Fig. 1.

Experimental demonstration of autoantibody redemption in the HEL transgenic mouse system. (A) The immunization schema that allowed detection of rescued anergic autoreactive B cells following HEL-RBC immunization. HEL-specific B cells from double-transgenic mice, rendered anergic because of their prior encounter with soluble-expressed HEL, were injected into HEL transgenic mice, together with a HEL-SRBC immunogen. Immunized mice driven to generate anergic HEL-specific GC B cells were induced to acquire mutations in the HEL antibody HCDR2 region that resulted in decreased affinity for HEL and increased B-cell survival. (B) An illustration of how such a mechanism may contribute to bnAb responses during HIV-1 infection, and how B-cell populations generated by this process could be harnessed in the setting of HIV-1 vaccination. Vaccination with HIV-1 Env may result in either a population of anergic GC B cells, which have accumulated somatic mutations that generate bnAb specifcity (red) and self-reactivity (black), but may also generate rare B cells with BCR that harbor decreased self-reactivity, while retaining bnAb HIV-1 Env affinity. The hypothesis is that Env vaccination targeted at disfavored bnAb B-cell clonal lineages could drive otherwise unfavored and rare HIV-1–specific B-cell clones in GC to survive and proliferate.