Prolonged severe acute respiratory syndrome coronavirus 2 infection and intrahost viral evolution in a severely immunocompromised patient with human immunodeficiency virus infection: A whole-genome sequencing study.

OBJECTIVES

Prolonged severe acute respiratory syndrome coronavirus 2 infection in immunocompromised individuals creates an environment conducive to intrahost viral evolution. We report persistent infection in a patient with advanced human immunodeficiency virus (HIV), aiming to delineate how partial immune reconstitution shapes viral evolution.

METHODS

Nasopharyngeal swabs were obtained at 12 time points over a period of 154 days. Viral RNA was extracted and analyzed using whole-genome sequencing (WGS). Viral genome dynamics were analyzed longitudinally.

RESULTS

All sequenced isolates were classified as Omicron sublineage BF.5 (BA.5.2.1.5). Between days 10 and 86, sequencing identified 30-60 mixed nucleotide positions per sample, indicating intrahost diversity. By day 93, a genetically uniform dominant genotype emerged and persisted through rebound detection, carrying multiple spike mutations atypical of BF.5, including T33K, R346K, V486F, T547K, and E554K. Phylogenetic analysis confirmed the patient-derived strain diverged significantly from other BF.5 isolates.

CONCLUSIONS

Serial WGS in advanced HIV infection revealed a selective sweep with fixation of spike substitutions atypical of the infecting lineage, consistent with immune-driven adaptation during prolonged infection. These findings highlight that persistent infections under profound immunosuppression can generate antigenically and genetically distinct viruses, emphasizing the value of longitudinal sequencing and targeted monitoring/management strategies in severely immunocompromised hosts.