In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17185 |
| _version_ | 1797380787978371072 |
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| author | Sergi Colomer-Castell Josep Gregori Damir Garcia-Cehic Mar Riveiro-Barciela Maria Buti Ariadna Rando-Segura Judit Vico-Romero Carolina Campos Marta Ibañez-Lligoña Caroline Melanie Adombi Maria Francesca Cortese David Tabernero Juan Ignacio Esteban Francisco Rodriguez-Frias Josep Quer |
| author_facet | Sergi Colomer-Castell Josep Gregori Damir Garcia-Cehic Mar Riveiro-Barciela Maria Buti Ariadna Rando-Segura Judit Vico-Romero Carolina Campos Marta Ibañez-Lligoña Caroline Melanie Adombi Maria Francesca Cortese David Tabernero Juan Ignacio Esteban Francisco Rodriguez-Frias Josep Quer |
| author_sort | Sergi Colomer-Castell |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T20:42:06Z |
| format | Article |
| id | doaj.art-bb0fa6f27e3e4876ae3cad40e735697f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:42:06Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bb0fa6f27e3e4876ae3cad40e735697f2023-12-22T14:13:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241718510.3390/ijms242417185In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral TreatmentsSergi Colomer-Castell0Josep Gregori1Damir Garcia-Cehic2Mar Riveiro-Barciela3Maria Buti4Ariadna Rando-Segura5Judit Vico-Romero6Carolina Campos7Marta Ibañez-Lligoña8Caroline Melanie Adombi9Maria Francesca Cortese10David Tabernero11Juan Ignacio Esteban12Francisco Rodriguez-Frias13Josep Quer14Liver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, SpainLiver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, 08035 Barcelona, SpainHere, 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.https://www.mdpi.com/1422-0067/24/24/17185quasispeciesdeep sequencingvariabilityrare haplotypesfitnessmutagens |
| spellingShingle | Sergi Colomer-Castell Josep Gregori Damir Garcia-Cehic Mar Riveiro-Barciela Maria Buti Ariadna Rando-Segura Judit Vico-Romero Carolina Campos Marta Ibañez-Lligoña Caroline Melanie Adombi Maria Francesca Cortese David Tabernero Juan Ignacio Esteban Francisco Rodriguez-Frias Josep Quer In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments International Journal of Molecular Sciences quasispecies deep sequencing variability rare haplotypes fitness mutagens |
| title | In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments |
| title_full | In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments |
| title_fullStr | In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments |
| title_full_unstemmed | In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments |
| title_short | In-Host HEV Quasispecies Evolution Shows the Limits of Mutagenic Antiviral Treatments |
| title_sort | in host hev quasispecies evolution shows the limits of mutagenic antiviral treatments |
| topic | quasispecies deep sequencing variability rare haplotypes fitness mutagens |
| url | https://www.mdpi.com/1422-0067/24/24/17185 |
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