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Prolonged SARS-CoV-2 infection in immunocompromised hosts enables sustained within-host viral evolution, yet its dynamics remain unclear. We analysed longitudinal sequencing data from 677 samples across 82 patients (52 immunocompromised, 30 non-immunocompromised), quantifying mutation accumulation and allele-frequency dynamics. Immunocompromised patients showed fewer transient but more convergent mutations, indicating enhanced retention of within-host variation. Early-pandemic lineages exhibited time-dependent accumulation driven by minor variants, whereas Omicron infections showed higher baseline mutational burdens but limited temporal change, suggesting constrained diversification. Gene-level analyses revealed a shift from diffuse exploration in replication-associated proteins to selective fixation in key regions, particularly Spike and processing-associated non-structural proteins. Two evolutionary trajectories emerged: neutral and accelerated. Accelerated evolution was linked to antiviral and corticosteroid exposure, increased transversion rates, reduced synonymous-to-non-synonymous ratios, and host-mediated RNA editing signatures. These findings show that prolonged infection stabilises intra-host diversity and drives treatment-dependent evolutionary pathways.
Prolonged SARS-CoV-2 infection in immunocompromised hosts enables sustained within-host viral evolution, yet its dynamics remain unclear. We analysed longitudinal sequencing data from 677 samples across 82 patients (52 immunocompromised, 30 non-immunocompromised), quantifying mutation accumulation and allele-frequency dynamics. Immunocompromised patients showed fewer transient but more convergent mutations, indicating enhanced retention of within-host variation. Early-pandemic lineages exhibited time-dependent accumulation driven by minor variants, whereas Omicron infections showed higher baseline mutational burdens but limited temporal change, suggesting constrained diversification. Gene-level analyses revealed a shift from diffuse exploration in replication-associated proteins to selective fixation in key regions, particularly Spike and processing-associated non-structural proteins. Two evolutionary trajectories emerged: neutral and accelerated. Accelerated evolution was linked to antiviral and corticosteroid exposure, increased transversion rates, reduced synonymous-to-non-synonymous ratios, and host-mediated RNA editing signatures. These findings show that prolonged infection stabilises intra-host diversity and drives treatment-dependent evolutionary pathways.
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana