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

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. In this paper, 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. Finally, these results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.

Authors:
 [1];  [1];  [1];  [1];  [2];  [1];  [3];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [4];  [1] more »;  [1];  [5];  [1];  [1];  [1];  [1];  [6];  [5];  [7];  [8];  [4];  [3];  [1];  [1] « less
  1. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Vaccine Research Center
  2. Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry
  3. The Scripps Research Inst., La Jolla, CA (United States). Dept. of Integrative Structural and Computational Biology. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery. Neutralizing Antibody Center. International AIDS Vaccine Initiative
  4. National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Lab. of Immunoregulation. HIV-Specific Immunity Section
  5. Yale Univ., New Haven, CT (United States). School of Medicine. Dept. of Microbial Pathogenesis
  6. Weill Cornell Medical College of Cornell Univ., New York, NY (United States). Dept. of Physiology and Biophysics
  7. The Scripps Research Inst., La Jolla, CA (United States). Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery. International AIDS Vaccine Initiative Neutralizing Antibody Center. Dept. of Immunology and Microbial Science; Massachusetts Inst. of Technology and Harvard Univ., Boston, MA (United States). Ragon Inst. of Massachusetts General Hospital
  8. International AIDS Vaccine Initiative, New York, NY (United States)
Publication Date:
Research Org.:
National Inst. of Health (NIH), Bethesda, MD (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States); International AIDS Vaccine Initiative’s (IAVI) Neutralizing Antibody Consortium (United States)
Contributing Org.:
Univ. of California, San Francisco, CA (United States); The Scripps Research Inst., La Jolla, CA (United States); Yale Univ., New Haven, CT (United States); Weill Cornell Medical College of Cornell Univ., New York, NY (United States); Massachusetts Inst. of Technology and Harvard Univ., Boston, MA (United States); International AIDS Vaccine Initiative, New York, NY (United States)
OSTI Identifier:
1257468
Grant/Contract Number:  
W-31-109-Eng-38; R01GM079238; P01GM56550; R01GM116654
Resource Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 352; Journal Issue: 6287; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Kong, Rui, Xu, Kai, Zhou, Tongqing, Acharya, Priyamvada, Lemmin, Thomas, Liu, Kevin, Ozorowski, Gabriel, Soto, Cinque, Taft, Justin D., Bailer, Robert T., Cale, Evan M., Chen, Lei, Choi, Chang W., Chuang, Gwo-Yu, Doria-Rose, Nicole A., Druz, Aliaksandr, Georgiev, Ivelin S., Gorman, Jason, Huang, Jinghe, Joyce, M. Gordon, Louder, Mark K., Ma, Xiaochu, McKee, Krisha, O'Dell, Sijy, Pancera, Marie, Yang, Yongping, Blanchard, Scott C., Mothes, Walther, Burton, Dennis R., Koff, Wayne C., Connors, Mark, Ward, Andrew B., Kwong, Peter D., and Mascola, John R. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. United States: N. p., 2016. Web. doi:10.1126/science.aae0474.
Kong, Rui, Xu, Kai, Zhou, Tongqing, Acharya, Priyamvada, Lemmin, Thomas, Liu, Kevin, Ozorowski, Gabriel, Soto, Cinque, Taft, Justin D., Bailer, Robert T., Cale, Evan M., Chen, Lei, Choi, Chang W., Chuang, Gwo-Yu, Doria-Rose, Nicole A., Druz, Aliaksandr, Georgiev, Ivelin S., Gorman, Jason, Huang, Jinghe, Joyce, M. Gordon, Louder, Mark K., Ma, Xiaochu, McKee, Krisha, O'Dell, Sijy, Pancera, Marie, Yang, Yongping, Blanchard, Scott C., Mothes, Walther, Burton, Dennis R., Koff, Wayne C., Connors, Mark, Ward, Andrew B., Kwong, Peter D., & Mascola, John R. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. United States. doi:10.1126/science.aae0474.
Kong, Rui, Xu, Kai, Zhou, Tongqing, Acharya, Priyamvada, Lemmin, Thomas, Liu, Kevin, Ozorowski, Gabriel, Soto, Cinque, Taft, Justin D., Bailer, Robert T., Cale, Evan M., Chen, Lei, Choi, Chang W., Chuang, Gwo-Yu, Doria-Rose, Nicole A., Druz, Aliaksandr, Georgiev, Ivelin S., Gorman, Jason, Huang, Jinghe, Joyce, M. Gordon, Louder, Mark K., Ma, Xiaochu, McKee, Krisha, O'Dell, Sijy, Pancera, Marie, Yang, Yongping, Blanchard, Scott C., Mothes, Walther, Burton, Dennis R., Koff, Wayne C., Connors, Mark, Ward, Andrew B., Kwong, Peter D., and Mascola, John R. Fri . "Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody". United States. doi:10.1126/science.aae0474. https://www.osti.gov/servlets/purl/1257468.
@article{osti_1257468,
title = {Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody},
author = {Kong, Rui and Xu, Kai and Zhou, Tongqing and Acharya, Priyamvada and Lemmin, Thomas and Liu, Kevin and Ozorowski, Gabriel and Soto, Cinque and Taft, Justin D. and Bailer, Robert T. and Cale, Evan M. and Chen, Lei and Choi, Chang W. and Chuang, Gwo-Yu and Doria-Rose, Nicole A. and Druz, Aliaksandr and Georgiev, Ivelin S. and Gorman, Jason and Huang, Jinghe and Joyce, M. Gordon and Louder, Mark K. and Ma, Xiaochu and McKee, Krisha and O'Dell, Sijy and Pancera, Marie and Yang, Yongping and Blanchard, Scott C. and Mothes, Walther and Burton, Dennis R. and Koff, Wayne C. and Connors, Mark and Ward, Andrew B. and Kwong, Peter D. and Mascola, John R.},
abstractNote = {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. In this paper, 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. Finally, these results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.},
doi = {10.1126/science.aae0474},
journal = {Science},
number = 6287,
volume = 352,
place = {United States},
year = {2016},
month = {5}
}

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