Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies

Laura E McCoy; Marit J van Gils; Gabriel Ozorowski; Terrence Messmer; Bryan Briney; James E Voss; Daniel W Kulp; Matthew S Macauley; Devin Sok; Matthias Pauthner; Sergey Menis; Christopher A Cottrell; Jonathan L Torres; Jessica Hsueh; William R Schief; Ian A Wilson; Andrew B Ward; Rogier W Sanders; Dennis R Burton

doi:10.1016/j.celrep.2016.07.074

Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies

Cell Rep. 2016 Aug 30;16(9):2327-38. doi: 10.1016/j.celrep.2016.07.074. Epub 2016 Aug 18.

Authors

Laura E McCoy¹, Marit J van Gils², Gabriel Ozorowski³, Terrence Messmer⁴, Bryan Briney⁴, James E Voss⁴, Daniel W Kulp⁴, Matthew S Macauley⁵, Devin Sok⁴, Matthias Pauthner⁴, Sergey Menis⁴, Christopher A Cottrell³, Jonathan L Torres³, Jessica Hsueh⁴, William R Schief⁶, Ian A Wilson³, Andrew B Ward⁷, Rogier W Sanders⁸, Dennis R Burton⁹

Affiliations

¹ Department of Immunology & Microbial Science, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Division of Infection & Immunity, University College London, London WC1E 6BT, UK.
² Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
³ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Immunology & Microbial Science, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁶ Department of Immunology & Microbial Science, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
⁷ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: abward@scripps.edu.
⁸ Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address: r.w.sanders@amc.uva.nl.
⁹ Department of Immunology & Microbial Science, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA. Electronic address: burton@scripps.edu.

Abstract

A major advance in the search for an HIV vaccine has been the development of a near-native Envelope trimer (BG505 SOSIP.664) that can induce robust autologous Tier 2 neutralization. Here, potently neutralizing monoclonal antibodies (nAbs) from rabbits immunized with BG505 SOSIP.664 are shown to recognize an immunodominant region of gp120 centered on residue 241. Residue 241 occupies a hole in the glycan defenses of the BG505 isolate, with fewer than 3% of global isolates lacking a glycan site at this position. However, at least one conserved glycan site is missing in 89% of viruses, suggesting the presence of glycan holes in most HIV isolates. Serum evidence is consistent with targeting of holes in natural infection. The immunogenic nature of breaches in the glycan shield has been under-appreciated in previous attempts to understand autologous neutralizing antibody responses and has important potential consequences for HIV vaccine design.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AIDS Vaccines / biosynthesis*
AIDS Vaccines / genetics
AIDS Vaccines / immunology
Animals
Antibodies, Neutralizing / biosynthesis
Antibodies, Neutralizing / chemistry*
Antibodies, Neutralizing / genetics
Antibodies, Viral / biosynthesis
Antibodies, Viral / chemistry*
Antibodies, Viral / genetics
Antibody Specificity
Binding Sites
HIV Antigens / chemistry*
HIV Antigens / immunology
HIV Antigens / metabolism
HIV Envelope Protein gp120 / chemistry*
HIV Envelope Protein gp120 / immunology
HIV Envelope Protein gp120 / metabolism
HIV Infections / immunology
HIV Infections / prevention & control
HIV Infections / virology
HIV-1 / chemistry
HIV-1 / immunology
Humans
Immunization
Models, Molecular
Mutagenesis, Site-Directed
Neutralization Tests
Polysaccharides / chemistry*
Polysaccharides / immunology
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Protein Structure, Secondary
Rabbits

Substances

AIDS Vaccines
Antibodies, Neutralizing
Antibodies, Viral
HIV Antigens
HIV Envelope Protein gp120
Polysaccharides

Abstract

Publication types

MeSH terms

Substances

Grants and funding