Glycoprotein H and α4β1 integrins determine the entry pathway of alphaherpesviruses

J Virol. 2013 May;87(10):5937-48. doi: 10.1128/JVI.03522-12. Epub 2013 Mar 20.


Herpesviruses enter cells either by direct fusion at the plasma membrane or from within endosomes, depending on the cell type and receptor(s). We investigated two closely related herpesviruses of horses, equine herpesvirus type 1 (EHV-1) and EHV-4, for which the cellular and viral determinants routing virus entry are unknown. We show that EHV-1 enters equine epithelial cells via direct fusion at the plasma membrane, while EHV-4 does so via an endocytic pathway, which is dependent on dynamin II, cholesterol, caveolin 1, and tyrosine kinase activity. Exchange of glycoprotein H (gH) between EHV-1 and EHV-4 resulted in rerouting of EHV-1 to the endocytic pathway, as did blocking of α4β1 integrins on the cell surface. Furthermore, a point mutation in the SDI integrin-binding motif of EHV-1 gH also directed EHV-1 to the endocytic pathway. Cumulatively, we show that viral gH and cellular α4β1 integrins are important determinants in the choice of alphaherpesvirus cellular entry pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Herpesvirus 1, Equid / physiology*
  • Herpesvirus 4, Equid / physiology*
  • Horses
  • Host-Pathogen Interactions*
  • Integrin alpha4beta1 / metabolism*
  • Viral Envelope Proteins / metabolism*
  • Virus Internalization*


  • Integrin alpha4beta1
  • Viral Envelope Proteins
  • glycoprotein H, Equid herpesvirus 1
  • glycoprotein H, Herpesvirus 4