Inlay

Understanding how immune status shapes within-host SARS-CoV-2 diversity is key for interpreting transmission risk and evolutionary potential. Immunocompromised patients are often presumed to harbor more diverse viral populations, yet evidence early in infection remains limited. Analyzing samples, we compared minor variant (intra-host single-nucleotide variant [iSNV]) patterns between immunocompromised and immunocompetent individuals and evaluated lineage-specific effects. We found comparable within-host diversity, but normalized polymorphic sites were higher in immunocompetent than in immunocompromised individuals when considering all lineages. We observed an Mµ-restricted S-region signal: immunocompetent hosts showed higher S-region iSNV allele frequencies, whereas immunocompromised hosts exhibited a shift toward synonymous S-region iSNVs. These results refine assumptions about early infection in immunocompromised hosts, emphasize the value of reporting synonymous and non-synonymous changes, and highlight that conclusions can depend on viral lineage and the diversity metric considered. Our study underscores the need for immunophenotype-informed studies to test whether synonymous iSNVs modulate viral expression, replication, and transmission.