Despite quantitatively robust humoral immune responses to HIV-1, prophylaxis is rare because broadly neutralizing antibodies are uncommon after natural immunization or vaccination. Increasing evidence suggests this reflects the counterselection of B cells needed for broadly neutralizing responses at checkpoints imposed during B cell development or activation. These observations predict that relaxing B cell counterselection should alter the quality of HIV-specific responses and establish repertoires with prophylactic potential, but this prediction has not been directly tested. The cytokine BLyS modulates B cell selection at two checkpoints: first at the transitional to mature preimmune B cell developmental step; and then among activated B cells in the germinal center. Importantly, treating mice with BLyS prior to HIV-1 envelope immunization yields an increased frequency of mice responding with broader neutralizing activity. Together, these observations position us for detailed study of how relaxed selection at the transitional and/or germinal center checkpoints impacts the ability to mount broadly neutralizing responses.
In Aim 1, we will determine whether relaxing transitional selection with BLyS establishes a preimmune repertoire more capable of broad neutralization. We will accomplish this through analyses of repertoire composition and diversity in the transitional, follicular and marginal zone B cell subsets, followed by single-cell cloning and re-expression of antibodies to assess HIV neutralizing capacity.
In Aim 2, we will use a similar strategy to determine whether surplus BLyS alters germinal center selection, and allows somatically mutated germinal center B cells capable of broadly neutralizing responses to persist and enter memory B cell pools. We will compare GC and memory B cells from mice treated with BLyS prior to immunization with Env, or from mice treated with exogenous BLyS in the early stages of GC formation after Env immunization.
In Aim 3, we will extend our findings to nonhuman primates, by determining whether rhesus macaques show similar enlargement of TR and FO pools after BLyS treatment, and whether BLyS treatment prior to Env vaccination improves neutralizing antibody breadth.
One roadblock to developing effective HIV vaccines is that some of the cells required for protective immune responses are naturally eliminated during their development or activation. Advances in our understanding of the factors that control these losses provide an opportunity to study how and why such HIV responsive cells are eliminated. The proposed research will exploit these advances to understand how these cells are lost, and to explore ways they can be preserved, through studies in both mice and non-human primates.
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