title: Hepatitis C virus envelope glycoprotein signatures are associated with treatment failure and modulation of viral entry and neutralization.
abstract: BACKGROUND
  A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape.
  
  
  METHODS
  We used a bioinformatics and functional approach to investigate whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with HCV genotype 1.
  
  
  RESULTS
  Bioinformatics analysis identified 1 sustain virological response (R)-related residue in E1 (219T) and 2 non-SVR (NR)-related molecular signatures in E2 (431A and 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating NR patients from R patients. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pretreatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C).
  
  
  CONCLUSIONS
  Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor use and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.
authors: INSERM U748, Université de Strasbourg, France. eschvoerer@gmail.com
authors: Evelyne
authors: E
authors: Schvoerer
authors: Rémy
authors: R
authors: Moenne-Loccoz
authors: John M
authors: JM
authors: Murray
authors: Aurélie
authors: A
authors: Velay
authors: Marine
authors: M
authors: Turek
authors: Isabel
authors: I
authors: Fofana
authors: Samira
authors: S
authors: Fafi-Kremer
authors: Anne-Claire
authors: AC
authors: Erba
authors: François
authors: F
authors: Habersetzer
authors: Michel
authors: M
authors: Doffoël
authors: Jean-Pierre
authors: JP
authors: Gut
authors: Maureen J
authors: MJ
authors: Donlin
authors: John E
authors: JE
authors: Tavis
authors: Mirjam B
authors: MB
authors: Zeisel
authors: Françoise
authors: F
authors: Stoll-Keller
authors: Thomas F
authors: TF
authors: Baumert
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D016174:Hepacivirus / Q000145:classification / Q000472:pathogenicity; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D006801:Humans; D057131:Immune Evasion; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009500:Neutralization Tests; D012254:Ribavirin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017211:Treatment Failure; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000276:immunology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; C087035:E1 protein, Hepatitis C virus; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D012254:Ribavirin