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; Ian A Wilson

doi:10.1038/s41467-018-04272-y

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

Nat Commun. 2018 May 16;9(1):1956. doi: 10.1038/s41467-018-04272-y.

Authors

Anita Sarkar^{1

2

3}, Shridhar Bale⁴, Anna-Janina Behrens⁵, Sonu Kumar^{1

2

3}, Shailendra Kumar Sharma^{1

2}, Natalia de Val^{1

3}, Jesper Pallesen^{2

3}, Adriana Irimia^{1

2

3}, Devan C Diwanji³, Robyn L Stanfield^{1

2

3}, Andrew B Ward^{1

2

3}, Max Crispin^{4

5

6}, Richard T Wyatt^{7

8

9}, Ian A Wilson^{10

11

12

13}

Affiliations

¹ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
² Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, 92037, USA.
³ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁴ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁵ Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
⁶ Centre for Biological Sciences and Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
⁷ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA. [email protected].
⁸ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, 92037, USA. [email protected].
⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA. [email protected].
¹⁰ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA. [email protected].
¹¹ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, 92037, USA. [email protected].
¹² Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA. [email protected].
¹³ Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / metabolism
Binding Sites
Crystallography, X-Ray
Epitopes / chemistry
Glycoproteins / chemistry*
Glycoproteins / metabolism
Glycosylation
HIV Antibodies / chemistry
HIV Antibodies / metabolism
HIV-1 / immunology
HIV-1 / metabolism
Humans
Models, Molecular
Protein Binding
Protein Multimerization*
Protein Structure, Quaternary*
env Gene Products, Human Immunodeficiency Virus / chemistry*
env Gene Products, Human Immunodeficiency Virus / immunology
env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

Antibodies, Neutralizing
Epitopes
Glycoproteins
HIV Antibodies
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding