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

Professor in Surgery

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. Dr. Saunders previously served as DHVI's director or research and currently serves as the associate director for DHVI.

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. His current research interests include vaccine and antibody development to combat HIV-1 and coronavirus infections.

About the Saunders Laboratory
The Saunders laboratory aims to understand the immunology of HIV-1 antibodies and the molecular biology of their interaction with HIV-1 envelope (Env) glycoprotein. Our overall goal is to develop protective antibody-based vaccines; therefore, the laboratory has two sections–antibody repertoire analysis and immunogen design. 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.

Anti-glycan HIV-1 antibody biology. The laboratory utilizes single B cell PCR to probe the antibody repertoire during natural infection and after vaccination. 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 are rarely elicited with HIV-1 vaccination; therefore we have studied the ontogeny of DH501 using longitudinal next generation sequencing and reversion of somatic mutations within the antibody variable regions. DH501 and DH502 antibodies are mostly 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. The results of these studies inform us about the similarities and differences between vaccine-induced glycan-reactive antibodies and known broadly neutralizing HIV-1 antibodies from human natural infection. These comparative studies define the molecular biology of glycan-reactive antibodies as well as determine how close current vaccines are to inducing glycan-dependent broadly neutralizing antibodies.

HIV-1 Env immunogen design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. With knowledge of the antibodies we desire to elicit we can engineer the HIV-1 Env to preferentially bind to those antibodies. 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 glycosylation of HIV-1 Env immunogens to be the optimal glycan type for engagement of the precursor antibody of glycan-reactive broadly neutralizing HIV-1 antibody lineages. 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. More specifically, we investigate the effects of various immunogen delivery platforms, such as protein or gold nanoparticles, nucleic acid, or recombinant viral vectors on B cell activation.

Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of glycoproteins in order to produce protective vaccines.

Wiehe

Kevin J Wiehe

Norman L. Letvin Associate Professor in Medicine

Dr. Kevin Wiehe is the associate 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 co-PI of a U19 program to develop a syphilis vaccine; this program is led by 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).

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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