Cell Reports (Apr 2017)
Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation
- Tongqing Zhou,
- Nicole A. Doria-Rose,
- Cheng Cheng,
- Guillaume B.E. Stewart-Jones,
- Gwo-Yu Chuang,
- Michael Chambers,
- Aliaksandr Druz,
- Hui Geng,
- Krisha McKee,
- Young Do Kwon,
- Sijy O’Dell,
- Mallika Sastry,
- Stephen D. Schmidt,
- Kai Xu,
- Lei Chen,
- Rita E. Chen,
- Mark K. Louder,
- Marie Pancera,
- Timothy G. Wanninger,
- Baoshan Zhang,
- Anqi Zheng,
- S. Katie Farney,
- Kathryn E. Foulds,
- Ivelin S. Georgiev,
- M. Gordon Joyce,
- Thomas Lemmin,
- Sandeep Narpala,
- Reda Rawi,
- Cinque Soto,
- John-Paul Todd,
- Chen-Hsiang Shen,
- Yaroslav Tsybovsky,
- Yongping Yang,
- Peng Zhao,
- Barton F. Haynes,
- Leonidas Stamatatos,
- Michael Tiemeyer,
- Lance Wells,
- Diana G. Scorpio,
- Lawrence Shapiro,
- Adrian B. McDermott,
- John R. Mascola,
- Peter D. Kwong
Affiliations
- Tongqing Zhou
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Nicole A. Doria-Rose
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Cheng Cheng
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Guillaume B.E. Stewart-Jones
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Gwo-Yu Chuang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Michael Chambers
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Aliaksandr Druz
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Hui Geng
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Krisha McKee
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Young Do Kwon
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Sijy O’Dell
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Mallika Sastry
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Stephen D. Schmidt
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Kai Xu
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Lei Chen
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Rita E. Chen
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Mark K. Louder
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Marie Pancera
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Timothy G. Wanninger
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Baoshan Zhang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Anqi Zheng
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- S. Katie Farney
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Kathryn E. Foulds
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Ivelin S. Georgiev
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- M. Gordon Joyce
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Thomas Lemmin
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Sandeep Narpala
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Reda Rawi
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Cinque Soto
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- John-Paul Todd
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Chen-Hsiang Shen
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Yaroslav Tsybovsky
- Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702-1201, USA
- Yongping Yang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Peng Zhao
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
- Barton F. Haynes
- Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA
- Leonidas Stamatatos
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, P.O. Box 19024, Seattle, WA 98109, USA
- Michael Tiemeyer
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
- Lance Wells
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
- Diana G. Scorpio
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Lawrence Shapiro
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Adrian B. McDermott
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- John R. Mascola
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Peter D. Kwong
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- DOI
- https://doi.org/10.1016/j.celrep.2017.04.013
- Journal volume & issue
-
Vol. 19,
no. 4
pp. 719 – 732
Abstract
While the HIV-1-glycan shield is known to shelter Env from the humoral immune response, its quantitative impact on antibody elicitation has been unclear. Here, we use targeted deglycosylation to measure the impact of the glycan shield on elicitation of antibodies against the CD4 supersite. We engineered diverse Env trimers with select glycans removed proximal to the CD4 supersite, characterized their structures and glycosylation, and immunized guinea pigs and rhesus macaques. Immunizations yielded little neutralization against wild-type viruses but potent CD4-supersite neutralization (titers 1: >1,000,000 against four-glycan-deleted autologous viruses with over 90% breadth against four-glycan-deleted heterologous strains exhibiting tier 2 neutralization character). To a first approximation, the immunogenicity of the glycan-shielded protein surface was negligible, with Env-elicited neutralization (ID50) proportional to the exponential of the protein-surface area accessible to antibody. Based on these high titers and exponential relationship, we propose site-selective deglycosylated trimers as priming immunogens to increase the frequency of site-targeting antibodies.
Keywords
- CD4-binding site
- crystal structure
- envelope glycoprotein
- glycan shield
- glycomics
- HIV-1
- immunogen design
- immunogenicity
- targeted deglycosylation
- vaccine design
