Neutralizing antibodies elicited in sequentially immunized macaques recognize V3 residues on altered conformations of HIV-1 Env trimer

Abstract

Eliciting broadly neutralizing antibodies that protect against diverse HIV-1 strains is a primary goal of AIDS vaccine research. We characterized Ab1456 and Ab1271, two heterologously-neutralizing antibodies elicited in non-human primates by priming with an engineered V3-targeting SOSIP Env immunogen and boosting with increasingly native-like SOSIP Envs derived from different strain backgrounds. Structures of Env trimers in complex with these antibodies revealed V3 targeting, but on conformational states of Env distinct from the typical closed, prefusion trimeric SOSIP structure. Env trimers bound by Ab1456 adopted conformations resembling CD4-bound open Env states in the absence of soluble CD4, whereas trimers bound by Ab1271 exhibited a trimer apex-altered conformation to accommodate antibody binding. The finding that elicited antibodies cross-neutralized by targeting altered, non-closed, prefusion Env trimer conformations provides important information about Env dynamics that is relevant for HIV-1 vaccine design aimed at raising antibodies to desired epitopes on closed pre-fusion Env trimers. Highlights- Sequential immunization regimen elicits V3 antibodies targeting non-closed Envs - Cryo-EM structures reveal recognition of multiple Env conformational states - Neutralization by elicited antibody does not require antibody-virus preincubation Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/605918v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6210b1org.highwire.dtl.DTLVardef@35f683org.highwire.dtl.DTLVardef@cb2d3corg.highwire.dtl.DTLVardef@106e066_HPS_FORMAT_FIGEXP M_FIG C_FIG