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Title: Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation

Authors:
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Publication Date:
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1394845
Grant/Contract Number:
W-31-109-Eng-38
Resource Type:
Journal Article: Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 19; Journal Issue: 4; Related Information: CHORUS Timestamp: 2017-09-26 01:16:30; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English

Citation Formats

Zhou, Tongqing, Doria-Rose, Nicole A., Cheng, Cheng, Stewart-Jones, Guillaume B. E., Chuang, Gwo-Yu, Chambers, Michael, Druz, Aliaksandr, Geng, Hui, McKee, Krisha, Kwon, Young Do, O’Dell, Sijy, Sastry, Mallika, Schmidt, Stephen D., Xu, Kai, Chen, Lei, Chen, Rita E., Louder, Mark K., Pancera, Marie, Wanninger, Timothy G., Zhang, Baoshan, Zheng, Anqi, Farney, S. Katie, Foulds, Kathryn E., Georgiev, Ivelin S., Joyce, M. Gordon, Lemmin, Thomas, Narpala, Sandeep, Rawi, Reda, Soto, Cinque, Todd, John-Paul, Shen, Chen-Hsiang, Tsybovsky, Yaroslav, Yang, Yongping, Zhao, Peng, Haynes, Barton F., Stamatatos, Leonidas, Tiemeyer, Michael, Wells, Lance, Scorpio, Diana G., Shapiro, Lawrence, McDermott, Adrian B., Mascola, John R., and Kwong, Peter D. Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation. Netherlands: N. p., 2017. Web. doi:10.1016/j.celrep.2017.04.013.
Zhou, Tongqing, Doria-Rose, Nicole A., Cheng, Cheng, Stewart-Jones, Guillaume B. E., Chuang, Gwo-Yu, Chambers, Michael, Druz, Aliaksandr, Geng, Hui, McKee, Krisha, Kwon, Young Do, O’Dell, Sijy, Sastry, Mallika, Schmidt, Stephen D., Xu, Kai, Chen, Lei, Chen, Rita E., Louder, Mark K., Pancera, Marie, Wanninger, Timothy G., Zhang, Baoshan, Zheng, Anqi, Farney, S. Katie, Foulds, Kathryn E., Georgiev, Ivelin S., Joyce, M. Gordon, Lemmin, Thomas, Narpala, Sandeep, Rawi, Reda, Soto, Cinque, Todd, John-Paul, Shen, Chen-Hsiang, Tsybovsky, Yaroslav, Yang, Yongping, Zhao, Peng, Haynes, Barton F., Stamatatos, Leonidas, Tiemeyer, Michael, Wells, Lance, Scorpio, Diana G., Shapiro, Lawrence, McDermott, Adrian B., Mascola, John R., & Kwong, Peter D. Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation. Netherlands. doi:10.1016/j.celrep.2017.04.013.
Zhou, Tongqing, Doria-Rose, Nicole A., Cheng, Cheng, Stewart-Jones, Guillaume B. E., Chuang, Gwo-Yu, Chambers, Michael, Druz, Aliaksandr, Geng, Hui, McKee, Krisha, Kwon, Young Do, O’Dell, Sijy, Sastry, Mallika, Schmidt, Stephen D., Xu, Kai, Chen, Lei, Chen, Rita E., Louder, Mark K., Pancera, Marie, Wanninger, Timothy G., Zhang, Baoshan, Zheng, Anqi, Farney, S. Katie, Foulds, Kathryn E., Georgiev, Ivelin S., Joyce, M. Gordon, Lemmin, Thomas, Narpala, Sandeep, Rawi, Reda, Soto, Cinque, Todd, John-Paul, Shen, Chen-Hsiang, Tsybovsky, Yaroslav, Yang, Yongping, Zhao, Peng, Haynes, Barton F., Stamatatos, Leonidas, Tiemeyer, Michael, Wells, Lance, Scorpio, Diana G., Shapiro, Lawrence, McDermott, Adrian B., Mascola, John R., and Kwong, Peter D. Sat . "Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation". Netherlands. doi:10.1016/j.celrep.2017.04.013.
@article{osti_1394845,
title = {Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation},
author = {Zhou, Tongqing and Doria-Rose, Nicole A. and Cheng, Cheng and Stewart-Jones, Guillaume B. E. and Chuang, Gwo-Yu and Chambers, Michael and Druz, Aliaksandr and Geng, Hui and McKee, Krisha and Kwon, Young Do and O’Dell, Sijy and Sastry, Mallika and Schmidt, Stephen D. and Xu, Kai and Chen, Lei and Chen, Rita E. and Louder, Mark K. and Pancera, Marie and Wanninger, Timothy G. and Zhang, Baoshan and Zheng, Anqi and Farney, S. Katie and Foulds, Kathryn E. and Georgiev, Ivelin S. and Joyce, M. Gordon and Lemmin, Thomas and Narpala, Sandeep and Rawi, Reda and Soto, Cinque and Todd, John-Paul and Shen, Chen-Hsiang and Tsybovsky, Yaroslav and Yang, Yongping and Zhao, Peng and Haynes, Barton F. and Stamatatos, Leonidas and Tiemeyer, Michael and Wells, Lance and Scorpio, Diana G. and Shapiro, Lawrence and McDermott, Adrian B. and Mascola, John R. and Kwong, Peter D.},
abstractNote = {},
doi = {10.1016/j.celrep.2017.04.013},
journal = {Cell Reports},
number = 4,
volume = 19,
place = {Netherlands},
year = {Sat Apr 01 00:00:00 EDT 2017},
month = {Sat Apr 01 00:00:00 EDT 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.celrep.2017.04.013

