Molecular recognition of a membrane-anchored HIV-1 pan-neutralizing epitope.

Antibodies against the carboxy-terminal section of the membrane-proximal external region (C-MPER) of the HIV-1 envelope glycoprotein (Env) are considered as nearly pan-neutralizing. Development of vaccines capable of producing analogous broadly neutralizing antibodies requires deep understanding of the mechanism that underlies C-MPER recognition in membranes. Here, we use the archetypic 10E8 antibody and a variety of biophysical techniques including single-molecule approaches to study the molecular recognition of C-MPER in membrane mimetics. In contrast to the assumption that an interfacial MPER helix embodies the entire C-MPER epitope recognized by 10E8, our data indicate that transmembrane domain (TMD) residues contribute to binding affinity and specificity. Moreover, anchoring to membrane the helical C-MPER epitope through the TMD augments antibody binding affinity and relieves the effects exerted by the interfacial MPER helix on the mechanical stability of the lipid bilayer. These observations support that addition of TMD residues may result in more efficient and stable anti-MPER vaccines.This study was supported by MCIN/AEI/10.13039/501100011033 - “ERDF A way of making Europe” (Grant PID2021-126014OB-I00 to J.L.N. and B.A.), MCIN/AEI/10.13039/501100011033 (Grant PID2020-112821GB-I00 to M.A.J.), Basque Government (Grant: IT1449-22 to J.L.N. and B.A.) and Kiban-B grant 20H03228 from JSPS to J.M.M.C. L.R.-M. acknowledges funding from the Agence National de la Recherche (ANR), as part of the ‘Investments d′Avenir’ Program (I-SITE ULNE/ANR-16-IDEX-0004 ULNE). This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 895819 (to C.V.). Work at Pompeu Fabra University was supported by the María de Maeztu network of Units of Excellence of the Spanish Ministry of Science and Innovation. Technical assistance from Miguel García-Porras is greatly acknowledged. The NMR experiments were performed in the “Manuel Rico” NMR laboratory, LMR, CSIC, a node of the Spanish Large-Scale National Facility ICTS R-LRB