Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry

PLoS Pathog. 2017 Apr 12;13(4):e1006281. doi: 10.1371/journal.ppat.1006281. eCollection 2017 Apr.

Abstract

Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO-PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs.

MeSH terms

  • Cell Line
  • Cells, Cultured
  • Cytomegalovirus / genetics
  • Cytomegalovirus / physiology*
  • Cytomegalovirus Infections / virology*
  • Fibroblasts / virology
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Multiprotein Complexes
  • Mutation
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Recombinant Proteins
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism*
  • Virion
  • Virus Internalization*

Substances

  • Membrane Glycoproteins
  • Multiprotein Complexes
  • Recombinant Proteins
  • UL115 protein, Human herpesvirus 5
  • Viral Envelope Proteins
  • glycoprotein H, Cytomegalovirus
  • glycoprotein O, cytomegalovirus
  • Receptor, Platelet-Derived Growth Factor alpha

Grants and funding

This work was supported by grants from the Deutsche Forschungsgemeinschaft given to BA (AD 131/3-2 and AD 131/4-1). YW was funded by a PhD grant from the China Scholarship Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.