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. 2016 Jun 30;11(6):e0158557.
doi: 10.1371/journal.pone.0158557. eCollection 2016.

Evidence of an Exponential Decay Pattern of the Hepatitis Delta Virus Evolution Rate and Fluctuations in Quasispecies Complexity in Long-Term Studies of Chronic Delta Infection

Maria Homs  1   2 , Francisco Rodriguez-Frias  1   2 , Josep Gregori  1   3   4 , Alicia Ruiz  2 , Pilar Reimundo  2 , Rosario Casillas  2   3 , David Tabernero  1   2 , Cristina Godoy  1   2 , Salma Barakat  5 , Josep Quer  1   3 , Mar Riveiro-Barciela  1   6 , Michael Roggendorf  7 , Rafael Esteban  1   6 , Maria Buti  1   6
Affiliations

Evidence of an Exponential Decay Pattern of the Hepatitis Delta Virus Evolution Rate and Fluctuations in Quasispecies Complexity in Long-Term Studies of Chronic Delta Infection

Maria Homs et al. PLoS One. .

Abstract

Chronic HDV infection can cause a severe form of viral hepatitis for which there is no specific treatment. Characterization of the hepatitis B or C viral quasispecies has provided insight into treatment failure and disease recurrence following liver transplantation, has proven useful to understand hepatitis B e antigen seroconversion, and has helped to predict whether hepatitis C infection will resolve or become chronic. It is likely that characterization of the hepatitis delta virus (HDV) quasispecies will ultimately have similar value for the management of this infection. This study sought to determine the RNA evolution rates in serum of chronic hepatitis delta (CHD) treatment-naïve patients, using next-generation sequencing methods. The region selected for study encompassed nucleotide positions 910 to 1270 of the genome and included the amber/W codon. Amber/W is a substrate of the editing process by the ADAR1 host enzyme and is essential for encoding the 2 delta antigens (HDAg). The amber codon encodes the small (unedited) HDAg form and the W codon the large (edited) HDAg form. The evolution rate was analyzed taking into account the time elapsed between samples, the percentage of unedited and edited genomes, and the complexity of the viral population. The longitudinal studies included 29 sequential samples from CHD patients followed up for a mean of 11.5 years. In total, 121,116 sequences were analyzed. The HDV evolution rate ranged from 9.5x10-3 to 1.2x10-3 substitutions/site/year and showed a negative correlation with the time elapsed between samples (p<0.05). An accumulation of transition-type changes was found to be responsible for higher evolution rates. The percentages of unedited and edited genomes and the quasispecies complexity showed no relationships with the evolution rate, but the fluctuations in the percentages of genomes and in complexity suggest continuous adaptation of HDV to the host conditions.

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Conflict of interest statement

Competing Interests: J. Gregori is an employee of Roche Diagnostics, Spain. Roche Diagnostics Spain did not participate in the study design, data collection, data analysis, data interpretation, or writing of the report. This commercial affiliation does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. All other authors have no conflicts of interest to declare.

Figures

Fig 1
Fig 1. Serum HDV RNA, HBV DNA, and ALT levels in the long-term follow-up studies of 3 patients.
Samples selected for evaluation of the HDV quasispecies and RNA changes are indicated by circles and numbers.
Fig 2
Fig 2. Exponential decay pattern of the evolution rate in relation to the time elapsed between samples.
Fig 3
Fig 3. Evolution rate of the unedited and edited genomes in relation to the time elapsed, for the 3 long-term studies.
Fig 4
Fig 4. Exponential growth pattern between the evolution rate and the percentage of transitions accumulated in HDV genome.
Fig 5
Fig 5
(A) Changes in the percentage of unedited and edited genomes (B) Quasispecies complexity dynamics (nucleotide diversity) in the long-term follow-up.
See this image and copyright information in PMC

References

    1. WHO | Hepatitis D. World Health Organization;
    1. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet (London, England). 2011;378: 73–85. 10.1016/S0140-6736(10)61931-9 - DOI - PubMed
    1. Flores R, Ruiz-Ruiz S, Serra P. Viroids and Hepatitis Delta Virus. Semin Liver Dis. 2012;32: 201–210. 10.1055/s-0032-1323624 - DOI - PubMed
    1. Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut. 2000;46: 420–6. - PMC - PubMed
    1. Chen PJ, Kalpana G, Goldberg J, Mason W, Werner B, Gerin J, et al. Structure and replication of the genome of the hepatitis delta virus. Proc Natl Acad Sci. 1986;83: 8774–8778. 10.1073/pnas.83.22.8774 - DOI - PMC - PubMed

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