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, séquencés puis assemblés de novo par 2 approches Overlap-Layout-Consensus (OLC)

, Une région du génome non couverte a été complétée par séquençage première génération (Sanger). L'assemblage du génome entier du VHC issu d'un algorithme OLC

, Pour le séquençage par synthèse, un séquençage shotgun « paired-end » a été réalisé et l'assemblage de novo du génome entier du VHC a fait appel à une méthode « seed and extend » et une approche OLC. L'assemblage issu de la méthode « seed and extend

, Une séquence consensus a été générée à partir de ces 3 séquençages et 4 analyses. L'analyse phylogénétique de l'assemblage final permet de mettre en évidence son regroupement avec la séquence du VHC 7a précédemment décrite ce qui oriente la classification de ce génome

, Comme mentionné précédemment, les technologies de séquençage haut débit permettent d'étudier l'évolution de populations virales au cours d'une infection en autorisant l'acquisition rapide de milliers de courtes séquences d'ARN à partir d'échantillons temporels multiples. Le séquençage haut débit est ainsi un outil essentiel pour la description de l'hétérogénéité génétique et la compréhension de la, Par ailleurs, nous avons aussi réalisé un séquençage haut débit d'amplicons de gènes cibles

, Nous avons en l'occurrence voulu étudier la relation entre l'absence de réponse au traitement associant l'Interféron pegylé à la Ribavirine et la variation et la dynamique de l'évolution virale de 2 régions du génome du VHC (Core et NS5B) au cours du traitement et des années qui ont suivi pour 2 patients suivis pour une hépatite C chronique

, Core et NS5B) a été réalisé pour chaque échantillon temporel ce qui a permis d'identifier leur composition (génotypes et sous-types) par BLAST et estimer leur diversité nucléotidique. Nos patients présentent ainsi des infections multiples à des génotypes (patient 1 : 1b & 4/4k) et sous-types (patient 2 : 1b & 1a) différents. La diversité nucléotidique de la région NS5B présente une augmentation l'année du traitement, Un pyroséquençage d'amplicons des gènes cibles

, L'exploration de la structure génétique de la population virale et de son évolution temporelle pour l'ensemble des échantillons de la région NS5B par analyse en composantes principales permet de reproduire, pour les 2 patients, l'évolution temporelle des fréquences des génotypes et sous-types obtenues dans l'analyse précédente (séparation des génotypes/sous-types selon la première composante principale, séparation des échantillons selon leur date d'échantillonnage

, Pour les 2 patients, tous les résultats issus de l'analyse en composantes principales sont cohérents avec ceux obtenus par l'analyse de la diversité nucléotidique des échantillons

, Une analyse basée sur une horloge moléculaire nous a permis de dater l'infection secondaire par les génotypes 4/4k et 1a après l'infection initiale par le génotype 1b, l'ensemble étant antérieur à l

. Pennings, Les résultats obtenus supportent l'hypothèse de l'apparition d'une résistance au traitement selon un mécanisme de soft selective sweeps, 2014.

, Il se produit lorsqu'une ou plusieurs souches résistantes (ici de génotypes 4/4k et 1a) sont présentes dans la population virale avant le traitement, y compris de façon minoritaire

, Comme précisé précédemment, le séquençage du génome entier du VHC est un processus long et fastidieux en séquençage première génération (Sanger) avec l'utilisation de multiples amplicons chevauchants et d'amorces spécifiques de souches. La variabilité du VHC doit être prise en compte afin de concevoir des amorces capables de s'hybrider sur tous les types de virus, sans biais et sur plusieurs A l'issue de cette étude, des échantillons cliniques séquencés sur système PacBio Sequel vont être analysés en, Les perspectives de ce travail sont d'étendre l'étude de l'évolution des populations virales au génome entier du VHC

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