title: Hepatitis C Virus Resistance to Carbohydrate-Binding Agents.
abstract: Carbohydrate binding agents (CBAs), including natural lectins, are more and more considered as broad-spectrum antivirals. These molecules are able to directly inhibit many viruses such as Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), Dengue Virus, Ebola Virus or Severe Acute Respiratory Syndrome Coronavirus through binding to envelope protein N-glycans. In the case of HIV, it has been shown that CBAs select for mutant viruses with N-glycosylation site deletions which are more sensitive to neutralizing antibodies. In this study we aimed at evaluating the HCV resistance to CBAs in vitro. HCV was cultivated in the presence of increasing Galanthus nivalis agglutinin (GNA), Cyanovirin-N, Concanavalin-A or Griffithsin concentrations, during more than eight weeks. At the end of lectin exposure, the genome of the isolated strains was sequenced and several potential resistance mutations in the E1E2 envelope glycoproteins were identified. The effect of these mutations on viral fitness as well as on sensitivity to inhibition by lectins, soluble CD81 or the 3/11 neutralizing antibody was assessed. Surprisingly, none of these mutations, alone or in combination, conferred resistance to CBAs. In contrast, we observed that some mutants were more sensitive to 3/11 or CD81-LEL inhibition. Additionally, several mutations were identified in the Core and the non-structural proteins. Thus, our results suggest that in contrast to HIV, HCV resistance to CBAs is not directly conferred by mutations in the envelope protein genes but could occur through an indirect mechanism involving mutations in other viral proteins. Further investigations are needed to completely elucidate the underlying mechanisms.
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Izquierdo
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Catarina
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Fournier
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Descamps
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Morel
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Dubuisson
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Brochot
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Francois
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Castelain
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Duverlie
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Helle
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D037102:Lectins / Q000494:pharmacology*; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D060225:Tetraspanin 28 / Q000037:antagonists & inhibitors; D014759:Viral Envelope Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; C554798:CD81 protein, human; D037102:Lectins; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins