Effects of partially dismantling the CD4 binding site glycan fence of HIV-1 Envelope glycoprotein trimers on neutralizing antibody induction

Abstract Previously, VLPs bearing JR-FL strain HIV-1 Envelope trimers elicited potent neutralizing antibodies (nAbs) in 2/8 rabbits (PLoS Pathog 11(5): e1004932) by taking advantage of a naturally absent glycanat position 197 that borders the CD4 binding site (CD4bs). In new immunizations, we attempted to improve nAb responses by removing the N362 glycanthat also lines the CD4bs. All 4 rabbits developed nAbs. One targeted the N197 glycanhole like our previous sera. Two sera depended on the N463 glycan, again suggesting CD4bs overlap. Heterologousboosts appeared to reduce nAb clashes with the N362 glycan. The fourth serum targeted a N362 glycan-sensitive epitope. VLP manufacture challenges prevented us from immunizing larger rabbit numbers to empower a robust statisticalanalysis. Nevertheless, trends suggest that targeted glycanremoval may improve nAb induction by exposing new epitopes and that it may be possible to modify nAb specificity using rational heterologousboosts.