Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.
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Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.
Published Version (Please cite this version)
Williams, Wilton B, R Ryan Meyerhoff, RJ Edwards, Hui Li, Kartik Manne, Nathan I Nicely, Rory Henderson, Ye Zhou, et al. (2021). Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies. Cell, 184(11). pp. 2955–2972.e25. 10.1016/j.cell.2021.04.042 Retrieved from https://hdl.handle.net/10161/23224.
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Dr. Williams completed a PhD in Biomedical Sciences (Immunology and Microbiology) from the University of Florida and did his postdoctoral work in the laboratory of Dr. Barton Haynes at the Duke Human Vaccine Institute (DHVI).
The key goals of HIV vaccine development are to define the host-virus events during natural HIV infection that lead to the induction of broadly neutralizing antibodies, and to recreate those events with a vaccine. As a junior faculty member in the DHVI, Dr. Williams is further characterizing SHIV non-human primate models for HIV infection, and evaluates B cell responses to HIV-1 vaccination in humans and non-human primates.
Program Start Year: 2013
Barton Haynes Laboratory
"Studies of Immunogens to Induce Broadly Neutralizing HIV Antibodies"
Dr. Rory Henderson is an assistant professor in Medicine at Duke University, the head of molecular modeling and simulation in the Division of Structural Biology at the Duke Human Vaccine Institute, and the Project 1 lead for the Duke Center for HIV Structural Biology (DCHSB).
Dr. Henderson’s lab focuses on understanding how the dynamics of macromolecules of the immune system and its antigenic targets determine the immune response to infection and how these dynamics can be manipulated to guide the selection of a favorable antibody response. We utilize a diverse computational and experimental tool set to interrogate key pathogen and antibody dynamics and use rational design principles to design immunogens and probe putative functional mechanisms.
With Dr. Henderson’s background in molecular modeling and simulation along with biochemical and cryo-electron microscopy (cryo-EM) techniques, he and his lab investigate these details at high spatial and temporal resolution. Together, these methods provide a promising approach toward accelerating the design and characterization of the next generation of vaccine immunogens.
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