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Cited by: 10works
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  • While the HIV-1-glycan shield is known to shelter Env from the humoral immune response, its quantitative impact on antibody elicitation has been unclear. Here, we use targeted deglycosylation to measure the impact of the glycan shield on elicitation of antibodies against the CD4 supersite. We engineered diverse Env trimers with select glycans removed proximal to the CD4 supersite, characterized their structures and glycosylation, and immunized guinea pigs and rhesus macaques. Immunizations yielded little neutralization against wild-type viruses but potent CD4-supersite neutralization (titers 1: >1,000,000 against four-glycan-deleted autologous viruses with over 90% breadth against four-glycan-deleted heterologous strains exhibiting tier 2 neutralizationmore » character). To a first approximation, the immunogenicity of the glycan-shielded protein surface was negligible, with Env-elicited neutralization (ID50) proportional to the exponential of the protein-surface area accessible to antibody. Based on these high titers and exponential relationship, we propose site-selective deglycosylated trimers as priming immunogens to increase the frequency of site-targeting antibodies.« less
  • The HIV envelope (Env) protein gp120 is protected from antibody recognition by a dense glycan shield. However, several of the recently identified PGT broadly neutralizing antibodies appear to interact directly with the HIV glycan coat. Crystal structures of antigen-binding fragments (Fabs) PGT 127 and 128 with Man{sub 9} at 1.65 and 1.29 angstrom resolution, respectively, and glycan binding data delineate a specific high mannose-binding site. Fab PGT 128 complexed with a fully glycosylated gp120 outer domain at 3.25 angstroms reveals that the antibody penetrates the glycan shield and recognizes two conserved glycans as well as a short {beta}-strand segment ofmore » the gp120 V3 loop, accounting for its high binding affinity and broad specificify. Furthermore, our data suggest that the high neutralization potency of PGT 127 and 128 immunoglobulin Gs may be mediated by cross-linking Env trimers on the viral surface.« less
  • HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1–V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1–V2, showing an epitope comprising both high mannose–type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, andmore » introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1–glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.« less
  • ABSTRACT All HIV-1-infected individuals develop strain-specific neutralizing antibodies to their infecting virus, which in some cases mature into broadly neutralizing antibodies. Defining the epitopes of strain-specific antibodies that overlap conserved sites of vulnerability might provide mechanistic insights into how broadly neutralizing antibodies arise. We previously described an HIV-1 clade C-infected donor, CAP257, who developed broadly neutralizing plasma antibodies targeting an N276 glycan-dependent epitope in the CD4 binding site. The initial CD4 binding site response potently neutralized the heterologous tier 2 clade B viral strain RHPA, which was used to design resurfaced gp120 antigens for single-B-cell sorting. Here we report themore » isolation and structural characterization of CAP257-RH1, an N276 glycan-dependent CD4 binding site antibody representative of the early CD4 binding site plasma response in donor CAP257. The cocrystal structure of CAP257-RH1 bound to RHPA gp120 revealed critical interactions with the N276 glycan, loop D, and V5, but not with aspartic acid 368, similarly to HJ16 and 179NC75. The CAP257-RH1 monoclonal antibody was derived from the immunoglobulin-variable IGHV3-33 and IGLV3-10 genes and neutralized RHPA but not the transmitted/founder virus from donor CAP257. Its narrow neutralization breadth was attributed to a binding angle that was incompatible with glycosylated V5 loops present in almost all HIV-1 strains, including the CAP257 transmitted/founder virus. Deep sequencing of autologous CAP257 viruses, however, revealed minority variants early in infection that lacked V5 glycans. These glycan-free V5 loops are unusual holes in the glycan shield that may have been necessary for initiating this N276 glycan-dependent CD4 binding site B-cell lineage. IMPORTANCEThe conserved CD4 binding site on gp120 is a major target for HIV-1 vaccine design, but key events in the elicitation and maturation of different antibody lineages to this site remain elusive. Studies have shown that strain-specific antibodies can evolve into broadly neutralizing antibodies or in some cases act as helper lineages. Therefore, characterizing the epitopes of strain-specific antibodies may help to inform the design of HIV-1 immunogens to elicit broadly neutralizing antibodies. In this study, we isolate a narrowly neutralizing N276 glycan-dependent antibody and use X-ray crystallography and viral deep sequencing to describe how gp120 lacking glycans in V5 might have elicited these early glycan-dependent CD4 binding site antibodies. These data highlight how glycan holes can play a role in the elicitation of B-cell lineages targeting the CD4 binding site.« less