Next-generation sequencing reveals large connected networks of intra-host HCV variants

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dc.contributor.authorCampo, David S.
dc.contributor.authorDimitrova, Zoya
dc.contributor.authorYamasaki, Lilian [UNESP]
dc.contributor.authorSkums, Pavel
dc.contributor.authorLau, Daryl T. Y.
dc.contributor.authorVaughan, Gilberto
dc.contributor.authorForbi, Joseph C.
dc.contributor.authorTeo, Chong-Gee
dc.contributor.authorKhudyakov, Yury
dc.contributor.institutionCtr Dis Control & Prevent
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionHarvard Univ
dc.date.accessioned2015-03-18T15:55:48Z
dc.date.available2015-03-18T15:55:48Z
dc.date.issued2014-07-14
dc.description.abstractBackground: Next-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host.Results: Intra-host variants of the HCV E1/E2 region were extensively sampled from 58 chronically infected patients. After NGS error correction, the average number of reads and variants obtained from each sample were 3202 and 464, respectively. The distance between each pair of variants was calculated and networks were created for each patient, where each node is a variant and two nodes are connected by a link if the nucleotide distance between them is 1. The work focused on large components having > 5% of all reads, which in average account for 93.7% of all reads found in a patient. The distance between any two variants calculated over the component correlated strongly with nucleotide distances (r = 0.9499; p = 0.0001), a better correlation than the one obtained with Neighbour-Joining trees (r = 0.7624; p = 0.0001). In each patient, components were well separated, with the average distance between (6.53%) being 10 times greater than within each component (0.68%). The ratio of nonsynonymous to synonymous changes was calculated and some patients (6.9%) showed a mixture of networks under strong negative and positive selection. All components were robust to in silico stochastic sampling; even after randomly removing 85% of all reads, the largest connected component in the new subsample still involved 82.4% of remaining nodes. In vitro sampling showed that 93.02% of components present in the original sample were also found in experimental replicas, with 81.6% of reads found in both. When syringe-sharing transmission events were simulated, 91.2% of all simulated transmission events seeded all components present in the source.Conclusions: Most intra-host variants are organized into distinct single-mutation components that are: well separated from each other, represent genetic distances between viral variants, robust to sampling, reproducible and likely seeded during transmission events. Facilitated by NGS, large components offer a novel evolutionary framework for genetic analysis of intra-host viral populations and understanding transmission, immune escape and drug resistance.en
dc.description.affiliationCtr Dis Control & Prevent, Div Viral Hepatitis, Atlanta, GA 30333 USA
dc.description.affiliationUNESP Sao Paulo State Univ, Dept Biol, Lab Genom Studies, Sao Paulo, Brazil
dc.description.affiliationHarvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Liver Ctr,Div Gastroenterol, Cambridge, MA 02138 USA
dc.description.affiliationUnespUNESP Sao Paulo State Univ, Dept Biol, Lab Genom Studies, Sao Paulo, Brazil
dc.description.sponsorshipCenters for Disease Control and Prevention
dc.format.extent9
dc.identifierhttp://dx.doi.org/10.1186/1471-2164-15-S5-S4
dc.identifier.citationBmc Genomics. London: Biomed Central Ltd, v. 15, 9 p., 2014.
dc.identifier.doi10.1186/1471-2164-15-S5-S4
dc.identifier.fileWOS000345682800004.pdf
dc.identifier.issn1471-2164
dc.identifier.urihttp://hdl.handle.net/11449/117309
dc.identifier.wosWOS:000345682800004
dc.language.isoeng
dc.publisherBiomed Central Ltd
dc.relation.ispartofBmc Genomics
dc.relation.ispartofjcr3.730
dc.relation.ispartofsjr2,110
dc.rights.accessRightsAcesso aberto
dc.sourceWeb of Science
dc.titleNext-generation sequencing reveals large connected networks of intra-host HCV variantsen
dc.typeArtigo
dcterms.rightsHolderBiomed Central Ltd
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências Letras e Ciências Exatas, São José do Rio Pretopt

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