Glycans Function as Anchors for Antibodies and Help Drive HIV Broadly Neutralizing Antibody Development

Raiees Andrabi; Ching-Yao Su; Chi-Hui Liang; Sachin S Shivatare; Bryan Briney; James E Voss; Salar Khan Nawazi; Chung-Yi Wu; Chi-Huey Wong; Dennis R Burton

doi:10.1016/j.immuni.2017.08.006

Glycans Function as Anchors for Antibodies and Help Drive HIV Broadly Neutralizing Antibody Development

Immunity. 2017 Sep 19;47(3):524-537.e3. doi: 10.1016/j.immuni.2017.08.006. Epub 2017 Sep 12.

Authors

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, 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.
² Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan.
³ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative, 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, Cambridge, MA 02114, USA. Electronic address: burton@scripps.edu.

Abstract

Apex broadly neutralizing HIV antibodies (bnAbs) recognize glycans and protein surface close to the 3-fold axis of the envelope (Env) trimer and are among the most potent and broad Abs described. The evolution of apex bnAbs from one donor (CAP256) has been studied in detail and many Abs at different stages of maturation have been described. Using diverse engineering tools, we investigated the involvement of glycan recognition in the development of the CAP256.VRC26 Ab lineage. We found that sialic acid-bearing glycans were recognized by germline-encoded and somatically mutated residues on the Ab heavy chain. This recognition provided an "anchor" for the Abs as the core protein epitope varies, prevented complete neutralization escape, and eventually led to broadening of the response. These findings illustrate how glycan-specific maturation enables a human Ab to cope with pathogen escape mechanisms and will aid in optimization of immunization strategies to induce V2 apex bnAb responses.

Keywords: B cell affinity maturation; Env glycans; HIV envelope trimer; V2 apex epitope; bnAbs; broadly neutralizing antibodies; glycan engineering; virus escape.

Publication types

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

MeSH terms

Amino Acid Sequence
Antibodies, Neutralizing / immunology*
Antibody Affinity / immunology
Antibody Formation / immunology
Binding Sites
Epitopes / immunology
HIV Antibodies / chemistry
HIV Antibodies / classification
HIV Antibodies / genetics
HIV Antibodies / immunology*
HIV Envelope Protein gp120 / chemistry
HIV Envelope Protein gp120 / immunology
HIV Infections / immunology*
HIV Infections / metabolism*
HIV Infections / virology
HIV-1 / immunology*
Humans
Immunoglobulin Heavy Chains / genetics
Models, Molecular
N-Acetylneuraminic Acid / metabolism
Neutralization Tests
Peptide Fragments / immunology
Phylogeny
Polysaccharides / metabolism*
Protein Binding / immunology
Protein Conformation
Protein Multimerization

Substances

Antibodies, Neutralizing
Epitopes
HIV Antibodies
HIV Envelope Protein gp120
Immunoglobulin Heavy Chains
Peptide Fragments
Polysaccharides
N-Acetylneuraminic Acid

Grants and funding

UM1 AI100663/AI/NIAID NIH HHS/United States