Intrahost evolution leading to distinct lineages in the upper and lower respiratory tracts during SARS-CoV-2 prolonged infection
Majdouline El Moussaoui, Sebastien Bontems, Cecile Meex, Marie-Pierre Hayette, Marie Lejeune, Samuel L Hong, Simon Dellicour, Michel Moutschen, Nadine Cambisano, Nathalie Renotte, Vincent Bours, Gilles Darcis, Maria Artesi, Keith Durkin
Virus Evolution, doi:10.1093/ve/veae073
Accumulating evidence points to persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised individuals as a source of novel lineages. While intrahost evolution of the virus in chronically infected patients has previously been reported, existing knowledge is primarily based on samples from the nasopharynx. In this study, we investigate the intrahost evolution and genetic diversity that accumulated during a prolonged SARS-CoV-2 infection with the Omicron BF.7 sublineage, which is estimated to have persisted for >1 year in an immunosuppressed patient. Based on the sequencing of eight samples collected at six time points, we identified 87 intrahost single-nucleotide variants, 2 indels, and a 362-bp deletion. Our analysis revealed distinct viral genotypes in the nasopharyngeal (NP), endotracheal aspirate, and bronchoalveolar lavage samples. This suggests that NP samples may not offer a comprehensive representation of the overall intrahost viral diversity. Our findings not only demonstrate that the Omicron BF.7 sublineage can further diverge from its already exceptionally mutated state but also highlight that patients chronically infected with SARS-CoV-2 can develop genetically specific viral populations across distinct anatomic compartments. This provides novel insights into the intricate nature of viral diversity and evolution dynamics in persistent infections.
Table S4 . Variant Call Format files (VCFs) and BAMs were checked in the Integrative Genomics Viewer (Thorvaldsdóttir et al. 2013) . The consensus sequence for the long-range PCR products was generated using the bcftools consensus command ( https://samtools. github.io/bcftools/bcftools.html ) and manually incorporated into the ARTIC network field bioinformatics pipeline consensus. In order to generate the patient BF.7 ancestral sequence, we used the bcftools isec tool to select SNVs and deletions with an allele frequency of >98% that are common to all patient samples. We also included an SNV found in the BAL and ETA samples, which overlaps with the 362-bp deletion in the NP samples. The resulting VCF file contains 72 SNVs/deletions, and this file was used in combination with the bcftools consensus tool to produce a consensus sequence for the ancestral lineage.
Phylogenetics Consensus genomes were placed on the existing phylogenetic tree via UShER using the phylogenetic tree generated with genomes from GISAID, GeneBank, COVID-19 Genomics UK Consortium, and China National Center for Bioinformation. In the case of the BF.7 samples, we used the genomes identified by UShER to infer a timescaled phylogenetic tree using the software package BEAST v1.10.5 (Suchard et al. 2018) with the following settings: a skygrid demographic model, a relaxed molecular clock with a normal (8 × 10 -4 , 1 × 10 -4 ) prior distribution, and an HKY + G4 + I substitution model (Hasegawa et al...
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