Stabilization of the V2 loop improves the presentation of V2 loop–associated broadly neutralizing antibody epitopes on HIV-1 envelope trimers

de Taeye, Steven W.Go, Eden P.Sliepen, Kwintende la Peña, Alba TorrentsBadal, KimberlyMedina-Ramírez, MaxLee, Wen-HsinDesaire, HeatherWilson, Ian A.Moore, John P.Ward, Andrew B.Sanders, Rogier W.2020-11-242020-11-242019-02-06de Taeye, S. W., Go, E. P., Sliepen, K., de la Peña, A. T., Badal, K., Medina-Ramírez, M., Lee, W. H., Desaire, H., Wilson, I. A., Moore, J. P., Ward, A. B., & Sanders, R. W. (2019). Stabilization of the V2 loop improves the presentation of V2 loop-associated broadly neutralizing antibody epitopes on HIV-1 envelope trimers. The Journal of biological chemistry, 294(14), 5616–5631. https://doi.org/10.1074/jbc.RA118.005396https://hdl.handle.net/1808/30913This research was originally published in the Journal of Biological Chemistry. de Taeye, S. W., Go, E. P., Sliepen, K., de la Peña, A. T., Badal, K., Medina-Ramírez, M., Lee, W. H., Desaire, H., Wilson, I. A., Moore, J. P., Ward, A. B., & Sanders, R. W. (2019). Stabilization of the V2 loop improves the presentation of V2 loop-associated broadly neutralizing antibody epitopes on HIV-1 envelope trimers. The Journal of biological chemistry, 294(14), 5616–5631. https://doi.org/10.1074/jbc.RA118.005396 © the Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License.A successful HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs) that target the envelope glycoprotein (Env) spike on the virus. Native-like recombinant Env trimers of the SOSIP design now serve as a platform for achieving this challenging goal. However, SOSIP trimers usually do not bind efficiently to the inferred germline precursors of bNAbs (gl-bNAbs). We hypothesized that the inherent flexibilities of the V1 and V2 variable loops in the Env trimer contribute to the poor recognition of gl-bNAb epitopes at the trimer apex that extensively involve V2 residues. To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and gl-bNAbs, we designed BG505 SOSIP.664 trimer variants containing newly created disulfide bonds intended to stabilize the V2 loop in an optimally antigenic configuration. The first variant, I184C/E190C, contained a new disulfide bond within the V2 loop, whereas the second variant, E153C/R178C, had a new disulfide bond that cross-linked V2 and V1. The resulting engineered native-like trimer variants were both more reactive with and were neutralized by V2 bNAbs and gl-bNAbs, a finding that may be valuable in the design of germline targeting and boosting trimer immunogens to create an antigenic conformation optimal for HIV vaccine development.© 2019 de Taeye et al.http://creativecommons.org/licenses/by/4.0/Human immunodeficiency virus (HIV)Glycoprotein structureStructure-functionProtein designAntibodyVaccine developmentHIV-1 envelope glycoprotein trimerStabilization of the V2 loop improves the presentation of V2 loop–associated broadly neutralizing antibody epitopes on HIV-1 envelope trimersArticle10.1074/jbc.RA118.005396https://orcid.org/0000-0001-9445-6671PMC6462529openAccess