Chronic infection perturbs the affinity hierarchy of antiviral B cells

A key function of the germinal center (GC) reaction consists in the preferential expansion and enrichment of high-affinity B cell clones. Whether and how persistent viral infection thwarts this purpose remains ill-defined. Here, we transferred monoclonal lymphocytic choriomeningitis virus–specific B cells into persistently infected hosts. High-affinity B cells expanded vigorously, forming GCs and abundant antibody-secreting cells. When failing to clear viremia or to drive viral mutational escape, the expanded B cell population contracted, ending in its quasi-complete disappearance from the spleen, a process we termed “attrition.” In stark contrast, low-affinity B cells expanded and persisted irrespective of high viral loads. B cell attrition was associated with phenotypic and transcriptional alterations including a prominent Blimp-1 transcriptional signature in high-affinity GC B cells. Blimp-1-deficient B cells were resistant to attrition, suggesting a B cell–intrinsic process. Moreover, exogenously supplied antibody feedback prevented attrition, suggesting that the latter may have resulted from excessive antigenic stimulation. Our findings suggest that in chronic viral infection, the incessant exposure to overwhelming amounts of antigen perturbs B cell affinity hierarchies by preferentially dysregulating high-affinity B cells. SIGNIFICANCE: Chronic viral infections pose a major challenge to global health, yet how viral persistence undermines antibody-mediated immunity is insufficiently understood. Here, we report that under continuous exposure to abundant viral antigen, high-affinity antiviral B cells undergo vigorous expansion followed by near-complete clonal deletion in the spleen—a process we term “attrition.” In striking contrast, low-affinity B cells sustain long-term responses throughout chronic viral infection. We further show that attrition is a B cell–intrinsic process that can be prevented by exogenously supplied antibody through a negative feedback–like mechanism. These findings offer an explanation for the long-standing observation that neutralizing antibody responses to chronic viral infections are often delayed and quantitatively inadequate, and they highlight potential avenues for therapeutic intervention.