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Structure of an HIV-1–neutralizing antibody target, the lipid-bound gp41 envelope membrane proximal region trimer

Significance A major roadblock in the development of an HIV vaccine is the need to develop vaccine regimens that will induce antibodies that bind to conserved regions of the HIV envelope and neutralize many different virus quasispecies. One such envelope target is at the region closest to the membrane, the glycoprotein (gp) 41 membrane proximal external region (MPER). Previous work has demonstrated that antibodies that target this region bind both to the gp41 polypeptide and to the adjacent viral membrane. However, what has been missing is a view of what the MPER-neutralizing epitopes may look like in the context of a trimeric orientation with lipids. We have constructed an MPER trimer associated with lipids and solved the trimer structure by NMR spectroscopy. The membrane proximal external region (MPER) of HIV-1 glycoprotein (gp) 41 is involved in viral–host cell membrane fusion. It contains short amino acid sequences that are binding sites for the HIV-1 broadly neutralizing antibodies 2F5, 4E10, and 10E8, making these binding sites important targets for HIV-1 vaccine development. We report a high-resolution structure of a designed MPER trimer assembled on a detergent micelle. The NMR solution structure of this trimeric domain, designated gp41-M-MAT, shows that the three MPER peptides each adopt symmetric α-helical conformations exposing the amino acid side chains of the antibody binding sites. The helices are closely associated at their N termini, bend between the 2F5 and 4E10 epitopes, and gradually separate toward the C termini, where they associate with the membrane. The mAbs 2F5 and 4E10 bind gp41-M-MAT with nanomolar affinities, consistent with the substantial exposure of their respective epitopes in the trimer structure. The traditional structure determination of gp41-M-MAT using the Xplor-NIH protocol was validated by independently determining the structure using the DISCO sparse-data protocol, which exploits geometric arrangement algorithms that guarantee to compute all structures and assignments that satisfy the data.