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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 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.
