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

Elife. 2018 Mar 21;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.

Keywords: HIV-1 Envelope; Single molecule FRET; infectious disease; microbiology; molecular biophysics; structural biology; virus; virus entry.

Publication types

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

MeSH terms

  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism
  • Fluorescence Resonance Energy Transfer
  • HIV Antibodies / chemistry
  • HIV Antibodies / metabolism
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / metabolism*
  • Humans
  • Protein Binding
  • Protein Conformation*
  • Protein Multimerization*
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Virion / metabolism
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / immunology
  • env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • CD4 Antigens
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Protein Subunits
  • env Gene Products, Human Immunodeficiency Virus