title: Characterization of hepatitis B virus surface antigen variability and impact on HBs antigen clearance under nucleos(t)ide analogue therapy.
abstract: For hepatitis B virus (HBV)-related chronic infection under treatment by nucleos(t)ide analogues (NUCs), HBsAg clearance is the ultimate therapeutic goal but very infrequent. We investigated how HBV envelope protein variability could lead to differential HBsAg clearance on NUCs. For 12 HBV genotype D patients receiving NUCs, six resolvers (HBsAg clearance) were compared to six matched nonresolvers (HBsAg persistence). PreS/S amino acid (aa) sequences were analysed with bioinformatics to predict HBV envelope antigenicity and aa covariance. To enrich our analyses on very rare resolvers, these were compared with other HBV genotype D strains in three characterized clinical cohorts including common chronically infected patients. The sT125M+sP127T combination was observed in four nonresolvers of six, corroborated by aa covariance analysis, associated with a lower predicted antigenicity than sT125T+sP127P. Concordant features within this HBV key functional domain, at positions 125 and 127, were reported from two of the three comparative cohorts. In our hands, a lower ELISA reactivity of HBV-vaccinated mice sera was observed against the sT125M mutant. In the S gene, 56 aa changes in minor variants were detected in non-resolvers, mainly in the major hydrophilic region, vs 28 aa changes in resolvers. Molecular features in patients showing HBsAg persistence on NUCs argue in favour of a different aa pattern in the HBV S gene compared to those showing HBsAg clearance. In nonresolvers, a decrease in HBs 'a' determinant antigenicity and more frequent mutations in the S gene suggest a role for the HBV envelope characteristics in HBsAg persistence.
authors.affiliation: EA 7300 'Stress, Immunité, Pathogènes', Université de Lorraine, Vandoeuvre-les-Nancy, France.
authors.forename: A
authors.initials: A
authors.lastname: Velay
authors.affiliation: EA 7300 'Stress, Immunité, Pathogènes', Université de Lorraine, Vandoeuvre-les-Nancy, France.|Laboratoire de Virologie, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: H
authors.initials: H
authors.lastname: Jeulin
authors.affiliation: EA 7300 'Stress, Immunité, Pathogènes', Université de Lorraine, Vandoeuvre-les-Nancy, France.
authors.forename: M
authors.initials: M
authors.lastname: Eschlimann
authors.affiliation: Laboratoire de Virologie, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: B
authors.initials: B
authors.lastname: Malvé
authors.affiliation: Service des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: F
authors.initials: F
authors.lastname: Goehringer
authors.affiliation: Service d'Hépato-gastroentérologie, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: M
authors.initials: M
authors.lastname: Bensenane
authors.affiliation: EA 7300 'Stress, Immunité, Pathogènes', Université de Lorraine, Vandoeuvre-les-Nancy, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Frippiat
authors.affiliation: Department of Clinical Virology, Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: P
authors.initials: P
authors.lastname: Abraham
authors.affiliation: Department of Clinical Virology, Christian Medical College, Vellore, Tamil Nadu, India.
authors.forename: A M
authors.initials: AM
authors.lastname: Ismail
authors.affiliation: School of Mathematics and Statistics, UNSW Australia, Sydney, NSW, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Murray
authors.affiliation: Unité Inserm UI1052, Université de Lyon, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Combet
authors.affiliation: Unité Inserm UI1052, Université de Lyon, Lyon, France.
authors.forename: F
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Service d'Hépato-gastroentérologie, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Bronowicki
authors.affiliation: EA 7300 'Stress, Immunité, Pathogènes', Université de Lorraine, Vandoeuvre-les-Nancy, France.|Laboratoire de Virologie, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.
authors.forename: E
authors.initials: E
authors.lastname: Schvoerer
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D000940:Antigenic Variation; D000998:Antiviral Agents / Q000627:therapeutic use*; D019295:Computational Biology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D014644:Genetic Variation; D006514:Hepatitis B Surface Antigens / Q000235:genetics* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D009705:Nucleosides / Q000627:therapeutic use*; D009711:Nucleotides / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA
chemical_list: D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D050505:Mutant Proteins; D009705:Nucleosides; D009711:Nucleotides
keywords: HBV preS/S variability; anti-HBV treatment; hepatitis B Virus