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Updated: May 4, 2026
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Ablation of nectin4 binding compromises CD46 usage by a hybrid vesicular stomatitis virus/measles virus
Yu-Ping Liu1, Samuel P Russell, Camilo Ayala-Breton
1Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
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.
Insights
Ablating nectin4 binding from VSVFH viruses reduced shedding but also compromised oncolytic potency by affecting CD46 binding. Continued preclinical development of VSVFH without nectin4 binding ablation is supported.
Area of Science:
- Virology
- Oncolytic Virotherapy
- Molecular Biology
Background:
- Measles virus (MV) causes immunosuppression via SLAM-positive immune cells and shedding via nectin4-positive airway cells.
- The Edmonston vaccine strain (MV-Edm) targets CD46, forming the basis for its oncolytic properties.
- Vesicular stomatitis virus (VSV) expressing MV-Edm F and H proteins (VSVFH) is a potent oncolytic with enhanced spread.
Purpose of the Study:
- To investigate if disrupting nectin4 tropism in VSVFH could reduce shedding and improve safety as an oncolytic.
- To assess the impact of nectin4 binding disruption on CD46 binding and oncolytic activity.
Main Methods:
- Generated VSVFH viruses with mutations in the H protein to disrupt SLAM and/or nectin4 attachment.
- Assessed virus release from nectin4-positive Calu-3 airway epithelial cells.
- Evaluated oncolytic potency against human cancer cells.
Main Results:
- Disrupting nectin4 binding reduced VSVFH release from airway epithelia.
- However, nectin4 and CD46 share overlapping binding surfaces on the H protein.
- Nectin4 binding disruption compromised CD46 binding and significantly diminished oncolytic potency.
Conclusions:
- Ablating nectin4 tropism from VSVFH negatively impacts its oncolytic efficacy due to compromised CD46 binding.
- VSVFH retains oncolytic potential, and further development should not involve nectin4 binding ablation.
- These findings support the continued preclinical development of VSVFH as an oncolytic virus.
