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Title: Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities

Abstract

Up to ~20% of HIV-infected individuals eventually develop broadly neutralizing antibodies (bnAbs), and many of these antibodies (~40%) target a region of dense high-mannose glycosylation on gp120 of the HIV envelope protein, known as the “high-mannose patch” (HMP). Thus, there have been numerous attempts to develop glycoconjugate vaccine immunogens that structurally mimic the HMP and might elicit bnAbs targeting this conserved neutralization epitope. Herein, we report on the immunogenicity of glycopeptides, designed by in vitro selection, that bind tightly to anti-HMP antibody 2G12. By analyzing the fine carbohydrate specificity of rabbit antibodies elicited by these immunogens, we found that they differ from some natural human bnAbs, such as 2G12 and PGT128, in that they bind primarily to the core structures within the glycan, rather than to the Manα1 → 2Man termini (2G12) or to the whole glycan (PGT128). Antibody specificity for the glycan core may result from extensive serum mannosidase trimming of the immunogen in the vaccinated animals. This finding has broad implications for vaccine design aiming to target glycan-dependent HIV neutralizing antibodies.

Authors:
 [1];  [1];  [2];  [1];  [1];  [1];  [3];  [4];  [4]; ORCiD logo [3];  [2]; ORCiD logo [1]
  1. Brandeis Univ., Waltham, MA (United States)
  2. Scripps Research Inst., La Jolla, CA (United States)
  3. Boston Univ. School of Medicine, Boston, MA (United States)
  4. Duke Univ., Durham, NC (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
National Inst. of Health; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1493660
Alternate Identifier(s):
OSTI ID: 1508820
Grant/Contract Number:  
AC02-76SF00515; HHSN27201100016C; P41GM103393
Resource Type:
Published Article
Journal Name:
ACS Central Science
Additional Journal Information:
Journal Volume: 5; Journal Issue: 2; Journal ID: ISSN 2374-7943
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Nguyen, Dung N., Xu, Bokai, Stanfield, Robyn L., Bailey, Jennifer K., Horiya, Satoru, Temme, J. Sebastian, Leon, Deborah R., LaBranche, Celia C., Montefiori, David C., Costello, Catherine E., Wilson, Ian A., and Krauss, Isaac J.. Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities. United States: N. p., 2019. Web. doi:10.1021/acscentsci.8b00588.
Nguyen, Dung N., Xu, Bokai, Stanfield, Robyn L., Bailey, Jennifer K., Horiya, Satoru, Temme, J. Sebastian, Leon, Deborah R., LaBranche, Celia C., Montefiori, David C., Costello, Catherine E., Wilson, Ian A., & Krauss, Isaac J.. Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities. United States. doi:10.1021/acscentsci.8b00588.
Nguyen, Dung N., Xu, Bokai, Stanfield, Robyn L., Bailey, Jennifer K., Horiya, Satoru, Temme, J. Sebastian, Leon, Deborah R., LaBranche, Celia C., Montefiori, David C., Costello, Catherine E., Wilson, Ian A., and Krauss, Isaac J.. Wed . "Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities". United States. doi:10.1021/acscentsci.8b00588.
@article{osti_1493660,
title = {Oligomannose Glycopeptide Conjugates Elicit Antibodies Targeting the Glycan Core Rather than Its Extremities},
author = {Nguyen, Dung N. and Xu, Bokai and Stanfield, Robyn L. and Bailey, Jennifer K. and Horiya, Satoru and Temme, J. Sebastian and Leon, Deborah R. and LaBranche, Celia C. and Montefiori, David C. and Costello, Catherine E. and Wilson, Ian A. and Krauss, Isaac J.},
abstractNote = {Up to ~20% of HIV-infected individuals eventually develop broadly neutralizing antibodies (bnAbs), and many of these antibodies (~40%) target a region of dense high-mannose glycosylation on gp120 of the HIV envelope protein, known as the “high-mannose patch” (HMP). Thus, there have been numerous attempts to develop glycoconjugate vaccine immunogens that structurally mimic the HMP and might elicit bnAbs targeting this conserved neutralization epitope. Herein, we report on the immunogenicity of glycopeptides, designed by in vitro selection, that bind tightly to anti-HMP antibody 2G12. By analyzing the fine carbohydrate specificity of rabbit antibodies elicited by these immunogens, we found that they differ from some natural human bnAbs, such as 2G12 and PGT128, in that they bind primarily to the core structures within the glycan, rather than to the Manα1 → 2Man termini (2G12) or to the whole glycan (PGT128). Antibody specificity for the glycan core may result from extensive serum mannosidase trimming of the immunogen in the vaccinated animals. This finding has broad implications for vaccine design aiming to target glycan-dependent HIV neutralizing antibodies.},
doi = {10.1021/acscentsci.8b00588},
journal = {ACS Central Science},
number = 2,
volume = 5,
place = {United States},
year = {2019},
month = {2}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1021/acscentsci.8b00588

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