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.
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: Ahmed A Quadeer; Raymond H Y Louie; Karthik Shekhar; Arup K Chakraborty; I-Ming Hsing; Matthew R McKay Journal: J Virol Date: 2014-04-23 Impact factor: 5.103
Authors: B E Pickett; M Liu; E L Sadat; R B Squires; J M Noronha; S He; W Jen; S Zaremba; Z Gu; L Zhou; C N Larsen; I Bosch; L Gehrke; M McGee; E B Klem; R H Scheuermann Journal: Virology Date: 2013-09-14 Impact factor: 3.616
Authors: John M Murray; Rémy Moenne-Loccoz; Aurélie Velay; François Habersetzer; Michel Doffoël; Jean-Pierre Gut; Isabel Fofana; Mirjam B Zeisel; Françoise Stoll-Keller; Thomas F Baumert; Evelyne Schvoerer Journal: PLoS One Date: 2013-06-20 Impact factor: 3.240