Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer

Anita Sarkar, Shridhar Bale, Anna-Janina Behrens, Sonu Kumar, Shailendra Kumar Sharma, Natalia de Val, Jesper Pallesen, Adriana Irimia, Devan C. Diwanji, Robyn L. Stanfield, Andrew B. Ward, Max Crispin, Richard T. Wyatt () and Ian A. Wilson ()
Additional contact information
Anita Sarkar: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Shridhar Bale: The Scripps Research Institute
Anna-Janina Behrens: University of Oxford
Sonu Kumar: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Shailendra Kumar Sharma: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Natalia de Val: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Jesper Pallesen: The Scripps Research Institute
Adriana Irimia: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Devan C. Diwanji: The Scripps Research Institute
Robyn L. Stanfield: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Andrew B. Ward: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Max Crispin: The Scripps Research Institute
Richard T. Wyatt: IAVI Neutralizing Antibody Center, The Scripps Research Institute
Ian A. Wilson: IAVI Neutralizing Antibody Center, The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04272-y

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