Figure 2.

Reasons underlying failed induction of antibodies to CD4BD. Competing hypotheses advanced to explain failure of adaptive antibody synthesis to the CD4BD. Middle white panel: regulatory check-points in B cell differentiation influencing neutralizing antibody production. Right yellow panel: the CD4BD^core is a B cell superantigenic epitope that binds the FRs of constitutive BCRs non-covalently, but this causes B cell down-regulation. In contrast, covalent vaccination up-regulates B cells. Left light blue panel: other popular hypotheses based on studies by Dimitrov and coworkers, Scripps Institute investigators and NIH Vaccine Research Center investigators. Sufficient V gene mutations needed to bind CD4BD do not occur. Alternatively, the affinity of conserved HIV epitopes for BCRs is too low. NAbs, neutralizing antibodies. X, weakness in B cell response. √, our proposed basis for HIV vaccination.