Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.
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2021-05-18
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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.
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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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Scholars@Duke
Wilton Bryan Williams
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.
Robert R Meyerhoff
Rory Henderson
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.
Mario-Juan Borgnia
Michael Anthony Moody
Tony Moody, MD is a Professor in the Department of Pediatrics, Division of Infectious Diseases and Professor in the Department of Integrative Immunobiology at Duke University Medical Center. Research in the Moody lab is focused on understanding the B cell responses during infection, vaccination, and disease. The lab has become a resource for human phenotyping, flow characterization, staining and analysis at the Duke Human Vaccine Institute (DHVI). The Moody lab is currently funded to study influenza, syphilis, HIV-1, and emerging infectious diseases.
Dr. Moody is the director of the Duke CIVICs Vaccine Center (DCVC) at (DHVI) and co-director of the Centers for Research of Emerging Infectious Disease Coordinating Center (CREID-CC). Dr. Moody is mPI of a U01 program to develop a syphilis vaccine; this program is a collaboration with mPI Dr. Justin Radolf at the University of Connecticut. Dr. Moody is also the director of the DHVI Accessioning Unit, a biorepository that provides support for work occurring at DHVI and with its many collaborators around the world by providing processing, shipping, and inventory support for a wide array of projects.
Dr. Moody and his team are involved in many networks studying vaccine response including the Collaborative Influenza Vaccine Innovation Centers (CIVICs) and the COVID-19 Prevention Network (CoVPN).
Kevin J Wiehe
Dr. Kevin Wiehe is the director of research, director of computational biology and co-director of the Quantitative Research Division at the Duke Human Vaccine Institute (DHVI). He has over 20 years of experience in the field of computational biology and has expertise in computational structural biology, computational genomics, and computational immunology.
For the past decade, he has applied his unique background to developing computational approaches for studying the B cell response in both the infection and vaccination settings. He has utilized his expertise in computational structural biology to structurally model and characterize HIV and influenza antibody recognition. Dr. Wiehe has utilized his expertise in computational genomics and computational immunology to develop software to analyze large scale next generation sequencing data of antibody repertoires as well as develop computational programs for estimating antibody mutation probabilities. Dr. Wiehe has shown that low probability antibody mutations can act as rate-limiting steps in the development of broadly neutralizing antibodies in HIV.
Through his PhD, postdoc work, and now his roles at DHVI, Dr. Wiehe always approaches the analysis and the scientific discovery process from a structural biology perspective. Supporting the Duke Center for HIV Structural Biology (DCHSB), Dr. Wiehe will conduct antibody sequence analysis for antibodies used in computational and molecular modeling analyses conducted.
Garnett H. Kelsoe
- Lymphocyte development and antigen-driven diversification of immunoglobulin and T cell antigen receptor genes.
2. The germinal center reaction and mechanisms for clonal selection and self - tolerance. The origins of autoimmunity.
3. Interaction of innate- and adaptive immunity and the role of inflammation in lymphoid organogenesis.
4. The role of secondary V(D)J gene rearrangment in lymphocyte development and malignancies.
5. Mathematical modeling of immune responses, DNA motifs, collaborations in bioinformatics.
6. Humoral immunity to influenza and HIV-1.
Kevin O'Neil Saunders
Kevin O. Saunders, PhD, graduated from Davidson College in 2005 with a Bachelor of Science in biology. At Davidson College, he trained in the laboratory of Karen Hales, PhD, identifying the genetic basis of infertility. Saunders completed his doctoral research on CD8+ T cell immunity against HIV-1 infection with Georgia Tomaras, PhD, at Duke University in 2010. He subsequently trained as a postdoctoral fellow in the laboratories of Drs. Gary Nabel and John Mascola at the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center.
In 2014, Saunders joined the faculty at the Duke Human Vaccine Institute as a medical instructor. In this role, he analyzed antibody responses in vaccinated macaques, which led to the identification of glycan-dependent HIV antibodies induced by vaccination. Dr. Saunders was appointed as a non-tenure track assistant professor of surgery and the director of the laboratory of protein expression in the Duke Human Vaccine Institute in 2015. He successfully transitioned to a tenure-track appointment in 2018 and was later promoted to the rank of associate professor in surgery in 2020. In 2022, Saunders became an associate professor with tenure. He rose to the rank of professor with tenure in 2024 and was subsequently awarded the Norman L. Letvin, MD Professor in Immunology and Infectious Diseases Research in Surgery and the Duke Human Vaccine Institute distinguished professorship. Saunders previously served as DHVI's associate director of research, director or research, and currently serves as the associate director for DHVI. Additionally, Saunders serves as the faculty chairperson for DHVI's Diversity, Equity, and Inclusion Committee.
