Intrahost evolution leading to distinct lineages in the upper and lower respiratory tracts during SARS-CoV-2 prolonged infection

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 sublineage BF.7, estimated to have persisted for over one year in an immunosuppressed patient. Based on the sequencing of eight samples collected at six time points, we identified 87 intrahost single-nucleotide variants (iSNVs), two indels, and a 362 bp deletion. Our analysis revealed distinct viral genotypes in the nasopharyngeal (NP), endotracheal aspirate (ETA), and bronchoalveolar (BAL) 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 sublineage BF.7 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 anatomical compartments. This provides novel insights into the intricate nature of viral diversity and evolution dynamics in persistent infections.