Targeting intrinsic regulators of antibody and B cell memory to control chronic viral infection

Abstract

Abstract The production of antibody and formation of immunological memory underpins vaccine success. Yet, chronic viral infections result in an inadequate humoral response, and little is known about the mechanisms underpinning this dysregulation. We therefore utilised acute or chronic strains of lymphocytic choriomeningitis virus (LCMV) to investigate B cell behaviour in vivo during chronic infection. Our work revealed that chronic infection altered epigenetic regulation of B cell fate, and a key epigenetic target could be therapeutically modulated to correct antibody responses. Deep-sequencing revealed key differences in chromatin accessibility of B cells responding to acute vs chronic infection, leading us to investigate the Polycomb repressive complex 1 component BMI-1. BMI-1 was upregulated in germinal centre B cells of mice infected with chronic LCMV, compared to acute LCMV. B cell-intrinsic deletion of BMI-1 resulted in a restoration of splenic architecture, and an enhanced and rapid ability to clear virus. Deletion of BMI-1 re-established appropriate c-Myc expression in B cells, concomitant with improved quality of antibody with enhanced antibody-dependent effector function and increased neutralising capacity. Together, our data defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection. Further, single-cell RNA-seq and genetic models revealed that excess immune complexes, in concert with dysregulated complement-mediated functions, contribute to ineffective memory formation during chronic viral infection. Understanding the molecular events that may sustain dysfunction lays the foundation for improving therapeutic interventions in chronic infectious diseases. Supported by Bellberry-Viertel Senior Medical Research Fellowship and an AAI Careers in Immunology Fellowship.