connaissance, la résistance virale aux CBA a seulement été évaluée sur des souches de VIH, caractérisées par un bouclier glycanique malléable. Donc, nos résultats apportent de nouvelles connaissances dans le développement d’une stratégie antivirale basée sur les CBA puisqu’ils confirment la haute barrière génétique de résistance vis-à-vis des CBA du VHC possédant des sites de N-glycosylation conservés.

Puisqu’aucune mutation de résistance aux CBA n’a été sélectionnée dans notre étude, nous ne pouvons envisager la théorie de Balzarini. Néanmoins, nous projetons d’étudier l’effet des mutations sélectionnées sur la sensibilité vis-à-vis d’anticorps monoclonaux neutralisants et d’anticorps polyclonaux purifiés à partir de sera de patients séropositifs pour le VHC ainsi que d’une forme soluble du récepteur CD81.

Face à l’émergence récente de nombreuses molécules ciblant directement les protéines virales NS3/4A, NS5A ou NS5B, les CBA, et plus généralement les inhibiteurs de l’entrée virale, ne sont pas susceptibles de trouver une indication dans le traitement contre l’infection par le VHC (579). Cependant, en raison du coût, l’accès aux DAA pourrait être freiné (580), notamment dans les pays émergents. De plus, environ 30 % des patients infectés par le VIH sont co-infectés par le VHC (581, 582). Chez ces patients, une progression plus rapide de l’hépatite et un risque plus important d’apparition d’une hépatotoxicité suite à l’initiation d’une thérapie antirétrovirale sont fréquemment reportés (581). Le développement de thérapies basées sur l’utilisation de CBA, efficaces contre les deux virus, pourrait être une alternative intéressante pour la prise en charge de ces patients. Les CBA pourraient également être utilisés comme inhibiteurs d’entrée chez des patients

transplantés hépatiques infectés par le VHC, en prévention de la réinfection du greffon (523, 583). Le développement de stratégies antivirales combinant des inhibiteurs d’entrée et des DAA pourraient, par ailleurs, tirer bénéfice de l’effet synergique de cette association (583).

Si les données actuelles ne permettent pas de présumer d’un usage clinique dans le cadre du traitement d’une infection par le VHC, les CBA constituent des molécules à large spectre antiviral. Il a déjà été montré que les CBA inhibent efficacement le HSV, le CMV, le virus de la grippe, ainsi que des virus émergents tels que le SRAS-CoV, le virus Ebola ou le virus de la dengue [tableau 2]. Ils pourraient ainsi permettre de lutter contre des infections causées par divers virus enveloppés. Nos résultats apportent des données intéressantes en vue de l’utilisation des CBA comme traitement antiviral contre les virus enveloppés.

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