Complex genotype mixtures analyzed by deep sequencing in two different regions of Hepatitis B virus

Andrea Caballero, Josep Gregori, Maria Homs, David Tabernero, Carolina Gonzalez, Josep Quer, Maria Blasi, Rosario Casillas, Leonardo Nieto, Mar Riveiro-Barciela, Rafael Esteban, Maria Buti, Francisco Rodriguez-Frias

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Abstract

© 2015 Caballero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This study assesses the presence and outcome of genotype mixtures in the polymerase/surface and X/preCore regions of the HBV genome in patients with chronic hepatitis B virus (HBV) infection. Thirty samples from ten chronic hepatitis B patients were included. The polymerase/surface and X/preCore regions were analyzed by deep sequencing (UDPS) in the first available sample at diagnosis, a pre-treatment sample, and a sample while under treatment. HBV genotype was determined by phylogenesis. Quasispecies complexity was evaluated by mutation frequency and nucleotide diversity. The polymerase/surface and X/preCore regions were validated for genotyping from 113 GenBank reference sequences. UDPS yielded a median of 10,960 sequences per sample (IQR 16,645) in the polymerase/surface region and 11 595 sequences per sample (IQR 14,682) in X/preCore. Genotype mixtures were more common in X/preCore (90%) than in polymerase/surface (30%) (p<0.001). On X/preCore genotyping, all samples were genotype A, whereas polymerase/surface yielded genotypes A (80%), D (16.7%), and F (3.3%) (p = 0.036). Genotype changes in polymerase/surface were observed in four patients during natural quasispecies dynamics and in two patients during treatment. There were no genotype changes in X/preCore. Quasispecies complexity was higher in X/preCore than in polymerase/surface (p = 0.004). The results provide evidence of genotype mixtures and differential genotype proportions in the polymerase/surface and X/preCore regions. The genotype dynamics in HBV infection and the different patterns of quasispecies complexity in the HBV genome suggest a new paradigm for HBV genotype classification.
Original languageEnglish
Article numbere0144816
JournalPLoS ONE
Volume10
Issue number12
DOIs
Publication statusPublished - 1 Dec 2015

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    Caballero, A., Gregori, J., Homs, M., Tabernero, D., Gonzalez, C., Quer, J., Blasi, M., Casillas, R., Nieto, L., Riveiro-Barciela, M., Esteban, R., Buti, M., & Rodriguez-Frias, F. (2015). Complex genotype mixtures analyzed by deep sequencing in two different regions of Hepatitis B virus. PLoS ONE, 10(12), [e0144816]. https://doi.org/10.1371/journal.pone.0144816