title: Duplication of the V3 domain in hepatitis C virus (1b) NS5A protein: Clonal analysis and physicochemical properties related to hepatocellular carcinoma occurrence.
abstract: BACKGROUND
  Hepatitis C virus non-structural protein 5A is known to play a role in development of hepatocellular carcinoma (HCC) via interactions with host cell pathways.
  
  
  OBJECTIVE
  Hepatitis C virus genotype 1b strains presenting a wide insertion of 31 amino acids in the non-structural protein 5A V3 domain (V3 DI) were studied to determine whether this V3-like additional domain (V3 DII) was associated with HCC occurrence.
  
  
  METHODS
  Seventy-four patients' sera were screened for V3 DII presence regarding clinical status.
  
  
  RESULTS
  Three strains with duplicated V3 were detected among patients with progression to HCC (n=28), two strains among patients with liver cirrhosis (Ci, n=27) and none among patients with chronic hepatitis (Chr, n=19). Phylogenetic trees built from V3 DI and V3 DII sequences indicated that the latter clustered separately. In between-group clonal analysis, V3 DII sequences from the HCC group were found to be more distant from HCV-J than V3 DI sequences (p<0.0001). Between-group comparisons showed significant differences in genetic distances from HCV-J, in HCC V3 DI and HCC V3 DII compared to Ci V3 DI and Ci V3 DII sequences (p<0.0001). HCC V3 DII domain and its junction with V3 DI exhibited higher Shannon entropy values and enrichment in disorder-promoting residues.
  
  
  CONCLUSIONS
  Taken together, our results suggest that V3 DII evolution may differ in strains associated with HCC occurrence. The presence of an intrinsically "disordered" V3 duplicate may alter the NS5A protein network. Further investigations are necessary to elucidate the potential impact of V3 duplication in the context of carcinogenesis.
authors.affiliation: CHU Universitaire La Cavale Blanche, Laboratoire de Microbiologie, 29200 Brest cedex, France; Université de Brest, Université Européenne de Bretagne, SFR IBSAM, LUBEM (EA3882), UFR Médecine et Sciences de la Santé, 29200 Brest, France. Electronic address: odilepetsaris@yahoo.fr.
authors.forename: Odile
authors.initials: O
authors.lastname: Petsaris
authors.affiliation: CHU Universitaire La Cavale Blanche, Laboratoire de Microbiologie, 29200 Brest cedex, France; Université de Brest, Université Européenne de Bretagne, SFR IBSAM, LUBEM (EA3882), UFR Médecine et Sciences de la Santé, 29200 Brest, France. Electronic address: sophie.vallet@chu-brest.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vallet
authors.affiliation: Laboratoire de virologie, CHU Angers, HIFI Laboratory, UPRES EA3859, SFR 4208, LUNAM University, Angers, France. Electronic address: heleguillou@chu-angers.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Le Guillou-Guillemette
authors.affiliation: Laboratoire de virologie, CHU Angers, HIFI Laboratory, UPRES EA3859, SFR 4208, LUNAM University, Angers, France. Electronic address: paveillon@chu-angers.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Veillon
authors.affiliation: Université de Brest, Université Européenne de Bretagne, SFR IBSAM, LUBEM (EA3882), UFR Médecine et Sciences de la Santé, 29200 Brest, France. Electronic address: stephanie.gouriou@univ-brest.fr.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Gouriou
authors.affiliation: Université de Brest, Université Européenne de Bretagne, SFR ScInBioS, LUBEM (EA3882), ESIAB, 29280 Plouzané, France. Electronic address: georges.barbier@univ-brest.fr.
authors.forename: Georges
authors.initials: G
authors.lastname: Barbier
authors.affiliation: Centre Hospitalier Universitaire La Cavale Blanche, Service d'Hépato-Gastroentérologie, 29200 Brest, France. Electronic address: jean-baptiste.nousbaum@chu-brest.fr.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Nousbaum
authors.affiliation: Université de Brest, Université Européenne de Bretagne, Laboratoire de Santé Publique, Epidémiologie, UFR Médecine et Sciences de la Santé, 29200 Brest, France. Electronic address: philippe.saliou@chu-brest.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Saliou
authors.affiliation: Hôpital Jean Verdier, Service d'Hépato-Gastroentérologie, Assistance Publique-Hôpitaux de Paris, UFR SMBH-Université Paris 13, 93143 Bondy cedex, France. Electronic address: gisele.nkontchou@jvr.aphp.fr.
authors.forename: Gisèle
authors.initials: G
authors.lastname: NKontchou
authors.affiliation: Hôpital Jean Verdier, Service d'Hépato-Gastroentérologie, Assistance Publique-Hôpitaux de Paris, UFR SMBH-Université Paris 13, 93143 Bondy cedex, France; Centre de Ressources Biologiques, Hôpital Jean Verdier, Assistance Publique-Hôpitaux de Paris, 93143 Bondy cedex, France. Electronic address: jean-claude.trinchet@jvr.aphp.fr.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Trinchet
authors.affiliation: Laboratoire de virologie, CHU Angers, HIFI Laboratory, UPRES EA3859, SFR 4208, LUNAM University, Angers, France. Electronic address: frlunel-fabiani@chu-angers.fr.
authors.forename: Francoise
authors.initials: F
authors.lastname: Lunel-Fabiani
authors.affiliation: CHU Universitaire La Cavale Blanche, Laboratoire de Microbiologie, 29200 Brest cedex, France; Université de Brest, Université Européenne de Bretagne, SFR IBSAM, LUBEM (EA3882), UFR Médecine et Sciences de la Santé, 29200 Brest, France. Electronic address: christopher.payan@chu-brest.fr.
authors.forename: Christopher
authors.initials: C
authors.lastname: Payan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology* / Q000821:virology*; D005260:Female; D020440:Gene Duplication; D016174:Hepacivirus / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D011446:Prospective Studies; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Duplication; Genetic variability; Hepatitis C virus; Hepatocellular carcinoma; NS5A-V3 domain