Ablation of nectin4 binding compromises CD46 usage by a hybrid vesicular stomatitis virus/measles virus

J Virol. 2014 Feb;88(4):2195-204. doi: 10.1128/JVI.02628-13. Epub 2013 Dec 11.

Abstract

Measles virus (MV) immunosuppression is due to infection of SLAM-positive immune cells, whereas respiratory shedding and virus transmission are due to infection of nectin4-positive airway epithelial cells. The vaccine lineage MV strain Edmonston (MV-Edm) acquired an additional tropism for CD46 which is the basis of its oncolytic specificity. VSVFH is a vesicular stomatitis virus (VSV) encoding the MV-Edm F and H entry proteins in place of G. The virus spreads faster than MV-Edm and is highly fusogenic and a potent oncolytic. To determine whether ablating nectin4 tropism from VSVFH might prevent shedding, increasing its safety profile as an oncolytic, or might have any effect on CD46 binding, we generated VSVFH viruses with H mutations that disrupt attachment to SLAM and/or nectin4. Disruption of nectin4 binding reduced release of VSVFH from the basolateral side of differentiated airway epithelia composed of Calu-3 cells. However, because nectin4 and CD46 have substantially overlapping receptor binding surfaces on H, disruption of nectin4 binding compromised CD46 binding and greatly diminished the oncolytic potency of these viruses on human cancer cells. Thus, our results support continued preclinical development of VSVFH without ablation of nectin4 binding.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • CHO Cells
  • Cell Adhesion Molecules / deficiency*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Cricetinae
  • Cricetulus
  • DNA Primers / genetics
  • Humans
  • Immunoblotting
  • Measles virus / immunology*
  • Membrane Cofactor Protein / metabolism
  • Receptors, Cell Surface / metabolism*
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • Vero Cells
  • Vesiculovirus / immunology*
  • Virus Shedding / genetics*
  • Virus Shedding / physiology

Substances

  • Antigens, CD
  • Cell Adhesion Molecules
  • DNA Primers
  • Membrane Cofactor Protein
  • Receptors, Cell Surface
  • NECTIN4 protein, human
  • Signaling Lymphocytic Activation Molecule Family Member 1