Pseudotyping Vesicular Stomatitis Virus with Lymphocytic Choriomeningitis Virus Glycoproteins Enhances Infectivity for Glioma Cells and Minimizes Neurotropism

Muik, Alexander; Kneiske, Inna; Werbizki, Marina; Wilflingseder, Doris; Giroglou, Tsanan; Ebert, Oliver; Kraft, Anna; Dietrich, Ursula; Zimmer, Gert; Momma, Stefan; Laer, Dorotheé von

doi:10.1128/jvi.02511-10

Cited by 74 publications

(75 citation statements)

References 42 publications

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“…Furthermore, the exact sequence of a G protein might determine its ability to direct infection of neurons vs. glia. A recent report using the LCMV-G protein from the WE strain of LCMV to pseudotype VSV showed infection of glia, but not neurons (44). The Armstrong strain clone 13 of LCMV-G was used in our study, which likely explains the difference in neuronal vs. glial infection, because a single amino acid change in G can alter receptor binding (45).…”

Section: Discussionmentioning

confidence: 99%

Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors

Beier

Saunders

Oldenburg

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

158

198

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To understand how the nervous system processes information, a map of the connections among neurons would be of great benefit. Here we describe the use of vesicular stomatitis virus (VSV) for tracing neuronal connections in vivo. We made VSV vectors that used glycoprotein (G) genes from several other viruses. The G protein from lymphocytic choriomeningitis virus endowed VSV with the ability to spread transsynaptically, specifically in an anterograde direction, whereas the rabies virus glycoprotein gave a specifically retrograde transsynaptic pattern. The use of an avian G protein fusion allowed specific targeting of cells expressing an avian receptor, which allowed a demonstration of monosynaptic anterograde tracing from defined cells. Synaptic connectivity of pairs of virally labeled cells was demonstrated by using slice cultures and electrophysiology. In vivo infections of several areas in the mouse brain led to the predicted patterns of spread for anterograde or retrograde tracers.

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Section: Discussionmentioning

confidence: 99%

Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors

Beier

Saunders

Oldenburg

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

158

198

View full text Add to dashboard Cite

show abstract

“…Brain cancer cell lines seem particularly susceptible to rVSV(GP)-mediated oncolysis. Importantly, in a previous study we showed that in addition to glioma cell lines, primary human glioma-derived stem cells (hGSC) were equally susceptible to LCMV-pseudotyped VSV vectors (20).…”

Section: Discussionmentioning

confidence: 99%

“…We removed the VSV glycoprotein G, the key neurovirulence determinant (20)(21)(22), and replaced it with the arenavirus glycoprotein LCMV-GP (23)(24)(25)(26), thereby generating rVSV(GP). While there are no doses at which wtVSV can be safely introduced into rodent brains, we found that rVSV(GP) caused no significant neurotoxicity even at doses of 10 8 plaque-forming units (PFU).…”

Section: Introductionmentioning

confidence: 99%

Re-engineering Vesicular Stomatitis Virus to Abrogate Neurotoxicity, Circumvent Humoral Immunity, and Enhance Oncolytic Potency

Stubbert²,

et al. 2014

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As cancer treatment tools, oncolytic viruses (OV) have yet to realize what some see as their ultimate clinical potential. In this study, we have engineered a chimeric vesicular stomatitis virus (VSV) that is devoid of its natural neurotoxicity while retaining potent oncolytic activity. The envelope glycoprotein (G) of VSV was replaced with a variant glycoprotein of the lymphocytic choriomeningitis virus (LCMV-GP), creating a replicating therapeutic, rVSV (GP), that is benign in normal brain but can effectively eliminate brain cancer in multiple preclinical tumor models in vivo. Furthermore, it can be safely administered systemically to mice and displays greater potency against a spectrum of human cancer cell lines than current OV candidates. Remarkably, rVSV(GP) escapes humoral immunity, thus, for the first time, allowing repeated systemic OV application without loss of therapeutic efficacy. Taken together, rVSV(GP) offers a considerably improved OV platform that lacks several of the major drawbacks that have limited the clinical potential of this technology to date. Cancer Res; 74(13); 3567-78. Ó2014 AACR.

