Molecular parameters governing antibody FcγR signaling and effector functions in the context of HIV envelope
Michael V. Bick,
Eduard Puig,
David Beauparlant,
Rebecca Nedellec,
Iszac Burton,
Keihvan Ardaghi,
Thea R. Zalunardo,
Raiza Bastidas,
Xuduo Li,
Javier Guenaga,
Wen-Hsin Lee,
Richard Wyatt,
Wenwen Zhu,
Max Crispin,
Gabriel Ozorowski,
Andrew B. Ward,
Dennis R. Burton,
Lars Hangartner
Affiliations
Michael V. Bick
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Eduard Puig
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
David Beauparlant
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Rebecca Nedellec
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Iszac Burton
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Keihvan Ardaghi
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Thea R. Zalunardo
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Raiza Bastidas
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Xuduo Li
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA
Javier Guenaga
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Wen-Hsin Lee
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92109, USA
Richard Wyatt
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Wenwen Zhu
School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK
Max Crispin
School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
Gabriel Ozorowski
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92109, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
Andrew B. Ward
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92109, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA
Dennis R. Burton
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA
Lars Hangartner
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92109, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: Antibody effector functions contribute to the immune response to pathogens and can influence the efficacy of antibodies as therapeutics. To date, however, there is limited information on the molecular parameters that govern fragment crystallizable (Fc) effector functions. In this study, using AI-assisted protein design, the influences of binding kinetics, epitope location, and stoichiometry of binding on cellular Fc effector functions were investigated using engineered HIV-1 envelope as a model antigen. For this antigen, stoichiometry of binding was found to be the primary molecular determinant of FcγRIIIa signaling, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis, while epitope location and antibodybinding kinetics, at least in the ranges investigated, were of no substantial impact. These findings are of importance for informing the development of vaccination strategies against HIV-1 and, possibly, other viral pathogens.
