VSV-tumor selective replication and protein translation

Barber, Glen N.

doi:10.1038/sj.onc.1209042

Cited by 134 publications

(146 citation statements)

References 91 publications

(107 reference statements)

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“…6 Because of the altered M protein, VSV-MD51 no longer blocks the nuclear export of host RNA encoding antiviral proteins, including multiple species of interferons, and thus triggers a stronger interferon response in normal tissues that inhibits VSV infection, whereas VSV replication in interferon-defective tumor cells is not altered. 4,6,23,24 In the present study we merged the attributes of VSV-MD51 with the CD::UPRT/5FC suicide gene system and further improved the previously reported VSV-CD::UPRT strategy. 22 Recombinant VSV-MD51 engineered to express CD::UPRT in combination with 5FC increased cancer cell killing in vitro in VSV-resistant cell lines and in a viral dissemination blocking model.…”

Section: Introductionmentioning

confidence: 92%

“…VSV is exquisitely sensitive to type 1 interferon-mediated antiviral responses in untransformed cells, and consequently its selective oncotropism is attributed to the innate antiviral response suppression in tumor cells. [4][5][6][7] Although successful tumor eradication and tumor growth delay have been reported in animal models following treatment with OVs, several cancer models remain partially or completely resistant to viral oncolysis. Barriers to effective tumor oncolysis include intrinsic resistance of tumor cells to infection, limited tumor cell death induced by direct viral replication and inefficient viral spreading within the tumor mass.…”

Section: Introductionmentioning

confidence: 99%

“…13 VSV represents an excellent choice as a vector for suicide gene transduction because of selective cancer cell tropism and the relative ease of foreign gene insertion. 4,5,14 VSV engineered to express suicide enzymes allow the conversion of non-toxic prodrug into a toxic form only at the site of viral replication, thus generating specific bystander killing at the tumor site. Recombinant VSV carrying the Herpes virus TK enzyme has been shown to phosphorylate the non-toxic prodrug ganciclovir, facilitating its DNA integration and subsequent local toxicity.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé

Samuel

et al. 2011

Cancer Gene Ther

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Oncolytic viruses (OVs) are promising therapeutic agents for cancer treatment, with recent studies emphasizing the combined use of chemotherapeutic compounds and prodrug suicide gene strategies to improve OV efficacy. In the present study, the synergistic activity of recombinant vesicular stomatitis virus (VSV)-MD51 virus expressing the cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) suicide gene and 5-fluorocytosine (5FC) prodrug was investigated in triggering tumor cell oncolysis. In a panel of VSV-sensitive and -resistant cells-prostate PC3, breast MCF7 and TSA, B-lymphoma Karpas and melanoma B16-F10-the combination treatment increased killing of non-infected bystander cells in vitro via the release of 5FC toxic derivatives. In addition, we showed a synergistic effect on cancer cell killing with VSV-MD51 and the active form of the drug 5-fluorouracil. Furthermore, by monitoring VSV replication at the tumor site and maximizing 5FC bioavailability, we optimized the treatment regimen and improved survival of animals bearing TSA mammary adenocarcinoma. Altogether, this study emphasizes the potency of the VSV-CD::UPRT and 5FC combination, and demonstrates the necessity of optimizing each step of a multicomponent therapy to design efficient treatment.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé

Samuel

et al. 2011

Cancer Gene Ther

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“…89 VSV oncoselectivity is based largely on defective or reduced type I IFN responses in tumor cells, 90 although abnormal translation machinery and other cellular proteins have also been shown to play a role. 91,92 All 3 strategies previously described (conditional replication, arming, and targeting) have been employed to increase efficacy of VSV. 88 Furthermore, combination therapy has been described with different other therapies.…”

