Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer
Abstract
Furin cleavage of the HIV envelope glycoprotein is an essential step for cell entry that enables formation of well-folded, native-like glycosylated trimers, releases constraints on the fusion peptide, and limits enzymatic processing of the N-glycan shield. Here, we show that a cleavage-independent, stabilized, soluble Env trimer mimic (BG505 NFL.664) exhibits a “closed-form”, native-like, prefusion conformation akin to furin-cleaved Env trimers. The crystal structure of BG505 NFL.664 at 3.39 Å resolution with two potent bNAbs also identifies the full epitopes of PGV19 and PGT122 that target the receptor binding site and N332 supersite, respectively. Quantitative site-specific analysis of the glycan shield reveals that native-like glycan processing is maintained despite furin-independent maturation in the secretory pathway. Thus, cleavage-independent NFL Env trimers exhibit quaternary protein and carbohydrate structures similar to the native viral spike that further validate their potential as vaccine immunogen candidates.
- Authors:
-
- The Scripps Research Inst., La Jolla, CA (United States)
- Univ. of Oxford (United Kingdom)
- The Scripps Research Inst., La Jolla, CA (United States); Univ. of Oxford (United Kingdom); Univ. of Southampton (United Kingdom)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); International AIDS Vaccine Initiative Neutralizing Antibody Center; Collaboration for AIDS Vaccine Discovery; Bill & Melinda Gates Foundation; US Agency for International Development (USAID); National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID); Corpus Christi College; National Institutes of Health (NIH)
- OSTI Identifier:
- 1502220
- Grant/Contract Number:
- CAVD OPP1084519; OPP1115782; AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Glycosylation; HIV infections; Vaccines; X-ray crystallography
Citation Formats
Sarkar, Anita, Bale, Shridhar, Behrens, Anna-Janina, Kumar, Sonu, Sharma, Shailendra Kumar, de Val, Natalia, Pallesen, Jesper, Irimia, Adriana, Diwanji, Devan C., Stanfield, Robyn L., Ward, Andrew B., Crispin, Max, Wyatt, Richard T., and Wilson, Ian A. Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer. United States: N. p., 2018.
Web. doi:10.1038/s41467-018-04272-y.
Sarkar, Anita, Bale, Shridhar, Behrens, Anna-Janina, Kumar, Sonu, Sharma, Shailendra Kumar, de Val, Natalia, Pallesen, Jesper, Irimia, Adriana, Diwanji, Devan C., Stanfield, Robyn L., Ward, Andrew B., Crispin, Max, Wyatt, Richard T., & Wilson, Ian A. Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer. United States. https://doi.org/10.1038/s41467-018-04272-y
Sarkar, Anita, Bale, Shridhar, Behrens, Anna-Janina, Kumar, Sonu, Sharma, Shailendra Kumar, de Val, Natalia, Pallesen, Jesper, Irimia, Adriana, Diwanji, Devan C., Stanfield, Robyn L., Ward, Andrew B., Crispin, Max, Wyatt, Richard T., and Wilson, Ian A. Wed .
"Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer". United States. https://doi.org/10.1038/s41467-018-04272-y. https://www.osti.gov/servlets/purl/1502220.
@article{osti_1502220,
title = {Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer},
author = {Sarkar, Anita and Bale, Shridhar and Behrens, Anna-Janina and Kumar, Sonu and Sharma, Shailendra Kumar and de Val, Natalia and Pallesen, Jesper and Irimia, Adriana and Diwanji, Devan C. and Stanfield, Robyn L. and Ward, Andrew B. and Crispin, Max and Wyatt, Richard T. and Wilson, Ian A.},
abstractNote = {Furin cleavage of the HIV envelope glycoprotein is an essential step for cell entry that enables formation of well-folded, native-like glycosylated trimers, releases constraints on the fusion peptide, and limits enzymatic processing of the N-glycan shield. Here, we show that a cleavage-independent, stabilized, soluble Env trimer mimic (BG505 NFL.664) exhibits a “closed-form”, native-like, prefusion conformation akin to furin-cleaved Env trimers. The crystal structure of BG505 NFL.664 at 3.39 Å resolution with two potent bNAbs also identifies the full epitopes of PGV19 and PGT122 that target the receptor binding site and N332 supersite, respectively. Quantitative site-specific analysis of the glycan shield reveals that native-like glycan processing is maintained despite furin-independent maturation in the secretory pathway. Thus, cleavage-independent NFL Env trimers exhibit quaternary protein and carbohydrate structures similar to the native viral spike that further validate their potential as vaccine immunogen candidates.},
doi = {10.1038/s41467-018-04272-y},
journal = {Nature Communications},
number = 1,
volume = 9,
place = {United States},
year = {Wed May 16 00:00:00 EDT 2018},
month = {Wed May 16 00:00:00 EDT 2018}
}
Web of Science
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