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Role of hepatitis B virus genetic barrier in drug-resistance and immune-escape development


Beggel,  Bastian
Computational Biology and Applied Algorithmics, MPI for Informatics, Max Planck Society;
International Max Planck Research School, MPI for Informatics, Max Planck Society;

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Svicher, V., Cento, V., Salpini, R., Mercurio, F., Fraune, M., Beggel, B., et al. (2011). Role of hepatitis B virus genetic barrier in drug-resistance and immune-escape development. Digestive and Liver Disease, 43(12), 975-983. doi:10.1016/j.dld.2011.07.002.

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 virusreverse transcriptase/HBV surface antigen sequences from 555 drug-naïve patients and 2927 antiviraltreated 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.