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Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients

H. Le Guillou-Guillemette 1, * A. Ducancelle 1 S. Bertrais 2 C. Lemaire 1 A. Pivert 1 P. Veillon 1 E. Bouthry 1 S. Alain 3 Valérie Thibault 4 Florence Legrand-Abravanel 5, 6 A. R. Rosenberg 7 C. Henquell 8 E. André-Garnier 9 O. Petsaris 10 S. Vallet 10 J. B. Bour 11 Y. Baazia 12 P. Trimoulet 13 P. André 14 C. Gaudy-Graffin 15 D. Bettinger 16 Sylvie Larrat 17 A. Signori-Schmuck 18 H. Saoudin 19 B. Pozzetto 19 G. Lagathu 20 S. Minjolle-Cha 20 F. Stoll-Keller 21 J. M. Pawlotsky 22 Jacques Izopet 5, 6 C. Payan 10 F Lunel-Fabiani 1
* Corresponding author
1 CHU Angers - Centre Hospitalier Universitaire d'Angers
2 ICAT - SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques
3 CHU Limoges
4 Service de virologie [CHU Pitié-Salpêtrière]
5 Laboratoire de Virologie [Toulouse]
6 CPTP - Centre de Physiopathologie Toulouse Purpan
7 Hôpital Cochin [AP-HP]
8 CHU Clermont-Ferrand
9 Hôtel-Dieu de Nantes
10 LUBEM - Laboratoire Universitaire de Biodiversité et Ecologie Microbienne
11 CHU Dijon
12 CHU Avicenne
13 Service de virologie et d'immunologie biologique
14 Laboratoire de Bactériologie de l'Hôpital de la Croix-Rousse
15 MAVIVH - U1259 Inserm - CHRU Tours - Morphogénèse et antigénicité du VIH et du virus des Hépatites
16 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
17 UVHCI - Unit for Virus Host-Cell Interactions [Grenoble]
18 UVHCI - Biologie structurale des interactions entre virus et cellule hôte
19 CHU de Saint-Etienne - Centre Hospitalier Universitaire de Saint-Etienne
20 CHU Pontchaillou [Rennes]
21 Interaction virus-hôte et maladies du foie
22 CHU Henri Mondor
Abstract : Background The NS5A protein of the hepatitis C virus has been shown to be involved in the development of hepatocellular carcinoma. Objectives In a French multicenter study, we investigated the clinical and epidemiological features of a new HCV genotype 1b strain bearing a wide insertion into the V3 domain. Study Design We studied NS5A gene sequences in 821 French patients infected with genotype 1b HCV. Results We identified an uncharacterized V3 insertion without ORF disruption in 3.05% of the HCV sequences. The insertion comprised 31 amino-acids for the majority of patients; 3 patients had 27 amino-acids insertions and 1 had a 12 amino-acids insertion. Sequence identity between the 31 amino-acids insertions and the V3 domain ranged from 48 to 96% with E-values above 4e-5, thus illustrating sequence homology and a partial gene duplication event that to our knowledge has never been reported in HCV. Moreover we showed the presence of the duplication at the time of infection and its persistence at least during 12 years in the entire quasispecies. No association was found with extrahepatic diseases. Conversely, patients with cirrhosis were two times more likely to have HCV with this genetic characteristic (p=0.04). Moreover, its prevalence increased with liver disease severity (from 3.0% in patients without cirrhosis to 9.4% in patients with both cirrhosis and HCC, p for trend=0.045). Conclusions We identified a duplicated V3 domain in the HCV-1b NS5A protein for the first time. The duplication may be associated with unfavorable evolution of liver disease including a possible involvement in liver carcinogenesis
Keywords : V3 domain NS5A hepatocellular carcinoma hepatitis C virus cirrhosis
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Submitted on : Wednesday, November 25, 2015 - 9:34:16 AM
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UNIV-RENNES1 | CNRS | UNIV-ANGERS | UNIV-BREST | HCL | UPMC | UNAM | INSERM | UNIV-TOURS | UNIV-RENNES | LUBEM | IBSAM | SORBONNE-UNIVERSITE | SITE-ALSACE | UVHCI | UVHCI-VEB | UNIV-TLSE3 | SU-MEDECINE | IRSET-10 | UGA | SU-TI | INFINITY

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H. Le Guillou-Guillemette, A. Ducancelle, S. Bertrais, C. Lemaire, A. Pivert, et al.. Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients. Journal of Clinical Virology, Elsevier, 2015, 69, pp.203-209. ⟨10.1016/j.jcv.2015.06.096⟩. ⟨hal-01231431⟩

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