1. Microbiology and Infectious Disease
  2. Structural Biology and Molecular Biophysics
Download icon

HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations

  1. Xiaochu Ma
  2. Maolin Lu
  3. Jason Gorman
  4. Daniel S Terry
  5. Xinyu Hong
  6. Zhou Zhou
  7. Hong Zhao
  8. Roger B Altman
  9. James Arthos
  10. Scott C Blanchard
  11. Peter D Kwong
  12. James B Munro  Is a corresponding author
  13. Walther Mothes  Is a corresponding author
  1. Yale University School of Medicine, United States
  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States
  3. Weill Cornell Medical College of Cornell University, United States
  4. Tufts University School of Medicine, United States
Research Article
  • Cited 65
  • Views 2,568
  • Annotations
Cite this article as: eLife 2018;7:e34271 doi: 10.7554/eLife.34271

Abstract

HIV-1 entry into cells requires binding of the viral envelope glycoprotein (Env) to receptor CD4 and coreceptor. Imaging of individual Env molecules on native virions shows Env trimers to be dynamic, spontaneously transitioning between three distinct well-populated conformational states: a pre-triggered Env (State 1), a default intermediate (State 2) and a three-CD4-bound conformation (State 3), which can be stabilized by binding of CD4 and coreceptor-surrogate antibody 17b. Here, using single-molecule Fluorescence Resonance Energy Transfer (smFRET), we show the default intermediate configuration to be asymmetric, with individual protomers adopting distinct conformations. During entry, this asymmetric intermediate forms when a single CD4 molecule engages the trimer. The trimer can then transition to State 3 by binding additional CD4 molecules and coreceptor.

Article and author information

Author details

  1. Xiaochu Ma

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  2. Maolin Lu

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  3. Jason Gorman

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  4. Daniel S Terry

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.
  5. Xinyu Hong

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
  6. Zhou Zhou

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.
  7. Hong Zhao

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.
  8. Roger B Altman

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.
  9. James Arthos

    Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  10. Scott C Blanchard

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2717-9365
  11. Peter D Kwong

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.
  12. James B Munro

    Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, United States
    For correspondence
    james.munro@tufts.edu
    Competing interests
    No competing interests declared.
  13. Walther Mothes

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    For correspondence
    walther.mothes@yale.edu
    Competing interests
    Walther Mothes, Patent applications pertaining to this work are U.S. Patent Application 13/202,351, Methods and Compositions for Altering Photophysical Properties of Fluorophores via Proximal Quenching (S.C.B., Z.Z.); U.S. Patent Application 14/373,402 Dye Compositions, Methods of Preparation, Conjugates Thereof, and Methods of Use (S.C.B., Z.Z.); and International and US Patent Application PCT/US13/42249 Reagents and Methods for Identifying Anti-HIV Compounds (S.C.B., J.B.M., W.M.). S.C.B. is a co-founder of Lumidyne Corporation.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3367-7240

Funding

National Institutes of Health (GM116654)

  • Walther Mothes

National Institutes of Health (AI116262)

  • James B Munro

National Institutes of Health (GM098859)

  • Scott C Blanchard

National Institutes of Health (GM056550)

  • Scott C Blanchard
  • Walther Mothes

Cancer Research Institute (Irvington Fellows Program)

  • James B Munro

National Institutes of Health (AI042853)

  • James B Munro

China Scholarship Council (Yale World Scholars)

  • Xiaochu Ma

National Institutes of Health (GM103310)

  • Peter D Kwong

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

Reviewing Editor

  1. Pamela J Bjorkman, California Institute of Technology, United States

Publication history

  1. Received: December 12, 2017
  2. Accepted: March 20, 2018
  3. Accepted Manuscript published: March 21, 2018 (version 1)
  4. Version of Record published: April 9, 2018 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 2,568
    Page views
  • 511
    Downloads
  • 65
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

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)

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

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

Further reading

    1. Microbiology and Infectious Disease
    Qi Yan Ang et al.
    Research Article Updated

    East Asians (EAs) experience worse metabolic health outcomes compared to other ethnic groups at lower body mass indices; however, the potential role of the gut microbiota in contributing to these health disparities remains unknown. We conducted a multi-omic study of 46 lean and obese East Asian and White participants living in the San Francisco Bay Area, revealing marked differences between ethnic groups in bacterial richness and community structure. White individuals were enriched for the mucin-degrading Akkermansia muciniphila. East Asian subjects had increased levels of multiple bacterial phyla, fermentative pathways detected by metagenomics, and the short-chain fatty acid end-products acetate, propionate, and isobutyrate. Differences in the gut microbiota between the East Asian and White subjects could not be explained by dietary intake, were more pronounced in lean individuals, and were associated with current geographical location. Microbiome transplantations into germ-free mice demonstrated stable diet- and host genotype-independent differences between the gut microbiotas of East Asian and White individuals that differentially impact host body composition. Taken together, our findings add to the growing body of literature describing microbiome variations between ethnicities and provide a starting point for defining the mechanisms through which the microbiome may shape disparate health outcomes in East Asians.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Amelia E Hinman et al.
    Research Article Updated

    For many intracellular pathogens, the phagosome is the site of events and interactions that shape infection outcome. Phagosomal membrane damage, in particular, is proposed to benefit invading pathogens. To define the innate immune consequences of this damage, we profiled macrophage transcriptional responses to wild-type Mycobacterium tuberculosis (Mtb) and mutants that fail to damage the phagosomal membrane. We identified a set of genes with enhanced expression in response to the mutants. These genes represented a late component of the TLR2-dependent transcriptional response to Mtb, distinct from an earlier component that included Tnf. Expression of the later component was inherent to TLR2 activation, dependent upon endosomal uptake, and enhanced by phagosome acidification. Canonical Mtb virulence factors that contribute to phagosomal membrane damage blunted phagosome acidification and undermined the endosome-specific response. Profiling cell survival and bacterial growth in macrophages demonstrated that the attenuation of these mutants is partially dependent upon TLR2. Further, TLR2 contributed to the attenuated phenotype of one of these mutants in a murine model of infection. These results demonstrate two distinct components of the TLR2 response and identify a component dependent upon endosomal uptake as a point where pathogenic bacteria interfere with the generation of effective inflammation. This interference promotes tuberculosis (TB) pathogenesis in both macrophage and murine infection models.