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Genetically distinct within-host subpopulations of hepatitis C virus persist after Direct-Acting Antiviral treatment
Lele Zhao1,2, Matthew Hall1,2, Prahalad Giridhar3
1Nuffield Department of Medicine, Pandemic Sciences Institute, University of Oxford, Oxford, United Kingdom.
Insights
Distinct hepatitis C virus (HCV) subpopulations persist after Direct-Acting Antiviral (DAA) treatment failure. Viral lineages show varying evolutionary rates, suggesting compartmentalization within patients.
Area of Science:
- Virology
- Genetics
- Evolutionary Biology
Background:
- Chronic hepatitis C virus (HCV) infections exhibit distinct within-host population structures.
- Intermittent observation of subpopulations occurred in untreated and interferon-treated patients.
- The persistence of population structure after Direct-Acting Antiviral (DAA) treatment failure was previously unknown.
Purpose of the Study:
- To investigate the maintenance of viral population structure following DAA treatment failure.
- To determine if distinct viral lineages exhibit different evolutionary rates post-DAA treatment.
Main Methods:
- Analysis of whole-genome next-generation sequencing data from 84 patients with DAA treatment failure.
- Identification of distinct within-host lineages using iSNV frequency concordance, clustering algorithms, and haplotype reconstruction.
- Application of maximum likelihood modeling to compare viral evolutionary rates.
Main Results:
- Distinct viral subpopulations were maintained in a high proportion of individuals after DAA treatment failure.
- Significant overdispersion of viral evolutionary rates was observed among individuals.
- Substantial differences in evolutionary rates were detected between distinct viral lineages within individuals.
Conclusions:
- Hepatitis C virus (HCV) populations appear compartmentalized within patients post-DAA treatment failure.
- Varying evolutionary rates suggest differences in viral replication or selection pressures across lineages.
- Lineage awareness is crucial for accurate analysis of HCV evolution and infection dynamics.
Abstract:
Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct-Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure, and whether there were different evolutionary rates along distinct lineages where they were observed. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e., treatment failure) and had sequenced virus from multiple timepoints. Given the short-read nature of the data, we used a number of methods to identify distinct within-host lineages including tracking concordance in intra-host nucleotide variant (iSNV) frequencies, applying sequenced-based and tree-based clustering algorithms to sliding windows along the genome, and haplotype reconstruction. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates and/or different selection pressures. We endorse lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.
