Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth.

Abstract

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-am ino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35S. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.

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Citation

Published Version (Please cite this version)

10.1126/science.abd2638

Publication Info

Roark, Ryan S, Hui Li, Wilton B Williams, Hema Chug, Rosemarie D Mason, Jason Gorman, Shuyi Wang, Fang-Hua Lee, et al. (2020). Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth. Science (New York, N.Y.). pp. eabd2638–eabd2638. 10.1126/science.abd2638 Retrieved from https://hdl.handle.net/10161/21823.

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Scholars@Duke

Williams

Wilton Bryan Williams

Associate Professor in Surgery

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.

Saunders

Kevin O'Neil Saunders

Norman L. Letvin M. D. Distinguished Professor in Surgery and the Duke Human Vaccine Institute

Dr. Kevin O. Saunders graduated from Davidson College in 2005 with a bachelor of science in biology. At Davidson College, he trained in the laboratory of Dr. Karen Hales identifying the genetic basis of infertility. Dr. Saunders completed his doctoral research on CD8+ T cell immunity against HIV-1 infection with Dr. Georgia Tomaras 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, Dr. 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, Dr. 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. Dr. Saunders previously served as DHVI's associate director of research, director or research, and currently serves as the associate director for DHVI. Additionally, Dr. Saunders serves as the faculty chairperson for the DHVI diversity, equity, and inclusion committee.

Dr. 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, Dr. 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. Our overall goal is to develop protective antibody-based vaccines; therefore, the laboratory is divided into two sections–Immunoprofiling and Vaccine/Therapeutics design. We employ a reverse vaccinology approach to vaccine design where we 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 our overall goal, we are also interested in the immunologic mechanisms that make the vaccines successful.

Anti-glycan HIV-1 antibody biology. Our 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 we 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). We 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 we are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. During this work, we discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. We translated this finding into a vaccine design strategy that we 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. We 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, we 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. We partner heavily with structural biologists and bioinformaticians to design optimized vaccine immunogens for in vitro and preclinical testing. We 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. We 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 laboratory 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 laboratory continues to apply similar approaches against other targets on coronaviruses to ultimately generate protective immunity against most coronaviruses. The laboratory 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.

Wiehe

Kevin J Wiehe

Associate Professor in Medicine

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.

Moody

Michael Anthony Moody

Professor of Pediatrics

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).

Wagh

Kshitij G. Wagh

Instructor in the Department of Medicine
Kelsoe

Garnett H. Kelsoe

James B. Duke Distinguished Professor of Immunology
  1. 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.

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