Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies

  1. Haoqing Wang
  2. Harry B Gristick
  3. Louise Scharf
  4. Anthony P West
  5. Rachel P Galimidi
  6. Michael S Seaman
  7. Natalia T Freund
  8. Michel C Nussenzweig
  9. Pamela J Bjorkman  Is a corresponding author
  1. California Institute of Technology, United States
  2. 23andMe, United States
  3. Beth Israel Deaconess Medical Center, United States
  4. Tel Aviv University, Israel
  5. The Rockefeller University, United States

Abstract

The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3. Comparisons between cryo-EM structures of Env trimer complexed with BG1 (6.2Å resolution) and PG9 (11.5Å resolution) revealed a new V1V2-targeting strategy by BG1. Analyses of the EM structures provided information relevant to vaccine design including molecular details for different modes of asymmetric recognition of Env trimer and a binding model for BG1 recognition of V1V2 involving glycan flexibility.

Data availability

The following data sets were generated
    1. Haoqing Wang
    2. Harry Gristick
    3. Pamela Bjorkman
    (2017) BG1-Env-8ANC195 complex
    Publicly available at the EMBL_EBI Protein Dtat Bank in Europe (accession no: EMD-8693).
    1. Haoqing Wang
    2. Harry Gristick
    3. Pamela Bjorkm
    (2017) PG9-Env-8ANC195 complex
    Publicly available at the EMBL_EBI Protein Dtat Bank in Europe (accession no: EMDB-8695).
    1. Louise Scharf
    2. Harry Gristick
    3. Pamela Bjorkman
    (2017) BG1 Fab coordinate
    Publicly available at the RCSB Protein Data Bank (accession no: 5VVF).

Article and author information

Author details

  1. Haoqing Wang

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  2. Harry B Gristick

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  3. Louise Scharf

    Therapeutics, 23andMe, Mountain View, United States
    Competing interests
    No competing interests declared.
  4. Anthony P West

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  5. Rachel P Galimidi

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  6. Michael S Seaman

    Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    No competing interests declared.
  7. Natalia T Freund

    Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    No competing interests declared.
  8. Michel C Nussenzweig

    Laboratory of Molecular Immunology, The Rockefeller University, New York, United States
    Competing interests
    Michel C Nussenzweig, Senior editor, eLife.
  9. Pamela J Bjorkman

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    bjorkman@caltech.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2277-3990

Funding

National Institutes of Health (GM082545-06)

  • Pamela J Bjorkman

National Institute of Allergy and Infectious Diseases (HIVRAD P01 AI100148)

  • Michel C Nussenzweig
  • Pamela J Bjorkman

Bill and Melinda Gates Foundation (1040753)

  • Michel C Nussenzweig
  • Pamela J Bjorkman

Comprehensive Antibody-Vaccine Immune Monitoring Consortium (1032144)

  • Michael S Seaman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,278
    views
  • 467
    downloads
  • 51
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Haoqing Wang
  2. Harry B Gristick
  3. Louise Scharf
  4. Anthony P West
  5. Rachel P Galimidi
  6. Michael S Seaman
  7. Natalia T Freund
  8. Michel C Nussenzweig
  9. Pamela J Bjorkman
(2017)
Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies
eLife 6:e27389.
https://doi.org/10.7554/eLife.27389

Share this article

https://doi.org/10.7554/eLife.27389

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Yamato Niitani, Kohei Matsuzaki ... Michio Tomishige
    Research Article

    The two identical motor domains (heads) of dimeric kinesin-1 move in a hand-over-hand process along a microtubule, coordinating their ATPase cycles such that each ATP hydrolysis is tightly coupled to a step and enabling the motor to take many steps without dissociating. The neck linker, a structural element that connects the two heads, has been shown to be essential for head–head coordination; however, which kinetic step(s) in the chemomechanical cycle is ‘gated’ by the neck linker remains unresolved. Here, we employed pre-steady-state kinetics and single-molecule assays to investigate how the neck-linker conformation affects kinesin’s motility cycle. We show that the backward-pointing configuration of the neck linker in the front kinesin head confers higher affinity for microtubule, but does not change ATP binding and dissociation rates. In contrast, the forward-pointing configuration of the neck linker in the rear kinesin head decreases the ATP dissociation rate but has little effect on microtubule dissociation. In combination, these conformation-specific effects of the neck linker favor ATP hydrolysis and dissociation of the rear head prior to microtubule detachment of the front head, thereby providing a kinetic explanation for the coordinated walking mechanism of dimeric kinesin.

    1. Structural Biology and Molecular Biophysics
    Christopher T Schafer, Raymond F Pauszek III ... David P Millar
    Research Article

    The canonical chemokine receptor CXCR4 and atypical receptor ACKR3 both respond to CXCL12 but induce different effector responses to regulate cell migration. While CXCR4 couples to G proteins and directly promotes cell migration, ACKR3 is G-protein-independent and scavenges CXCL12 to regulate extracellular chemokine levels and maintain CXCR4 responsiveness, thereby indirectly influencing migration. The receptors also have distinct activation requirements. CXCR4 only responds to wild-type CXCL12 and is sensitive to mutation of the chemokine. By contrast, ACKR3 recruits GPCR kinases (GRKs) and β-arrestins and promiscuously responds to CXCL12, CXCL12 variants, other peptides and proteins, and is relatively insensitive to mutation. To investigate the role of conformational dynamics in the distinct pharmacological behaviors of CXCR4 and ACKR3, we employed single-molecule FRET to track discrete conformational states of the receptors in real-time. The data revealed that apo-CXCR4 preferentially populates a high-FRET inactive state, while apo-ACKR3 shows little conformational preference and high transition probabilities among multiple inactive, intermediate and active conformations, consistent with its propensity for activation. Multiple active-like ACKR3 conformations are populated in response to agonists, compared to the single CXCR4 active-state. This and the markedly different conformational landscapes of the receptors suggest that activation of ACKR3 may be achieved by a broader distribution of conformational states than CXCR4. Much of the conformational heterogeneity of ACKR3 is linked to a single residue that differs between ACKR3 and CXCR4. The dynamic properties of ACKR3 may underly its inability to form productive interactions with G proteins that would drive canonical GPCR signaling.