Molecular Characterization of Persistent SARS-CoV-2 Infections in Immunocompromised Patients

Immunocompromised patients, including those with advanced HIV infection, hematologic malignancies treated with anti-CD20 monoclonal antibodies, or combined immunodeficiencies, are at increased risk of persistent SARS-CoV-2 infection. While long-term viral shedding has been described in these patients, the extent and nature of intra-host viral evolution during long-term infection remain insufficiently documented. In this study, we report longitudinal genomic analyses of SARS-CoV-2 from three immunocompromised individuals with persistent COVID-19: (i) a female patient with follicular lymphoma receiving bendamustine-rituximab therapy with 9 months of persistence, (ii) a male patient with advanced HIV infection following prolonged antiretroviral therapy interruption with 10 months of persistence, and (iii) a female patient with Good’s Syndrome characterized by combined humoral and cellular immune deficiency with apparently four years of persistence. Replication-competent virus was detected over extended periods. Sequential whole-genome sequencing revealed the gradual accumulation of non-synonymous mutations across multiple viral genes, consistent with ongoing viral replication and intra-host diversification in the absence of effective immune control. Although based on a limited number of cases, these findings provide descriptive evidence that persistent SARS-CoV-2 infection in immunocompromised hosts can be associated with sustained viral evolution. This work highlights the importance of continued virological monitoring in selected patients with prolonged infection and contributes to the understanding of SARS-CoV-2 dynamics in settings of impaired immunity.