Characterization of human monoclonal antibodies is providing considerable insight into mechanisms of broad HIV-1 neutralization. Here we report an HIV-1 gp41 membrane-proximal external region (MPER)-specific antibody, named 10E8, which neutralizes ∼98% of tested viruses. An analysis of sera from 78 healthy HIV-1-infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificities. In contrast to other neutralizing MPER antibodies, 10E8 did not bind phospholipids, was not autoreactive, and bound cell-surface envelope. The structure of 10E8 in complex with the complete MPER revealed a site of vulnerability comprising a narrow stretch of highly conserved gp41-hydrophobic residues and a critical arginine or lysine just before the transmembrane region. Analysis of resistant HIV-1 variants confirmed the importance of these residues for neutralization. The highly conserved MPER is a target of potent, non-self-reactive neutralizing antibodies, suggesting that HIV-1 vaccines should aim to induce antibodies to this region of HIV-1 envelope glycoprotein. A novel neutralizing antibody from a healthy HIV-1-infected donor that is specific for the membrane proximal region of gp41 is reported; the antibody has high potency and breadth, is not autoreactive and does not bind phospholipids. Jinghe Huang et al. report a novel neutralizing antibody from a healthy HIV-1-infected donor that is specific for the membrane-proximal region of gp41. The antibody has high potency and breadth, is not autoreactive and does not bind phospholipids. This work demonstrates a conserved site of gp41 vulnerability that is an important target antigen for HIV neutralization, with implications for efforts to elicit broadly neutralizing antibodies with vaccines.

Broad and potent neutralization of HIV-1 by a gp41-specific human antibody