Integrated EBV and host DNA methylation profiling identifies distinct candidate EBV-host junction patterns in chronic active EBV infection.

. In CAEBV, candidate junctions were enriched in intronic and promoter regions, common fragile sites, and repetitive elements. At the gene level, recurrently targeted host loci included genes implicated in genomic instability and cancer-related pathways. In exploratory longitudinal analyses, allogeneic hematopoietic stem cell transplantation was associated with lower EBV methylation levels and fewer detectable candidate EBV-host junctions, whereas chemotherapy alone was not associated with comparable changes. These data characterize EBV and host methylation landscapes together with candidate EBV-host junction patterns in CAEBV. The findings provide epigenetic and genomic clues to CAEBV pathogenesis and generate hypotheses regarding potential biomarkers of treatment response, but require validation in larger, independent cohorts. IMPORTANCE: Chronic active Epstein-Barr virus (CAEBV) infection is a rare but severe disease that can progress to life-threatening inflammation or lymphoma, yet its molecular basis remains poorly understood. We found that both the EBV genome and the host genome exhibit distinct DNA methylation patterns in children with CAEBV compared with infectious mononucleosis. We also identified more frequent candidate EBV-host junction signals in CAEBV and observed that these signals became less detectable after successful hematopoietic stem cell transplantation. These findings improve our understanding of host-virus interactions in CAEBV and provide candidate molecular features that may be useful for future studies of disease mechanisms and treatment monitoring.