The HIV-1 fusion protein subunit gp41 contains a highly conserved sequence that is essential for membrane fusion and targeted by broadly neutralizing antibodies such as 2F5, 4E10, Z13e1, and 10E8. These antibodies recognize a linear gp41 epitope with high affinity, but require additional hydrophobic sequences present in their heavy chain CDR3 for neutralization. Recent structural studies on mAbs 4E10 and 10E8 provide molecular details for specific interactions with lipids and implicate part of the transmembrane region as the relevant 10E8 epitope. Although many different approaches have been applied to engineer gp41 immunogens that can induce broadly neutralizing antibodies directed toward MPER, only modest success has yet been reported.

The new structural details on the complex gp41-lipidic epitope will spur new approaches to design gp41-MPER immunogens that might induce broadly neutralizing antibody responses.