In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments
Colomer-Castell, Sergi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Gregori i Font, Josep (Vall d'Hebron Institut de Recerca (VHIR))
Garcia-Cehic, D. (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain; (A.R.-S.); (M.F.C.); (D.T.); (F.R.-F.))
Riveiro Barciela, Mar (Universitat Autònoma de Barcelona. Departament de Medicina)
Buti, Maria (Universitat Autònoma de Barcelona. Departament de Medicina)
Rando-Segura, Ariadna (Vall d'Hebron Institut de Recerca (VHIR))
Vico-Romero, Judit (Vall d'Hebron Institut de Recerca (VHIR))
Campos, Carolina (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ibañez Lligoña, Marta (Universitat Autònoma de Barcelona. Departament de Medicina)
Adombi, Caroline Melanie (Institute of Agropastoral Management, University Peleforo Gon Coulibaly, Korhogo BP 1328, Côte d'Ivoire)
Cortese, Maria Francesca (Vall d'Hebron Institut de Recerca (VHIR))
Tabernero, David (Vall d'Hebron Institut de Recerca (VHIR))
Esteban Mur, Juan Ignacio (Universitat Autònoma de Barcelona. Departament de Medicina)
Rodríguez Frías, Francisco (Vall d'Hebron Institut de Recerca (VHIR))
Quer, Josep 1965- (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2023
Resum:	Here, we report the in-host hepatitis E virus (HEV) quasispecies evolution in a chronically infected patient who was treated with three different regimens of ribavirin (RBV) for nearly 6 years. Sequential plasma samples were collected at different time points and subjected to RNA extraction and deep sequencing using the MiSeq Illumina platforms. Specifically, we RT-PCR amplified a single amplicon from the core region located in the open-reading frame 2 (ORF2). At the nucleotide level (genotype), our analysis showed an increase in the number of rare haplotypes and a drastic reduction in the frequency of the master (most represented) sequence during the period when the virus was found to be insensitive to RBV treatment. Contrarily, at the amino acid level (phenotype), our study revealed conservation of the amino acids, which is represented by a high prevalence of the master sequence. Our findings suggest that using mutagenic antivirals concomitant with high viral loads can lead to the selection and proliferation of a rich set of synonymous haplotypes that express the same phenotype. This can also lead to the selection and proliferation of conservative substitutions that express fitness-enhanced phenotypes. These results have important clinical implications, as they suggest that using mutagenic agents as a monotherapy treatment regimen in the absence of sufficiently effective viral inhibitors can result in diversification and proliferation of a highly diverse quasispecies resistant to further treatment. Therefore, such approaches should be avoided whenever possible.
Ajuts:	Spanish Ministry of Economy and Business IDI-20200297 Agencia Estatal de Investigación PID2021-126447OB-I00 Instituto de Salud Carlos III PI19/00301 Instituto de Salud Carlos III PI22/00258 Spanish Ministry of Educatio FPU21/04150 "la Caixa" Foundation LCF/BQ/DR23/12000020
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Quasispecies ; Deep sequencing ; Variability ; Rare haplotypes ; Fitness ; Mutagens
Publicat a:	International journal of molecular sciences, Vol. 24 (december 2023) , ISSN 1422-0067

DOI: 10.3390/ijms242417185
PMID: 38139013

14 p, 1.5 MB

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