IGHV1-69 BCRs with virus-neutralizing mutations show lymphoma-like transcriptomes in patients with chronic HCV infection

Author:

Schultheiß Christoph1ORCID,Willscher Edith2ORCID,Paschold Lisa3ORCID,Ackermann Christin4,Escher Moritz2,Scholz Rebekka2,Knapp Maximilian4,Lützkendorf Jana2ORCID,Müller Lutz5,Wiesch Julian Schulze zur6,Binder Mascha2ORCID

Affiliation:

1. Martin Luther University Halle-Wittenberg

2. Martin-Luther-University Halle-Wittenberg

3. Martin-Luther-University Halle, Saale

4. University Medical Center Hamburg-Eppendorf

5. Universitätsklinikum Halle

6. University Medical Center Hamburg-Eppendorf, Germany

Abstract

Abstract Chronic hepatitis C virus (HCV) infection leads to a complex interplay with adaptive immune cells that may result in cryoglobulinemia or lymphoma. Although direct-acting antiviral (DAA) therapy has decreased the incidence of severe liver damage, its effect on extrahepatic HCV manifestations such as B cell dyscrasias is still unclear. Here, we used immunosequencing to analyze HCV imprinting on B cell receptor (BCR) repertoires in patients with chronic HCV mono-infection or a sustained virological response (SVR) after DAA therapy. The majority of patients had a B cell signature with high somatic hypermutation and richness. Convergence to specific immunoglobulin genes produced high-connectivity complementarity-determining region 3 (CDR3) networks. Interestingly, IGHV1-69 CDR1 and CDR3 mutations characterizing highly neutralizing HCV antibodies corresponded to recurrent point mutations found in clonotypic BCRs of high-grade lymphomas. These BCRs did not show autonomous signaling but a lower activation threshold. B cells carrying these point mutations showed a persisting oncogenic transcriptome signature with dysregulation in signaling nodes such as CARD11, MALT1, RelB, MAPK, and NFAT. Collectively, this study provides evidence that lymphoma-like cells may result from the anti-HCV immune response and may persist for years after SVR, leading to HCV-related B cell dyscrasias and increased lymphoma risk beyond viral elimination.

Publisher

Research Square Platform LLC

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