Immunological dysfunction associated with SARS-CoV-2 persistence in immunocompromised patients

Advances in coronavirus disease 2019 management has led to decreases in disease burden; however, immunocompromised patients continue to experience prolonged or persistent infections. We investigated immunological factors associated with time to viral clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunocompromised patients. By integrating clinical follow-up data, SARS-CoV-2-specific humoral and cellular response data, and single-cell RNA transcriptomic data, we uncovered differential immune responses between patients exhibiting short or long time-to-clearance (TTC), both at diagnosis and later during infection. We found that prolonged infection was associated with reduced SARS-CoV-2-specific humoral responses (P = 0.035) and diminished development of CD4+ and CD8+ T-cell activation (P = 0.045 and P = 0.038, respectively) despite levels of interferon-γ-producing T cells not being negatively affected. Baseline transcriptional profiles revealed increased immunological engagement of CD8+ cytotoxic T and natural killer (NK) cells among patients with prolonged TTC, potentially to compensate for impaired functional T-cell activation. Differential gene expression further pointed towards features of impaired T-cell functionality and exhaustion as contributors to prolonged TTC, including enrichment of NEAT1, CD52, and IL12RB2 in Long TTC patients. Our findings indicate that impaired viral clearance in some immunocompromised patients reflects an actively engaged yet dysregulated immune response. This underscores the complexity of immune dysfunction in this population and highlights the need for targeted interventions to restore effective, antiviral immunity, with a particular focus on regaining functional activation of antigen-specific T cells.