Structural Basis for Broad HIV-1 Neutralization by a Novel MPER-Specific Human Broadly Neutralizing Antibody

Potent and broadly neutralizing antibodies (bNAbs) are the hallmark of HIV-1 protection by vaccination. The membrane-proximal external region (MPER) of the HIV-1 gp41 fusion protein is highly conserved and targeted by the most broadly-reactive HIV-1 neutralizing antibodies. Here we report on a new anti-MPER bNAB, LN01, isolated from lymph-node derived germinal center B cells of an Elite Controller, which neutralizes 92% of a 118-strain virus panel. MPER and the transmembrane region (TM) form a continuous helix in complex with LN01, whereas the tilted TM conformation allows LN01 to interact simultaneously with its epitope and with membrane via two specific lipid binding sites of the antibody paratope as revealed by molecular dynamics simulation. Although LN01 carries a high load of somatic mutations, most of the key residues interacting with the MPER epitope and lipids are germline encoded, lending support for the LN01 epitope as a candidate for lineage-based vaccine development.