A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope

Tongqing Zhou; Anqi Zheng; Ulrich Baxa; Gwo-Yu Chuang; Ivelin S Georgiev; Rui Kong; Sijy O'Dell; Syed Shahzad-Ul-Hussan; Chen-Hsiang Shen; Yaroslav Tsybovsky; Robert T Bailer; Syna K Gift; Mark K Louder; Krisha McKee; Reda Rawi; Catherine H Stevenson; Guillaume B E Stewart-Jones; Justin D Taft; Eric Waltari; Yongping Yang; Baoshan Zhang; Sachin S Shivatare; Vidya S Shivatare; Chang-Chun D Lee; Chung-Yi Wu; NISC Comparative Sequencing Program; James C Mullikin; Carole A Bewley; Dennis R Burton; Victoria R Polonis; Lawrence Shapiro; Chi-Huey Wong; John R Mascola; Peter D Kwong; Xueling Wu

doi:10.1016/j.immuni.2018.02.013

A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope

Immunity. 2018 Mar 20;48(3):500-513.e6. doi: 10.1016/j.immuni.2018.02.013. Epub 2018 Mar 13.

Authors

Tongqing Zhou¹, Anqi Zheng¹, Ulrich Baxa², Gwo-Yu Chuang¹, Ivelin S Georgiev³, Rui Kong¹, Sijy O'Dell¹, Syed Shahzad-Ul-Hussan⁴, Chen-Hsiang Shen¹, Yaroslav Tsybovsky², Robert T Bailer¹, Syna K Gift⁵, Mark K Louder¹, Krisha McKee¹, Reda Rawi¹, Catherine H Stevenson¹, Guillaume B E Stewart-Jones¹, Justin D Taft¹, Eric Waltari⁶, Yongping Yang¹, Baoshan Zhang¹, Sachin S Shivatare⁷, Vidya S Shivatare⁷, Chang-Chun D Lee⁷, Chung-Yi Wu⁷; NISC Comparative Sequencing Program; James C Mullikin⁸, Carole A Bewley⁹, Dennis R Burton¹⁰, Victoria R Polonis¹¹, Lawrence Shapiro¹², Chi-Huey Wong¹³, John R Mascola¹⁴, Peter D Kwong¹⁵, Xueling Wu¹⁶

Collaborators

NISC Comparative Sequencing Program:
Betty Benjamin, Robert Blakesley, Gerry Bouffard, Shelise Brooks, Holly Coleman, Mila Dekhtyar, Michael Gregory, Xiaobin Guan, Jyoti Gupta, Joel Han, April Hargrove, Shiling Ho, Richelle Legaspi, Quino Maduro, Cathy Masiello, Baishali Maskeri, Jenny McDowell, Casandra Montemayor, James Mullikin, Morgan Park, Nancy Riebow, Karen Schandler, Brian Schmidt, Christina Sison, Mal Stantripop, James Thomas, Pam Thomas, Meg Vemulapalli, Alice Young

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
² Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
³ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Vanderbilt Vaccine Center, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, and Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN 37232, USA.
⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
⁵ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA.
⁶ Aaron Diamond AIDS Research Center, Affiliate of the Rockefeller University, New York, NY 10016, USA.
⁷ Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
⁸ NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
⁹ Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
¹⁰ Department of Immunology and Microbiology, IAVI Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
¹¹ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
¹² Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
¹³ Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
¹⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: jmascola@nih.gov.
¹⁵ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Electronic address: pdkwong@nih.gov.
¹⁶ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA; Aaron Diamond AIDS Research Center, Affiliate of the Rockefeller University, New York, NY 10016, USA. Electronic address: xwu@adarc.org.

Abstract

Virtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the "silent face" on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center. Somatic hypermutation occurred preferentially at antibody residues that interacted with these glycans, suggesting somatic development of glycan recognition. Resistance to VRC-PG05 in donor #74 involved shifting of glycan-N448 to N446 or mutation of glycan-proximal residue E293. HIV-1 neutralization can thus be achieved at the silent face center by glycan-recognizing antibody; along with other known epitopes, the VRC-PG05 epitope completes coverage by neutralizing antibody of all major exposed regions of the prefusion closed trimer.

Keywords: HIV silent face; HIV vaccine; broadly neutralizing antibody; crystal structure; glycan cluster; glycan recognition; glycopeptide epitope; prefusion-closed Env trimer; viral escape.

Publication types

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

MeSH terms

Amino Acid Sequence
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / genetics
Antibodies, Neutralizing / immunology*
Antibodies, Neutralizing / metabolism
Antigens, Viral / chemistry
Antigens, Viral / immunology
Binding Sites
Epitope Mapping
Epitopes / chemistry
Epitopes / immunology
Epitopes / metabolism
Glycopeptides / chemistry
Glycopeptides / immunology
Glycosylation
HIV Antibodies / chemistry
HIV Antibodies / genetics
HIV Antibodies / immunology*
HIV Antibodies / metabolism
HIV Envelope Protein gp120 / chemistry
HIV Envelope Protein gp120 / immunology*
HIV Envelope Protein gp120 / metabolism
HIV Infections / immunology*
HIV-1 / immunology*
Humans
Models, Molecular
Molecular Conformation
Polysaccharides / chemistry
Polysaccharides / immunology*
Protein Binding / immunology
Somatic Hypermutation, Immunoglobulin / immunology
Structure-Activity Relationship

Substances

Antibodies, Neutralizing
Antigens, Viral
Epitopes
Glycopeptides
HIV Antibodies
HIV Envelope Protein gp120
Polysaccharides

Abstract

Publication types

MeSH terms

Substances

Grants and funding