The key to HIV vaccine development is the induction of broadly neutralizing antibodies (bnAb). The currently known bnAbs are directed against six regions of the HIV envelope glycoprotein trimer composed of gp120 and gp41. Several bnAbs that target a highly conserved epitope named "MPER" located on gp41 have been identified. Candidates for the development of a vaccine based on peptides mimicking this epitope have been tested without success. What is the reason for these failures ? In this study, researchers from EBEV group at IBS in collaboration with several universities characterized a novel highly potent human bnAb (LN01) directed against the MPER epitope of HIV. LN01 neutralizes 92% of a multi-clade 118 primary virus panel. By examining the structural details of LN01 epitope recognition, the researchers showed that the MPER epitope extends into the transmembrane region, which is essential for LN01 gp41 recognition. The structural studies revealed that the MPER epitope forms a continuous helix with the transmembrane region (TM) and identified two lipid binding sites. Based on molecular dynamics simulation, the researchers propose a model of interaction of LN01 with its epitope inserted in the viral membrane thereby allowing LN01 interaction with lipids. Both epitope and lipid interaction have been shown to be important for virus neutralization. All these data demonstrate that a candidate for vaccine development must include the MPER and transmembrane domain of gp41 correctly inserted into a lipid bilayer to induce broadly, cross-clade neutralizing antibodies.
Structural basis for broad HIV-1 neutralization by the MPER-specific human Broadly neutralizing antibody LN01. Pinto D, Fenwick C, Caillat C, Silacci C, Guseva S, Dehez F, Chipot C, Barbieri S, Minola A, Jarrossay D, Tomaras GD, Shen X, Riva A, Tarkowski M, Schwartz O, Bruel T, Dufloo J, Seaman MS, Montefiori DC, Lanzavecchia A, Corti D, Pantaleo G and Weissenhorn W. Cell Host Microbe ; 26(5):623-637.e8.