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Prefacio signed: Anselmo Lorenzo.Mode of access: Internet

Ultra-Deep Pyrosequencing Detects Conserved Genomic Sites and Quantifies Linkage of Drug-Resistant Amino Acid Changes in the Hepatitis B Virus Genome

Selection of amino acid substitutions associated with resistance to nucleos(t)ide-analog (NA) therapy in the hepatitis B virus (HBV) reverse transcriptase (RT) and their combination in a single viral genome complicates treatment of chronic HBV infection and may affect the overlapping surface coding region. In this study, the variability of an overlapping polymerase-surface region, critical for NA resistance, is investigated before treatment and under antiviral therapy, with assessment of NA-resistant amino acid changes simultaneously occurring in the same genome (linkage analysis) and their influence on the surface coding region

Differences in variability throughout the fragment of reverse transcriptase and overlapping surface region analyzed.

<p>In the pre-treatment samples (1 to 4A), each bar represents the difference between the average frequency of amino acid substitutions in each reverse transcriptase (RT) position and its overlapped amino acid in the surface (S) region, assuming that any substitution in the first nucleotide of an RT codon affects the third nucleotide of the overlapping S codon. Bars with positive values indicate positions with a higher tolerance for amino acid substitutions in RT than in S, whereas the opposite is indicated by bars with negative values.</p

Relationship between frequencies of lamivudine resistance-related amino acid changes detected at pre-treatment and their selection at lamivudine viral breakthrough in the four patients.

<p>Relationship between frequencies of lamivudine resistance-related amino acid changes detected at pre-treatment and their selection at lamivudine viral breakthrough in the four patients.</p

Frequencies of amino acid substitutions with the highest variability during sequential treatment in each of the five treatment samples.

<p>Frequencies of amino acid substitutions with the highest variability during sequential treatment in each of the five treatment samples.</p

Enrichment in amino acid changes related to nucleos(t)ide analog resistance in the pre-treatment quasispecies.

<p>Enrichment in amino acid changes related to nucleos(t)ide analog resistance in the pre-treatment quasispecies.</p

Changes in percentages of reverse transcriptase variants during follow-up of patient 4.

<p>Frequencies of the most variable variants in the 5 samples from patient 4 (ie, those detected in frequencies ≥1% by linkage analysis in any of the samples) are shown in a pie chart for each sample. Each variant has been numbered as sorted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037874#pone-0037874-t005" target="_blank">Table 5</a> (by decreasing SD of the frequency), except for the variant with no mutations in any of the positions included in the analysis. This variant, which was the most variable of all, is designated <i>baseline combination</i>.</p

Poisson model for quantification of artifactual errors.

<p>Poisson model for quantification of artifactual errors.</p