B CELLS WITH VIRUS‐NEUTRALIZING IGHV1‐69 MUTATIONS SHOW LYMPHOMA‐LIKE TRANSCRIPTOMES IN PATIENTS WITH CHRONIC HEPATITIS C INFECTION

Introduction: Chronic hepatitis C virus (HCV) infection leads to a complex interplay with adaptive immune cells that may result in B cell dyscrasias such as type II mixed cryoglobulinemia and lymphoma. The introduction of direct-acting antiviral (DAA) therapy has reduced the burden severe liver damage its clinical consequences. However, effect viral elimination on extrahepatic manifestations HCV accompanying dyscrasia remains be defined. Methods: We sequenced repertoires patients chronic sustained virological response (SVR) after DAA therapy. This data set was mined for highly neutralizing antibodies compared diffuse large lymphoma set. TKO model used test signaling strength selected receptors (BCRs) vitro. Single-cell RNA sequencing SVR samples performed analyze transcriptome HCV-neutralizing antigen receptor. Results: majority showed fingerprint high richness somatic hypermutation. Convergence specific immunoglobulin genes produced complementarity-determining region 3 (CDR3) sequence networks connectivity. IGHV1-69 CDR1 CDR3 mutations characterizing corresponded recurrent point found clonotypic BCRs high-grade lymphomas. These did not confer autonomous BCR but lowered threshold activation-induced signaling. In addition, carrying these persisting oncogenic signature dysregulation nodes CARD11, MALT1, RelB MAPK, NFAT pathways. Conclusions: provide evidence lymphoma-like derive from anti-HCV response. many patients, persist years can interpreted mechanistic basis HCV-related increased risk even beyond elimination. research funded by: by Deutsche Forschungsgemeinschaft (DFG). Grant numbers: SFB841 DFG BI 1711/4-1 MB. Keywords: Non-Hodgkin (Pediatric, Adolescent, Young Adult), Tumor Biology Heterogeneity No conflicts interests pertinent abstract.