Abstract
Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.
Highlights
An effective HIV vaccine will likely require the elicitation of protective titers of broadly neutralizing antibodies (NAbs [broadly neutralizing antibody (NAb) (bNAb)])
The panel included a BG505.T332N-LAI chimeric infectious molecular clone derived from the BG505 isolate, as well as BL035 and Q23 clade A envelope glycoprotein (Env)-pseudotyped viruses that have epidemiological and genetic links to BG505 (Table S2; Neilson et al, 1999;Wu et al, 2006; Bonsignori et al, 2011).The remaining viruses were 27 clade B clinical isolates obtained 1–12 mo after infection from patients enrolled in the Amsterdam Cohort Studies on HIV/AIDS (ACS) that developed moderate to strong neutralization breadth (Table S2; Euler et al, 2010, 2011; van den Kerkhof et al, 2013; Lynch et al, 2015)
The rationale for choosing these 27 viruses was that early Env sequences from patients whose neutralization response broadened over time might be markedly more reactive with gl-broadly NAb (bNAb) than Env sequences shaped by the antibody response in chronically infected people (Liao et al, 2013; Doria-Rose et al, 2014)
Summary
An effective HIV vaccine will likely require the elicitation of protective titers of broadly neutralizing antibodies (NAbs [bNAbs]). The envelope glycoprotein (Env) on the virion surface is the only relevant target for bNAbs and, is the main focus for antibody-based vaccine strategies.Approximately 30%–50% of infected individuals eventually develop bNAbs (Mascola and Haynes, 2013; van Gils and Sanders, 2013; Hraber et al, 2014; Burton and Mascola, 2015), and passive immunization studies have shown that various bNAbs can protect macaques from experimental challenge It has not yet been possible to induce bNAbs by vaccination.Even eliciting NAbs with narrow specificity against neutralization-resistant (Tier-2) primary viruses has been challenging but is possible (Sanders et al, 2015; Escolano et al, 2017; Sanders and Moore, 2017)
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