Particulate Array of Well‐Ordered HIV Clade C Env Trimers Elicits Neutralizing Antibodies that Display a Unique V2 Cap Approach

Summary The development of soluble envelope glycoprotein (Env) mimetics displaying ordered trimeric symmetry has ushered in a new era in HIV‐1 vaccination. The recently reported native, flexibly linked (NFL) design allows the generation of native‐like trimers from clinical isolates at high yields and homogeneity. As the majority of infections world‐wide are of the clade C subtype, we examined responses in non‐human primates to well‐ordered subtype C 16055 trimers administered in soluble or high‐density liposomal formats. We detected superior germinal center formation and enhanced autologous neutralizing antibodies against the neutralization‐resistant (tier 2) 16055 virus following inoculation of liposome‐arrayed trimers. Epitope mapping of the neutralizing monoclonal antibodies (mAbs) indicated major contacts with the V2 apex, and 3D electron microscopy reconstructions of Fab‐trimer complexes revealed a horizontal binding angle to the Env spike. These vaccine‐elicited mAbs target the V2 cap, demonstrating a means to accomplish tier 2 virus neutralization by penetrating the dense N‐glycan shield. Graphical Abstract Figure. No Caption available. HighlightsWell‐ordered Env trimers conjugated to liposomes maintain the desired antigenic profileSuperior B cell responses were induced using liposome display of Env trimersmAbs capable of neutralizing the clade C 16055 virus (tier 2) were isolatedThe mAbs target the glycan‐shrouded V2 cap with a unique angle of approach &NA; Elicitation of antibodies capable of neutralizing circulating HIV‐1 strains is a priority for HIV‐1 vaccine development. Using a liposome‐based Env vaccine, Martinez‐Murillo et al. demonstrate induction of antibodies capable of neutralizing an autologous primary clade C isolate by targeting the Env V2 cap using a unique binding mode.

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