Memory B-cells and antibody are key providers of long-lived immunity against
infectious disease. How chronic viral infection disrupts memory B-cells and antibody,
and whether such changes are reversible through therapeutic intervention, remains
unknown. Epigenetic programs establish the identity and function of B-cell subsets.
We therefore set out to determine how antibody responses and memory B-cells are
epigenetically altered by inflammatory signals during chronic viral infection, using
single-cell resolution of the transcriptome and chromatin landscape. Using this
system, our study revealed that type-I interferon (IFN-I) dynamics are a key
determinant in shaping chronic memory B-cell development in vivo. We further
identified the histone modifier BMI-1 as a key target to correct dysregulated antibody
responses during chronic viral infection and autoimmunity. Collectively, our research
identifies key mechanisms to instruct antibody and memory B-cell identity during viral
infection, thus laying the foundation for improving therapeutic interventions in chronic
infectious disease.