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“…Recent studies demonstrated that VSV neurotoxicity can be circumvented by pseudotyping with the surface glycoproteins of lymphocytic choriomeningitis virus (15) or measles virus (16). However, the reported viruses were replication incompetent and had substantially reduced titers compared to unmodified VSVs.…”

mentioning

confidence: 99%

Characteristics of Oncolytic Vesicular Stomatitis Virus Displaying Tumor-Targeting Ligands

Ammayappan

Peng

Russell

2013

J Virol

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bWe sought proof of principle that tumor-targeting ligands can be displayed on the surface of vesicular stomatitis virus (VSV) by engineering its glycoprotein. Here, we successfully rescued VSVs displaying tumor vasculature-targeting ligands. By using a rational approach, we investigated various feasible insertion sites on the G protein of VSV (VSV-G) for display of tumor vasculature-targeting ligands, cyclic RGD (cRGD) and echistatin. We found seven sites on VSV-G that tolerated insertion of the 9-residue cRGD peptide, two of which could tolerate insertion of the 49-amino acid echistatin domain. All of the ligand-displaying viruses replicated as well as the parental virus. In vitro studies demonstrated that the VSVechistatin viruses specifically bound to targeted integrins. Since the low-density lipoprotein receptor (LDLR) was recently identified as a major receptor for VSV, we investigated the entry of ligand-displaying viruses after masking LDLR. The experiment showed that the modified viruses can enter the cell independently of LDLR, whereas entry of unmodified virus is significantly blocked by a specific monoclonal antibody against LDLR. Both parental and ligand-displaying viruses displayed equal oncolytic efficacies in a syngeneic mouse myeloma model. We further demonstrated that single-chain antibody fragments against tumor-specific antigens can be inserted at the N terminus of the G protein and that corresponding replication-competent VSVs can be rescued efficiently. Overall, we demonstrated that functional tumor-targeting ligands can be displayed on replication-competent VSVs without perturbing viral growth and oncolytic efficacy. This study provides a rational foundation for the future development of fully retargeted oncolytic VSVs. V esicular stomatitis virus (VSV) is an enveloped, negativestrand RNA virus that belongs to the Vesiculovirus genus of the Rhabdoviridae family. VSV has the ability to infect and kill cancer cells while sparing normal cells (1-4). Exploitation of this oncolytic property provides a promising alternative approach for the treatment of cancer. For disseminated cancer, virotherapy should ideally be administered systemically (2, 5-7), but this route of delivery brings its own set of problems. The major concerns for VSV virotherapy are neurotoxicity, antibody neutralization, and sequestration in off-target organs, especially the liver and spleen. Many attempts have been made to address these drawbacks. To reduce the neurotoxicity, the matrix protein of VSV was mutated (8, 9), and microRNA targets (10) or picornaviral internal ribosome entry sites (11) were engineered into the VSV genome. Serum neutralization has been avoided by PEGylating the virus (12, 13) or loading onto antigen-specific T cells (14), which ultimately improved virotherapy outcomes.To circumvent all of the above hurdles in a single step, pseudotyping VSV with other viral envelope glycoproteins was considered a potentially feasible approach. Recent studies demonstrated that VSV neurotoxicity can be circumvented by...

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Pseudotyping Vesicular Stomatitis Virus with Lymphocytic Choriomeningitis Virus Glycoproteins Enhances Infectivity for Glioma Cells and Minimizes Neurotropism

Cited by 74 publications

References 42 publications

Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors

Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors

Re-engineering Vesicular Stomatitis Virus to Abrogate Neurotoxicity, Circumvent Humoral Immunity, and Enhance Oncolytic Potency

Characteristics of Oncolytic Vesicular Stomatitis Virus Displaying Tumor-Targeting Ligands

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