TY - JOUR
T1 - Role of hepatitis B virus genetic barrier in drug-resistance and immune-escape development
AU - Svicher, Valentina
AU - Cento, Valeria
AU - Salpini, Romina
AU - Mercurio, Fabio
AU - Fraune, Maria
AU - Beggel, Bastian
AU - Han, Yue
AU - Gori, Caterina
AU - Wittkop, Linda
AU - Bertoli, Ada
AU - Micheli, Valeria
AU - Gubertini, Guido
AU - Longo, Roberta
AU - Romano, Sara
AU - Visca, Michela
AU - Gallinaro, Valentina
AU - Marino, Nicoletta
AU - Mazzotta, Francesco
AU - De Sanctis, Giuseppe Maria
AU - Fleury, Hervè
AU - Trimoulet, Pascale
AU - Angelico, Mario
AU - Cappiello, Giuseppina
AU - Zhang, Xin Xin
AU - Verheyen, Jens
AU - Ceccherini-Silberstein, Francesca
AU - Perno, Carlo Federico
PY - 2011/12
Y1 - 2011/12
N2 - 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. Conclusion: 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.
AB - 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. Conclusion: 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.
KW - Drug resistance
KW - Genetic barrier
KW - Immune escape
KW - RT/HBsAg overlapping
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U2 - 10.1016/j.dld.2011.07.002
DO - 10.1016/j.dld.2011.07.002
M3 - Article
C2 - 21831732
AN - SCOPUS:80055092755
VL - 43
SP - 975
EP - 983
JO - Digestive and Liver Disease
JF - Digestive and Liver Disease
SN - 1590-8658
IS - 12
ER -