Authors
Jiaxuan Cheng, Evan M Cale, Amirabbas Maghsoudi, Matthew S Sutton, Nancy S Longo, Rebecca A Gillespie, Lingshu Wang, Ivan Kosik, Sue Chong, Atsuhiro Yasuhara, Tatsiana Bylund, Arne Schön, Prabhanshu Tripathi, Yaroslav Tsybovsky, Haotian Lei, Nicholas C Morano, Allison B Lupatkin, Abraham J Morton, Zabrina C Lang, Jordan E Becker, Isabella R Frascilla, Myungjin Lee, Ning Li, Cuiping Liu, Ryan S Roark, Chen-Hsiang Shen, I-Ting Teng, David J Van Wazer, Danyi Wang, Lingyuan Wu, Goran Ahlsen, Mike Castro, Haijuan Du, Michael J Ernandes, Tiansheng Li, Bob C Lin, Mark K Louder, Krisha McKee, Jonah S Merriam, Sijy O'Dell, Li Ou, Sergei Pletnev, David Prikryl, Qi Qiu, Sarah Rubin, Mallika Sastry, Stephen D Schmidt, Asif Shajahan, Andrea R Shiakolas, Sanjay Srivatsan, Baoshan Zhang, Qiong Zhou, Mark Connors, Jason G Gall, Yicheng Guo, Rick K Huang, Yaoxing Huang, Richard A Koup, Q Paula Lei, John R Mascola, Reda Rawi, Leonid Serebryannyy, Lawrence Shapiro, Zizhang Sheng, David D Ho, Patrick C Wilson, Jonathan W Yewdell, Theodore C Pierson, Masaru Kanekiyo, Nicole A Doria-Rose, Peter D Kwong, Tongqing Zhou
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77172. Aug 14, 2026. Epub Aug 14, 2026.
Abstract
Viral entry glycoproteins are often shielded from immune recognition by dense N-linked glycans that limit antibody access to protein epitopes. While glycan-reactive antibodies with unusual architectures have been described, how canonical Y-shaped antibodies engage these glycan-rich surfaces remains poorly defined. Here, we characterize two human antibodies, VRC35 and VRC36, isolated from an HIV-1-infected donor, that recognize diverse glycosylated viral glycoproteins. Cryo-electron microscopy structural analyses of these antibodies in complex with viral entry glycoproteins, including HIV-1 envelope, influenza hemagglutinin, SARS-CoV-2 spike, and the Lassa virus glycoprotein complex, reveal adaptive Fab stoichiometries ranging from single-Fab binding to dimeric and higher-order assemblies are mediated by intra- and inter-IgG interactions that depend on local glycan organization. Dense glycan clustering on HIV-1 and influenza glycoproteins supports multivalent Fab assemblies and correlates with neutralization activity, whereas sparse glycan environments on SARS-CoV-2 and Lassa virus favor weak or heterogeneous engagement without neutralization. Structural and mutational analyses further demonstrate that homotypic Fab-Fab interactions stabilize multivalent engagement and contribute to neutralizing activity. Together, these findings define a structural framework in which viral glycan organization constrains antibody valency and engagement, while somatic hypermutation contributes to the acquisition of homotypic Fab-Fab interactions that facilitate multivalent recognition of viral glycan shields.
PMID:
42598737
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.
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