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J Virol. 2020 Feb 12. pii: JVI.01967-19. doi: 10.1128/JVI.01967-19. [Epub ahead of print]

Mucin-like domain of Ebola virus glycoprotein enhances selective oncolytic actions against brain tumors.

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Department of Neurosurgery Yale University School of Medicine, New Haven, Connecticut, USA.
Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Department of Neurosurgery Yale University School of Medicine, New Haven, Connecticut, USA


Given that the Ebola virus (EBOV) infects a wide array of organs and cells yet displays a relative lack of neurotropism, we asked whether a chimeric vesicular stomatitis virus (VSV) expressing the EBOV glycoprotein (GP) might selectively target brain tumors. The mucin-like domain (MLD) of the EBOV GP may enhance virus immune system evasion. Here we compare chimeric VSVs in which EBOV GP replaces the VSV glycoprotein, thereby reducing the neurotoxicity associated with wildtype VSV. A chimeric VSV expressing the full-length EBOV GP (VSV-EBOV) containing the MLD was substantially more effective and safer than a parallel construct with an EBOV GP lacking the MLD (VSV-EBOVΔMLD). One-step growth, RT-qPCR, and Western blot assessment showed VSV-EBOVΔMLD produced substantially more progeny faster than VSV-EBOV. Using immunodeficient SCID mice, we focused on targeting human brain tumors with these VSV-EBOVs. Similar to our previous report using an attenuated VSV-EBOV with no MLD that expressed GFP (VSV-EBOVΔMLD-GFP), VSV-EBOVΔMLD without GFP targeted glioma, but yielded only a modest extension of survival. In contrast, VSV-EBOV containing the MLD showed substantially better targeting and elimination of brain tumors after intravenous delivery, and increased the survival of brain tumor-bearing mice. Despite the apparent destruction of most tumor cells by VSV-EBOVΔMLD, the virus remained active within the SCID mouse brain and showed widespread infection of normal brain cells. In contrast, VSV-EBOV eliminated the tumors, and showed relatively little infection of normal brain cells. Parallel experiments with direct intracranial virus infection generated similar results. Neither VSV-EBOV nor VSV-EBOVΔMLD showed substantive infection of the brains of normal immunocompetent mice.Importance The Ebola virus glycoprotein contains a mucin-like domain which may play a role in immune evasion. Chimeric vesicular stomatitis viruses with the EBOV glycoprotein substituted for the VSV glycoprotein show greater safety and efficacy in targeting brain tumors in immunodeficient mice when the MLD is expressed within the EBOV glycoprotein compared with EBOV lacking the mucin-like domain.


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