The development of an HIV-1 vaccine is the best way to control and eradicate the HIV epidemic. 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 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, IRIG researchers and their collaborators characterized a novel, highly potent human bnAb (LN01) directed against the epitope called "MPER gp41" 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 (Figure). Thus, their results indicate that stabilizing the helix formed by MPER-TM, for example by chemical means, and its proper orientation in a lipid bilayer could mimic an immunogen that is capable of stimulating naïve B lymphocytes in order to initiate antibody production a key step in the activation of the body's defenses against HIV.

All these data demonstrate that a candidate for vaccine development must include the MPER and trans-membrane domain of gp41 correctly inserted into a lipid bilayer to induce broadly, cross-clade neutralizing antibodies.


The region of the gp41 protein that crosses the membrane (MPER in purple and TM in beige) adopts an alpha helix conformation whose orientation in the membrane depends on the lysine and arginine residues.  The LN01 antibody (light chain in yellow and heavy chain in orange) interacts with the MPER domain of gp41 and with the surface of the lipid bilayer. The CDR3 loop of the heavy chain is inserted into the bilayer to interact with the TM.