Purpose of review: This review discusses progress in understanding the impact of immune tolerance on inducing broadly neutralizing antibodies (bnAbs), and how such knowledge can be incorporated into novel immunization approaches.
Recent findings: Over 120 bnAbs have now been isolated, all of which bear unusual features associated with host tolerance controls, but paradoxically may also be required for their function. Evidence that poly/autoreactivity of membrane proximal external region bnAbs can invoke such controls has been demonstrated by knock-in technology, highlighting its potential for studying the impact of tolerance in the generation of bnAb lineages to distinct HIV-1 envelope targets. The requirement for extensive affinity maturation in developing neutralization breadth/potency during infection is being examined, and similar studies in the setting of immunization will be aided by testing novel vaccine approaches in knock-in models that either selectively express reverted V(D)J rearrangements, or unrearranged germline segments, from which bnAb lineages originate.
Summary: It is increasingly apparent that immune tolerance, sometimes invoked by self-reactivity that overlaps with bnAb epitope specificity, adds to a formidable set of roadblocks impeding bnAb induction. The path to an effective HIV-1 vaccine may thus benefit from a deeper understanding of host controls, including categorizing those that are unique or common at distinct bnAb targets, and ranking those most feasible to overcome by immunization. Ultimately, such emerging information will be critical to incorporate into new vaccine approaches that can be tested in human trials.