Blood virome profiling reveals subtype-specific viral signatures and reduced diversity in non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL), a heterogeneous lymphoid malignancy, demonstrates molecular diversity linked to genetic and immune factors, with emerging roles for viral infections in pathogenesis. Yet, the blood virome's composition and dynamics in NHL remain poorly characterized. This study characterizes the blood virome in NHL subtypes using viral metagenomic sequencing of serum from 217 patients (B-cell: BCL, T-cell: TCL, NK-cell: NKCL) and 40 healthy controls. Bioinformatic analysis identified 45 viral families, revealing subtype-specific viromic signatures. BCL exhibited a dominance of Anelloviridae, which accounted for 86% of eukaryotic viruses, compared with only 3% in controls, correlating with immunosuppression. Additionally, picobirnavirus, an opportunistic pathogen particularly in hosts with compromised immune systems, also showed a significant difference compared to controls. NKCL showed Flaviviridae enrichment, accounting for 82% of eukaryotic viruses, with nearly all of them being human pegivirus-1 (HPgV-1). Compared with healthy controls, patients with NHL exhibited significantly lower blood virome α-diversity at the genus level, and T-cell lymphomas showed the lowest species-level richness (140 vs. 332 in controls). Beta diversity highlighted BCL-specific viral heterogeneity, contrasting conserved T/NKCL viral profiles. Anelloviridae and Picobirnavirus expansion aligns with immune dysfunction, whereas NKCL-restricted HPgV-1 prevalence underscores biomarker potential. These findings implicate blood virome alterations marked by viral family predominance and diversity loss in NHL pathogenesis via immune modulation or oncogenesis. This first comprehensive NHL virome profile identifies subtype-specific signatures (Anelloviridae/Picobirnavirus/HPgV-1) for potential diagnostic and therapeutic targeting. Validation of these biomarkers may refine NHL subtyping and elucidate virome-lymphomagenesis mechanisms.