Section: Family Herpesviridae: Herpes Simplex Virus 1 (Hsv)mentioning

confidence: 99%

Oncolytic viruses: From bench to bedside with a focus on safety

Buijs

Verhagen

Eijck

et al. 2015

Human Vaccines & Immunotherapeutics

114

105

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“…M51R) were shown to abolish the M protein-mediated host shut-off (Ahmed & Lyles, 1997; Desforges et al, 2001). Correspondingly, these mutants do not suppress IFN synthesis and have been proposed as oncolytic viruses for the therapy of tumours that show defects in the type I IFN system (Barber, 2004(Barber, , 2005Lichty et al, 2004; Stojdl et al, 2000;Wollmann et al, 2007). Although these VSV mutants expressed M proteins devoid of host shut-off activity, they still revealed cytotoxic features in BHK-21 and HeLa cells, suggesting that other factors also contribute to the induction of apoptosis (Kopecky et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Fusion-active glycoprotein G mediates the cytotoxicity of vesicular stomatitis virus M mutants lacking host shut-off activity

Hoffmann

Gerber

et al. 2010

Journal of General Virology

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The cytopathogenicity of vesicular stomatitis virus (VSV) has been attributed mainly to the host shut-off activity of the viral matrix (M) protein, which inhibits both nuclear transcription and nucleocytoplasmic RNA transport, thereby effectively suppressing the synthesis of type I interferon (IFN). The M protein from persistently VSV-infected cells was shown to harbour characteristic amino acid substitutions (M51R, V221F and S226R) implicated in IFN induction. This study demonstrates that infection of human fibroblasts with recombinant VSV containing the M51R substitution resulted in IFN induction, whereas neither the V221F nor the S226R substitution effected an IFN-inducing phenotype. Only when V221F was combined with S226R were the host shut-off activity of the M protein abolished and IFN induced, independently of M51R. The M33A substitution, previously implicated in VSV cytotoxicity, did not affect host shutoff activity. M-mutant VSV containing all four amino acid substitutions retained cytotoxic properties in both Vero cells and IFN-competent primary fibroblasts. Infected-cell death was associated with the formation of giant polynucleated cells, suggesting that the fusion activity of the VSV G protein was involved. Accordingly, M-mutant VSV expressing a fusion-defective G protein or with a deletion of the G gene showed significantly reduced cytotoxic properties and caused long-lasting infections in Vero cells and mouse hippocampal slice cultures. In contrast, a G-deleted VSV expressing wild-type M protein remained cytotoxic. These findings indicate that the host shut-off activity of the M protein dominates VSV cytotoxicty, whilst the fusion-active G protein is mainly responsible for the cytotoxicity remaining with M-mutant VSV. INTRODUCTIONVesicular stomatitis virus (VSV) is a prototype member of the family Rhabdoviridae. The virus genome is composed of a non-segmented, single-strand, negative-sense RNA encoding five genes, which are arranged in a module-like, non-overlapping manner. The RNA genome combines with the nucleoprotein N, the phosphoprotein P and the large protein L to form the helical ribonucleoprotein (RNP) complex. This complex is connected to the envelope via the matrix protein M, which binds to both the N protein and the inner leaflet of the lipid-bilayer membrane (Dancho et al., 2009). The M protein plays a key role in VSV morphogenesis and budding (Jayakar et al., 2004).The VSV envelope contains a single-type transmembrane glycoprotein (G), which has receptor-binding and fusion activities. Following uptake of the virion by receptormediated endocytosis and acidification of the endosome, the G protein can perform fusion between the membranes of the viral envelope and the endosome. This results in the release of the RNP complex into the cytosol, where transcription and replication take place. In addition to its role in virus entry, the G protein is important for efficient virus budding and release (Jeetendra et al., 2003).VSV shows a very broad cell tropism and replicates rapidly in various c...

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VSV-tumor selective replication and protein translation

Cited by 134 publications

References 91 publications

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Oncolytic viruses: From bench to bedside with a focus on safety

Fusion-active glycoprotein G mediates the cytotoxicity of vesicular stomatitis virus M mutants lacking host shut-off activity

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