Ectopic EBV Infection in T Cells Identifies Reduced Therapeutic Responsiveness and Immune Dysfunction After Allogeneic Hematopoietic Stem Cell Transplantation.
Abstract
Objectives
EBV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is typically monitored by plasma viral load, but this fails to capture cellular reservoirs. Lineage-specific testing, though usually performed in high-risk patients, may identify biologically distinct disease states. We aimed to evaluate the clinical and biological significance of lineage-specific EBV quantification especially ectopic EBV infection in T cells in allo-HSCT recipients with EBV reactivation.
Methods
We analyzed 144 allo-HSCT recipients with EBV reactivation who underwent lineage-specific EBV quantification, assessed whether T-cell tropic EBV burden identifies a phenotype with reduced responsiveness to rituximabtherapy, an increased risk of post-transplant lymphoproliferative disorder (PTLD), and specific features of underlying immune dysfunction.
Results
Among the tested high-risk patients with high EBV loads and clinical symptoms, 66.6% exhibited T-cell tropic EBV infection. Compared with non-T-cell tropic infection, T-cell tropism was associated with higher rituximab courses and lower complete response rates (67% vs. 81%, P=0.029), suggesting insufficient efficacy of CD20-directed therapy. Patients with T-cell tropic infection had a significantly higher 1-year cumulative incidence of PTLD compared to the non-T-cell tropic group(77% vs. 41.6%; P < 0.001). Single-cell RNA sequencing and mass cytometry analyses revealed an exhausted T-cell phenotype with diminished stemness in T-cell tropic EBV infected patients.
Conclusions
These findings suggest that T-cell EBV quantification distinguishes a therapeutically challenging subtype of EBV reactivation characterized by immune dysfunction and reduced responsiveness to rituximab-based therapy. Incorporating assessment of cellular viral reservoirs into post-transplant EBV monitoring strategies may facilitate early risk stratification and support timely therapeutic escalation beyond rituximab alone.