The recent isolation of broad neutralizing antibodies (bnAbs) from HIV-1 clonally infected patients has invigorated the HIV-1 vaccine development field. However, all bnAbs have one or more unusual traits: polyreactivity, significantly higher frequency of somatic hypermutations and/or long HCDR3 regions-traits that pre-dispose bnAbs to immune tolerance control. Our strategy to overcome host limitation of induction of bnAbs is to design immunogens based on their binding affinity for unmutated ancestor (UA) and/or intermediate ancestor (IA) antibodies of bnAbs and to formulate antigenic envelope proteins with potent adjuvants for optimal stimulation of anergic or subdominant bnAbs clonal lineages. To achieve this, numerous clonal lineages of bnAbs must be isolated and their UAs and IAs inferred. We have isolated clonal lineages of gp41 membrane proximal, CD4 bind site, V1/V2 and glycan-specific bnAbs, and designed immunogens targeted at their UAs and IAs. The characteristics of B cell maturation pathways of bnAbs will be presented, and the results of testing Env immunogens in humanized bnAb Ig VH+VL knock-in mice and rhesus macaques will be discussed.
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