Saunders has given invited lectures at international conferences such as HIVR4P and the Keystone Symposia for HIV Vaccines. He has authored book chapters and numerous journal articles and holds patents on vaccine design concepts and antiviral antibodies. As a faculty member at Duke, Saunders has received the Duke Human Vaccine Institute Outstanding Leadership Award and the Norman Letvin Center For HIV/AIDS Vaccine Immunology and Immunogen Discovery Outstanding Investigator Award, Ruth and A. Morris Williams Faculty Research Prize, and the Duke Medical Alumni Emerging Leader Award. His current research interests include vaccine and antibody development to combat HIV-1, coronavirus, and other emerging viral infections.
About the Saunders Laboratory
The Saunders laboratory aims to understand the immunology of broadly protective antibodies and the molecular biology of their interaction with viral glycoprotein. The laboratory utilizes single B cell PCR, bulk B cell sequencing, and antigen-specific next-generation sequencing to probe the antibody repertoire during natural infection and after vaccination. The lab's overall goal is to develop protective antibody-based vaccines; therefore, the laboratory is divided into two sections–Immunoprofiling and Vaccine/Therapeutics design. They employ a reverse vaccinology approach to vaccine design where they study broadly protective antibodies in order to design vaccines that elicit such antibodies. To elicit broadly protective antibody responses, the Saunders laboratory utilizes epitope-focused nanoparticle vaccines. While eliciting broad protection is their overall goal, they are also interested in the immunologic mechanisms that make the vaccines successful.
Anti-glycan HIV-1 antibody biology. Their research premise is that vaccine-elicited antibodies will broadly neutralize HIV-1 if they can bind directly to the host glycans on Env. However, Env glycans are poorly immunogenic and require specific targeting by a vaccine immunogen to elicit an antibody response. Using this technique they identified two monoclonal antibodies from HIV Env vaccinated macaques called DH501 and DH502 that bind directly to mannose glycans and to HIV-1 envelope (Env). They have characterized these antibodies using glycan immunoassays, antibody engineering, and x-ray crystallography to define the mechanisms of Env-glycan interaction by these antibodies. Glycan-reactive HIV antibodies have mostly been found in the repertoire as IgG2 and IgM isotypes—similar to known natural glycan antibodies. Therefore they are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. During this work, they discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. They translated this finding into a vaccine design strategy that they have termed “glycan learning.” This approach modifies the number of glycans and type of glycosylation of HIV-1 Env immunogens to be optimal for engagement of the precursor antibody. The Env glycosylation sites and glycan type are then modified on subsequent Env immunogens to select antibodies that are maturing towards a broadly neutralizing phenotype. They have developed cell culture procedures and purification strategies combined with mass spectrometry analyses to create Env immunogens with specific glycosylation profiles. While the overall goal is to elicit protective neutralizing antibodies in vivo, they use these Env antigens in vitro to investigate the biology of B cell receptor engagement.
HIV-1 Sequential vaccine design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. Utilizing viral sequences from individuals that make broadly neutralizing antibodies, we further engineer the viral protein to preferentially bind the desired type of antibody. The Saunders lab partners heavily with structural biologists and bioinformaticians to design optimized vaccine immunogens for in vitro and preclinical testing. They are investigating the hypothesis that broadly neutralizing antibodies can be engaged with envelope immunogens specifically designed to target them, and that engineered envelopes can select for the broadly neutralizing antibody precursors to develop into a broadly neutralizing antibody. They examine antibody responses in vaccinated humanized mice and monkeys to discern if the vaccine elicits antibodies that are similar to the known human broadly neutralizing antibody targets. Vaccines that are effective in animal models are translated for manufacturing and evaluation in Phase I clinical trials.
Pancoronavirus vaccine development. During the COVID-19 pandemic, the Saunders lab and DHVI as a whole worked to isolate broadly neutralizing antibodies against SARS-CoV-2 and related viruses. These antibodies then served as a template for the development of receptor binding domain nanoparticle vaccines we call RBD-scNP. These vaccines protected monkeys and mice from SARS-CoV-2 and animal coronaviruses. This vaccine has been translated to GMP manufacturing and will be examined in a Phase I clinical trial. The lab continues to apply similar approaches against other targets on coronaviruses to ultimately generate protective immunity against most coronaviruses. The lab explores different delivery methods including slow-release technology and nucleoside-modified mRNA delivery.
Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of viral glycoproteins in order to produce protective vaccines.
Alberto Bartesaghi
Dr. Bartesaghi is an Associate Professor in the departments of Computer Science, Biochemistry and Electrical and Computer Engineering at Duke University. The Bartesaghi Lab focuses on the development of machine learning approaches to determine the structure of macromolecular complexes of general biomedical interest using single-particle cryo-electron microscopy, cryo-electron tomography, and sub-volume averaging. Some of our targets include glycoproteins of enveloped viruses like HIV, Influenza and Ebola, transporters and channels involved in signaling and metabolism, GPCRs, DNA-targeting CRISPR-Cas surveillance complexes, and targets for cancer drugs. The lab also works more broadly in the fields of deep learning and artificial intelligence, computer vision, biomedical imaging, and high-performance computing.
Priyamvada Acharya
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