B cell transcriptomics reveals lasting dysregulation and rapid decline of protective memory after hepatitis C cure

Chen, F.; Giang, E.; Natarajan, P.; Mondala, T. S.; Head, S. R.; Lau, S. C.; Sundaresan, A.; Kulakova, L.; Lin, X.; Aneja, J.; Andrabi, R.; Zhang, Y.; Scheuermann, R. H.; Toth, E. A.; Fuerst, T. R.; Lewis-Ximenez, L.; Kim, A. Y.; Pockros, P.; Lauer, G. M.; Law, M.

doi:10.1101/2025.10.24.664545

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bioRxiv · 10.1101/2025.10.24.664545

B cell transcriptomics reveals lasting dysregulation and rapid decline of protective memory after hepatitis C cure

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Abstract

O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/664545v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@d12426org.highwire.dtl.DTLVardef@9c54daorg.highwire.dtl.DTLVardef@186d559org.highwire.dtl.DTLVardef@120f2f3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG HighlightsO_LIB cells in CHC patients retained dysregulated transcriptional profiles despite successful DAA treatment C_LIO_LIB cell dysregulation is marked by global B cell hyperactivation and antigen-specific atypical MBC expansion C_LIO_LISustained upregulation of TNF- signaling via NF-{kappa}B (TNF-/NF-{kappa}B) is a central driver of persistent B cell dysregulation and chronic inflammation C_LIO_LIViral clearance leads to restoration of IFN responses and IFN-stimulated gene (ISG) signatures in B cells but not TNF-/NF-{kappa}B C_LIO_LIHCV IGHV1-69 bnAb-producing B cells are enriched within the CD86hi IgG MBC subset before treatment C_LIO_LICD86hi IgG MBC subset contracts rapidly post-cure in parallel with the rapid decline of cross-nAb responses and loss of protective immune memory against HCV reinfection C_LI Chronic hepatitis C (CHC) disrupts host humoral immune response by impairing the timely generation of neutralizing antibody (nAb) and durable immune memory. However, the underlying mechanisms and their reversibility after viral clearance remain poorly defined. Here, through integrated single-cell transcriptomics and antibody repertoire characterization, we show that B cells from CHC patients retain transcriptional dysregulation even after successful antiviral therapy. Sustained TNF- signaling emerged as a central driver of chronic B cell hyperactivation, persistent dysregulation and unresolved inflammation following cure. Furthermore, a CD86hi memory B cell subset, responsible for an IGHV1-69-encoded multi-donor class recall nAb response, declined rapidly following viral clearance, compromising immune memory against reinfection. Together, these findings reveal how CHC imprints lasting B cell dysregulation, impairs nAb memory, and sustains inflammation in the B cell compartment, after viral clearance. The insights underscore the need for strategies aimed at restoring B cell homeostasis to achieve durable immune protection.

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Chen, F., Giang, E., Natarajan, P., Mondala, T. S., Head, S. R., Lau, S. C., Sundaresan, A., Kulakova, L., Lin, X., Aneja, J., Andrabi, R., Zhang, Y., Scheuermann, R. H., Toth, E. A., Fuerst, T. R., Lewis-Ximenez, L., Kim, A. Y., Pockros, P., Lauer, G. M., Law, M.. 2025-10-24. B cell transcriptomics reveals lasting dysregulation and rapid decline of protective memory after hepatitis C cure. https://doi.org/10.1101/2025.10.24.664545

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