Dysregulation of humoral immunity in chronic infection

Chronic viral infections disrupt the ability of the humoral immune response to produce neutralizing antibody or form effective immune memory, preventing viral clearance and making vaccine design difficult. Multiple components of the B-cell response are affected by pathogens that are not cleared from the host. Changes in the microenvironment shift production of B cells to short-lived plasma cells early in the response. Polyclonal B cells are recruited into both the plasma cell and germinal center compartments, inhibiting the formation of a targeted, high-affinity response. Finally, memory B cells shift toward an "atypical" phenotype, which may in turn result in changes to the functional properties of this population. While similar properties of B-cell dysregulation have been described across different types of persistent infections, key questions about the underlying mechanisms remain. This review will discuss the recent advances in this field, as well as highlight the critical questions about the interplay between viral load, microenvironment, the polyclonal response and atypical memory B cells that are yet to be answered. Design of new preventative treatments will rely on identifying the extrinsic and intrinsic modulators that push B cells toward an ineffective response, and thus identify new ways to guide them back onto the best path for clearance of virus and formation of effective immune memory.