Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody

Rui Kong; Kai Xu; Tongqing Zhou; Priyamvada Acharya; Thomas Lemmin; Kevin Liu; Gabriel Ozorowski; Cinque Soto; Justin D Taft; Robert T Bailer; Evan M Cale; Lei Chen; Chang W Choi; Gwo-Yu Chuang; Nicole A Doria-Rose; Aliaksandr Druz; Ivelin S Georgiev; Jason Gorman; Jinghe Huang; M Gordon Joyce; Mark K Louder; Xiaochu Ma; Krisha McKee; Sijy O'Dell; Marie Pancera; Yongping Yang; Scott C Blanchard; Walther Mothes; Dennis R Burton; Wayne C Koff; Mark Connors; Andrew B Ward; Peter D Kwong; John R Mascola

doi:10.1126/science.aae0474

Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody

Science. 2016 May 13;352(6287):828-33. doi: 10.1126/science.aae0474.

Authors

Rui Kong¹, Kai Xu¹, Tongqing Zhou¹, Priyamvada Acharya¹, Thomas Lemmin², Kevin Liu¹, Gabriel Ozorowski³, Cinque Soto¹, Justin D Taft¹, Robert T Bailer¹, Evan M Cale¹, Lei Chen¹, Chang W Choi¹, Gwo-Yu Chuang¹, Nicole A Doria-Rose¹, Aliaksandr Druz¹, Ivelin S Georgiev¹, Jason Gorman¹, Jinghe Huang⁴, M Gordon Joyce¹, Mark K Louder¹, Xiaochu Ma⁵, Krisha McKee¹, Sijy O'Dell¹, Marie Pancera¹, Yongping Yang¹, Scott C Blanchard⁶, Walther Mothes⁵, Dennis R Burton⁷, Wayne C Koff⁸, Mark Connors⁴, Andrew B Ward³, Peter D Kwong⁹, John R Mascola⁹

Affiliations

¹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
² Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
³ Department of Integrative Structural and Computational Biology, 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. International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
⁶ Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA.
⁷ Department of Immunology and Microbial Science, International AIDS Vaccine Initiative Neutralizing Antibody Center, 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, Boston, MA 02142, USA.
⁸ International AIDS Vaccine Initiative, New York, NY 10038, USA.
⁹ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. pdkwong@nih.gov jmascola@nih.gov.

Abstract

The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.

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

AIDS Vaccines / immunology*
Amino Acid Sequence
Antibodies, Neutralizing / chemistry*
Antibodies, Neutralizing / isolation & purification
Antibodies, Neutralizing / ultrastructure
Antibodies, Viral / chemistry*
Antibodies, Viral / ultrastructure
B-Lymphocytes / immunology
B-Lymphocytes / virology
Crystallography, X-Ray
HIV Envelope Protein gp120 / immunology*
HIV Envelope Protein gp41 / immunology*
HIV-1 / immunology*
Humans
Hydrophobic and Hydrophilic Interactions
Immunodominant Epitopes / immunology
Molecular Sequence Data
Peptides / immunology
Protein Conformation
Viral Fusion Proteins / immunology*
Virus Internalization

Substances

AIDS Vaccines
Antibodies, Neutralizing
Antibodies, Viral
HIV Envelope Protein gp120
HIV Envelope Protein gp41
Immunodominant Epitopes
Peptides
Viral Fusion Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding