Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile
Edurne Rujas,
Daniel P. Leaman,
Sara Insausti,
Pablo Carravilla,
Miguel García-Porras,
Eneko Largo,
Izaskun Morillo,
Rubén Sánchez-Eugenia,
Lei Zhang,
Hong Cui,
Ibon Iloro,
Félix Elortza,
Jean-Philippe Julien,
Christian Eggeling,
Michael B. Zwick,
Jose M.M. Caaveiro,
José L. Nieva
Affiliations
Edurne Rujas
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Corresponding author
Daniel P. Leaman
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Sara Insausti
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain
Pablo Carravilla
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain; Institute of Applied Optics and Biophysics Friedrich-Schiller-University Jena, Max-Wien Platz 1, 07743 Jena, Germany; Leibniz Institute of Photonic Technology e.V., Albert-Einstein-Straße 9, 07745 Jena, Germany
Miguel García-Porras
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain
Eneko Largo
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain
Izaskun Morillo
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain
Rubén Sánchez-Eugenia
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain
Lei Zhang
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Hong Cui
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
Ibon Iloro
Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, 48160 Derio, Spain
Félix Elortza
Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, 48160 Derio, Spain
Jean-Philippe Julien
Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
Christian Eggeling
Institute of Applied Optics and Biophysics Friedrich-Schiller-University Jena, Max-Wien Platz 1, 07743 Jena, Germany; Leibniz Institute of Photonic Technology e.V., Albert-Einstein-Straße 9, 07745 Jena, Germany; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, OX3 9DS Oxford, UK
Michael B. Zwick
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
Jose M.M. Caaveiro
Laboratory of Global Healthcare, School of Pharmaceutical Sciences, Kyushu University, Fukuoka 819-0395, Japan; Corresponding author
José L. Nieva
Instituto Biofisika (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain; Corresponding author
Summary: Broadly neutralizing antibodies (bnAbs) against HIV-1 are frequently associated with the presence of autoreactivity/polyreactivity, a property that can limit their use as therapeutic agents. The bnAb 4E10, targeting the conserved Membrane proximal external region (MPER) of HIV-1, displays almost pan-neutralizing activity across globally circulating HIV-1 strains but exhibits nonspecific off-target interactions with lipid membranes. The hydrophobic apex of the third complementarity-determining region of the heavy chain (CDRH3) loop, which is essential for viral neutralization, critically contributes to this detrimental effect. Here, we have replaced the aromatic/hydrophobic residues from the apex of the CDRH3 of 4E10 with a single aromatic molecule through chemical modification to generate a variant that preserves the neutralization potency and breadth of 4E10 but with reduced autoreactivity. Collectively, our study suggests that the localized accumulation of aromaticity by chemical modification provides a pathway to ameliorate the adverse effects triggered by the CDRH3 of anti-HIV-1 MPER bnAbs.
