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Open AccessArticle

Hepatitis E Virus Shows More Genomic Alterations in Cell Culture than In Vivo

1
Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Postbus 2040 3000 CA Rotterdam, The Netherlands
2
Department of Viroscience, Erasmus University Medical Center, Postbus 2040 3000 CA Rotterdam, The Netherlands
3
Laboratory of Experimental Medicine and Pediatrics, Faculty of Medicine and Health Sciences, University of Antwerp and Department of Gastroenterology and Hepatology, Antwerp University Hospital, 10 2650 Antwerp, Belgium
4
Microvida, Location Bravis Roosendaal, Molengracht 21 4818 CK Breda, The Netherlands
*
Author to whom correspondence should be addressed.
Equal Contribution.
Pathogens 2019, 8(4), 255; https://doi.org/10.3390/pathogens8040255
Received: 1 October 2019 / Revised: 12 November 2019 / Accepted: 18 November 2019 / Published: 22 November 2019
(This article belongs to the Special Issue Hepatitis E Virus (HEV) Infections)
Hepatitis E Virus (HEV) mutations following ribavirin treatment have been associated with treatment non-response and viral persistence, but spontaneous occurring genomic variations have been less well characterized. We here set out to study the HEV genome composition in 2 patient sample types and 2 infection models. Near full HEV genome Sanger sequences of serum- and feces-derived HEV from two chronic HEV genotype 3 (gt3) patients were obtained. In addition, viruses were sequenced after in vitro or in vivo expansion on A549 cells or a humanized mouse model, respectively. We show that HEV acquired 19 nucleotide mutations, of which 7 nonsynonymous amino acids changes located in Open Reading Frame 1 (ORF1), ORF2, and ORF3 coding regions, after prolonged in vitro culture. In vivo passage resulted in selection of 8 nucleotide mutations with 2 altered amino acids in the X domain and Poly-proline region of ORF1. Intra-patient comparison of feces- and serum-derived HEV gt3 of two patients showed 7 and 2 nucleotide mutations with 2 and 0 amino acid changes, respectively. Overall, the number of genomic alterations was up to 1.25× per 1000 nucleotides or amino acids in in vivo samples, and up to 2.84× after in vitro expansion of the same clinical HEV strain. In vitro replication of a clinical HEV strain is therefore associated with more mutations, compared to the minor HEV genomic alterations seen after passage of the same strain in an immune deficient humanized mouse; as well as in feces and blood of 2 immunosuppressed chronically infected HEV patients. These data suggest that HEV infected humanized mice more closely reflect the HEV biology seen in solid organ transplant recipients. View Full-Text
Keywords: Hepatitis E virus; HEV whole genome sequencing; viral adaptation; spontaneous mutagenesis Hepatitis E virus; HEV whole genome sequencing; viral adaptation; spontaneous mutagenesis
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Sari, G.; van de Garde, M.D.; van Schoonhoven, A.; Voermans, J.J.; van der Eijk, A.A.; de Man, R.A.; Boonstra, A.; Vanwolleghem, T.; Pas, S.D. Hepatitis E Virus Shows More Genomic Alterations in Cell Culture than In Vivo. Pathogens 2019, 8, 255.

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