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Title: Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability

Abstract

The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [1];  [1];  [1];  [1];  [4];  [5];  [3];  [3];  [3];  [1] more »;  [3];  [5];  [4];  [1];  [2];  [3];  [1];  [1] « less
  1. The Scripps Research Inst., La Jolla, CA (United States)
  2. Univ. of Southampton (United Kingdom)
  3. National Inst. of Health (NIH), Bethesda, MD (United States)
  4. Karolinska Inst., Stockholm (Sweden)
  5. Fred Hutchinson Cancer Research Center, Seattle, WA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); Scripps CHAVI-ID; Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery
OSTI Identifier:
1577147
Grant/Contract Number:  
AC02-06CH11357; P01 AI104722; R01 AI136621; UM1 AI100663; OPP1115782; OPP1084519; OPP1196345
Resource Type:
Accepted Manuscript
Journal Name:
Immunity
Additional Journal Information:
Journal Volume: 51; Journal Issue: 5; Journal ID: ISSN 1074-7613
Publisher:
Cell Press
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; HIV-1; Env; NFL; trimer; liposomes; 1C2; E70; glycan deletion; vaccine; bNAbs

Citation Formats

Dubrovskaya, Viktoriya, Tran, Karen, Ozorowski, Gabriel, Guenaga, Javier, Wilson, Richard, Bale, Shridhar, Cottrell, Christopher A., Turner, Hannah L., Seabright, Gemma, O’Dell, Sijy, Torres, Jonathan L., Yang, Lifei, Feng, Yu, Leaman, Daniel P., Vázquez Bernat, Néstor, Liban, Tyler, Louder, Mark, McKee, Krisha, Bailer, Robert T., Movsesyan, Arlette, Doria-Rose, Nicole A., Pancera, Marie, Karlsson Hedestam, Gunilla B., Zwick, Michael B., Crispin, Max, Mascola, John R., Ward, Andrew B., and Wyatt, Richard T.. Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability. United States: N. p., 2019. Web. https://doi.org/10.1016/j.immuni.2019.10.008.
Dubrovskaya, Viktoriya, Tran, Karen, Ozorowski, Gabriel, Guenaga, Javier, Wilson, Richard, Bale, Shridhar, Cottrell, Christopher A., Turner, Hannah L., Seabright, Gemma, O’Dell, Sijy, Torres, Jonathan L., Yang, Lifei, Feng, Yu, Leaman, Daniel P., Vázquez Bernat, Néstor, Liban, Tyler, Louder, Mark, McKee, Krisha, Bailer, Robert T., Movsesyan, Arlette, Doria-Rose, Nicole A., Pancera, Marie, Karlsson Hedestam, Gunilla B., Zwick, Michael B., Crispin, Max, Mascola, John R., Ward, Andrew B., & Wyatt, Richard T.. Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability. United States. https://doi.org/10.1016/j.immuni.2019.10.008
Dubrovskaya, Viktoriya, Tran, Karen, Ozorowski, Gabriel, Guenaga, Javier, Wilson, Richard, Bale, Shridhar, Cottrell, Christopher A., Turner, Hannah L., Seabright, Gemma, O’Dell, Sijy, Torres, Jonathan L., Yang, Lifei, Feng, Yu, Leaman, Daniel P., Vázquez Bernat, Néstor, Liban, Tyler, Louder, Mark, McKee, Krisha, Bailer, Robert T., Movsesyan, Arlette, Doria-Rose, Nicole A., Pancera, Marie, Karlsson Hedestam, Gunilla B., Zwick, Michael B., Crispin, Max, Mascola, John R., Ward, Andrew B., and Wyatt, Richard T.. Tue . "Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability". United States. https://doi.org/10.1016/j.immuni.2019.10.008. https://www.osti.gov/servlets/purl/1577147.
@article{osti_1577147,
title = {Vaccination with Glycan-Modified HIV NFL Envelope Trimer-Liposomes Elicits Broadly Neutralizing Antibodies to Multiple Sites of Vulnerability},
author = {Dubrovskaya, Viktoriya and Tran, Karen and Ozorowski, Gabriel and Guenaga, Javier and Wilson, Richard and Bale, Shridhar and Cottrell, Christopher A. and Turner, Hannah L. and Seabright, Gemma and O’Dell, Sijy and Torres, Jonathan L. and Yang, Lifei and Feng, Yu and Leaman, Daniel P. and Vázquez Bernat, Néstor and Liban, Tyler and Louder, Mark and McKee, Krisha and Bailer, Robert T. and Movsesyan, Arlette and Doria-Rose, Nicole A. and Pancera, Marie and Karlsson Hedestam, Gunilla B. and Zwick, Michael B. and Crispin, Max and Mascola, John R. and Ward, Andrew B. and Wyatt, Richard T.},
abstractNote = {The elicitation of broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer remains a major vaccine challenge. Most cross-conserved protein determinants are occluded by self-N-glycan shielding, limiting B cell recognition of the underlying polypeptide surface. The exceptions to the contiguous glycan shield include the conserved receptor CD4 binding site (CD4bs) and glycoprotein (gp)41 elements proximal to the furin cleavage site. Accordingly, we performed heterologous trimer-liposome prime:boosting in rabbits to drive B cells specific for cross-conserved sites. To preferentially expose the CD4bs to B cells, we eliminated proximal N-glycans while maintaining the native-like state of the cleavage-independent NFL trimers, followed by gradual N-glycan restoration coupled with heterologous boosting. This approach successfully elicited CD4bs-directed, cross-neutralizing Abs, including one targeting a unique glycan-protein epitope and a bNAb (87% breadth) directed to the gp120:gp41 interface, both resolved by high-resolution cryoelectron microscopy. This study provides proof-of-principle immunogenicity toward eliciting bNAbs by vaccination.},
doi = {10.1016/j.immuni.2019.10.008},
journal = {Immunity},
number = 5,
volume = 51,
place = {United States},
year = {2019},
month = {11}
}

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