title: Role of hepatitis B virus genetic barrier in drug-resistance and immune-escape development.
abstract: BACKGROUND
  Impact of hepatitis B virus genetic barrier, defined as the number and type of nucleotide substitutions required to overcome drug/immune selective pressure, on drug-resistance/immune-escape development is unknown.
  
  
  METHODS
  Genetic barrier was calculated according to Van de Vijver (2006) in 3482 hepatitis B virus-reverse transcriptase/HBV surface antigen sequences from 555 drug-naïve patients and 2927 antiviral-treated patients infected with hepatitis B virus genotypes A-G.
  
  
  RESULTS
  Despite high natural variability, genetic barrier for drug-resistance development is identical amongst hepatitis B virus genotypes, but varies according to drug-resistance mutation type. Highest genetic barrier is found for secondary/compensatory mutations (e.g. rtL80I/V-rtL180M-rtV173L), whilst most primary mutations (including rtM204V-rtA181T/V-rtI169T-rtA194T) are associated with low genetic barrier. An exception is rtM204I, which can derive from a transition or a transversion. Genotypes A and G are more prone to develop immune/diagnostic-escape mutations sT114R and sG130N. Vaccine-escape associated sT131N-mutation is a natural polymorphism in both A and G genotypes.
  
  
  CONCLUSIONS
  Genetic barrier and reverse transcriptase/HBV surface antigen overlapping can synergistically influence hepatitis B virus drug-resistance/immune-escape development. The different immune-escape potential of specific hepatitis B virus genotypes could have important clinical consequences in terms of disease progression, vaccine strategies and correct HBV surface antigen detection.
authors.affiliation: Department of Experimental Medicine and Biochemical Science, University of Tor Vergata Rome, Italy.
authors.forename: Valentina
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authors.lastname: Svicher
authors.forename: Valeria
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authors.lastname: Cento
authors.forename: Romina
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authors.lastname: Salpini
authors.forename: Fabio
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authors.lastname: Mercurio
authors.forename: Maria
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authors.lastname: Fraune
authors.forename: Bastian
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authors.lastname: Beggel
authors.forename: Yue
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authors.lastname: Han
authors.forename: Caterina
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authors.lastname: Gori
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authors.lastname: Wittkop
authors.forename: Ada
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authors.lastname: Bertoli
authors.forename: Valeria
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authors.lastname: Micheli
authors.forename: Guido
authors.initials: G
authors.lastname: Gubertini
authors.forename: Roberta
authors.initials: R
authors.lastname: Longo
authors.forename: Sara
authors.initials: S
authors.lastname: Romano
authors.forename: Michela
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authors.lastname: Visca
authors.forename: Valentina
authors.initials: V
authors.lastname: Gallinaro
authors.forename: Nicoletta
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authors.lastname: Marino
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzotta
authors.forename: Giuseppe Maria
authors.initials: GM
authors.lastname: De Sanctis
authors.forename: Hervè
authors.initials: H
authors.lastname: Fleury
authors.forename: Pascale
authors.initials: P
authors.lastname: Trimoulet
authors.forename: Mario
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authors.lastname: Angelico
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cappiello
authors.forename: Xin Xin
authors.initials: XX
authors.lastname: Zhang
authors.forename: Jens
authors.initials: J
authors.lastname: Verheyen
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D000596:Amino Acids / Q000235:genetics; D003062:Codon / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D006509:Hepatitis B / Q000188:drug therapy / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018709:Statistics, Nonparametric; D017211:Treatment Failure
chemical_list: D000596:Amino Acids; D003062:Codon; D006514:Hepatitis B Surface Antigens; D012194:RNA-Directed DNA Polymerase