The receptor-ligand interactions and intracellular signaling pathways that govern the production of antibodyproducing plasma cells and the persistence of plasma and memory B cells are poorly understood. Additional information on the mechanisms responsible for B cell migration, selection, and differentiation within and between specialized anatomical sites, particularly within lymphoid follicles, might be used to target suitable Env epitopes to appropriate B cell inductive pathways. An example would be to provide necessary signals to generate long-lived and high affinity memory in the marginal zone B cell compartment. Another example would be to discover ways to modify germinal center formation, positive and negative selection, and B cell differentiation to drive long-lived high affinity antibody responses against key epitopes that tend to be poorly immunogenic.