Ability of the Matrix Protein of Vesicular Stomatitis Virus To Suppress Beta Interferon Gene Expression Is Genetically Correlated with the Inhibition of Host RNA and Protein Synthesis

Ahmed, Maryam; McKenzie, Margie O.; Puckett, Shelby; Hojnacki, Michael; Poliquin, Laurent; Lyles, Douglas S.

doi:10.1128/jvi.77.8.4646-4657.2003

Cited by 213 publications

(240 citation statements)

References 45 publications

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“…as low as 0.1 ( Figure 4B). These results indicated that mutant VSV T1026R1 was able to induce type I IFN production by neuronal cells and are consistent with wt VSV M protein blockade of cellular transcription and nuclear transport, as has been described for non-neuronal host cells (Ahmed et al, 2003;Ferran and Lucas-Lenard, 1997;Petersen et al, 2000;Stojdl et al, 2003).…”

Section: Mutant Vsv Replicates and Induces Ifn In Neuronal Cells In Vsupporting

confidence: 65%

“…Importantly, VSV infection of neuronal cells induced the nuclear translocation of IRF-3, indicating that these cells sensed VSV infection and activated IFN signaling pathways. The wt VSV M protein blocks nucleocytoplasmic transport, thereby inhibiting IFN production from infected cells (Ahmed et al, 2003;Stojdl et al, 2003). In contrast, neuronal cells were able to produce type I IFN in response to infection by NDV (Figure 1) and the M protein mutant VSV T1026R1 infection in vitro ( Figure 5B), indicating that neurons can respond to and produce type I IFN in response to viral infection, and when VSV M is inactivated, produce IFN in response to VSV infection.…”

Section: Discussionmentioning

confidence: 93%

“…The VSV M protein has been shown to play an important role in suppressing IFN induction by VSV infection of L929, HeLa, and Baby Hampster Kidney (BHK) cells in vitro (Ahmed et al, 2003;Stojdl et al, 2003). VSV T1026R1 has been reported as an IFN-inducing mutant of VSV due to a mutation in the M protein (methionine to arginine in amino acid 51; M51R) (Francoeur et al, 1980(Francoeur et al, , 1987.…”

Section: Introductionmentioning

confidence: 99%

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Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

2007

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Type I interferon (IFN) is critical for resistance of mice to infection with vesicular stomatitis virus (VSV). Wild type (wt) VSV infection did not induce type I IFN production in vitro or in the central nervous system (CNS) of mice; however IFN-β was detected in lungs, spleen, and serum within 24 h. The M protein mutant VSV, T1026R1 (also referred to as M51R), induced type I IFN production in vitro and in the CNS, with poor expression in spleens. In addition, VSV T1026R1 was not pathogenic to mice after intranasal infection, illustrating the importance of IFN in controlling VSV replication in the CNS. Experiments with chemical sympathectomy, sRAGE, and neutralizing antibody to VSV were performed to investigate the mechanism(s) utilized for induction of peripheral IFN; neither sRAGE infusion nor chemical sympathectomy had an effect on peripheral IFN production. In contrast, administration of neutralizing antibody (Ab) readily blocked the response. Infectious VSV was transiently present in lungs and spleens at 24 h post infection. The results are consistent with VSV traffic from the olfactory neuroepithelium to peripheral lymphoid organs hematogenously or via lymphatic circulation. These results suggest that VSV replicates to high titers in the brains of mice because of the lack of IFN production in the CNS after intranasal VSV infection. In contrast, replication of VSV in peripheral organs is controlled by the production of large amounts of IFN.Address correpondence to

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Section: Mutant Vsv Replicates and Induces Ifn In Neuronal Cells In Vsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

2007

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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%

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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“…14 The VSV matrix (M) protein is a virulence factor that is capable of inhibiting host gene expression at the level of transcription, 15,16 as well as nuclear-cytoplasmic transport of host RNAs and protein. 17,18 Earlier studies have demonstrated the feasibility of isolating VSV mutants with strong IFN-inducing phenotypes, 19 with many of these mutants containing point mutations in their M proteins, including the M51R mutation originally found in the ts082 and T1026R1 mutant viruses.…”

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confidence: 99%

Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice

et al. 2004

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In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Oncolytic vesicular stomatitis virus (VSV) is a promising novel therapeutic agent for the treatment of cancer. The aim of this study was to evaluate the potential of recombinant VSV containing the M51R mutation in the matrix (M) protein gene administered intravenously as an effective and safe therapeutic agent for treating mice with experimental breast cancer metastases. Recombinant VSV(M51R)-LacZ was generated and characterized in vitro on human and murine breast cancer cells. Breast cancer metastases were established in immune-competent Balb/c mice by intravenous injection of syngeneic 4T1 cells. The vector was infused into the tumor-bearing animals via the tail vein, and productive infection of pulmonary breast cancer lesions was assessed by X-gal stainings of frozen lung sections. To evaluate potential systemic toxicity, histology of major organs and serum chemistries were analyzed. To assess effectiveness, buffer-or vector-treated tumor-bearing mice were followed for survival and the results were analyzed by the Kaplan-Meier method and the log-rank test. We found that VSV(M51R)-LacZ efficiently replicated and lysed human breast cancer cells but was partially attenuated in 4T1 cells in vitro. We also demonstrated that its maximum tolerated dose after intravenous infusion in normal Balb/c mice was elevated by at least 100-fold over that of the parental VSV vector containing the wild-type M gene. When VSV(M51R)-LacZ was repeatedly injected intravenously into mice bearing syngeneic 4T1 tumors, the virus was able to infect multiple breast cancer lesions in the lungs without apparent toxicities, which led to significant prolongation of animal survival (P ¼ .003). In conclusion, systemic administration of M mutant VSV is both effective and safe in the treatment of experimental breast cancer metastases in immune-competent mice, suggesting that further development of this approach may have potential for clinical application in patients.

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Ability of the Matrix Protein of Vesicular Stomatitis Virus To Suppress Beta Interferon Gene Expression Is Genetically Correlated with the Inhibition of Host RNA and Protein Synthesis

Cited by 213 publications

References 45 publications

Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

Peripheral, but not central nervous system, type I interferon expression in mice in response to intranasal vesicular stomatitis virus infection

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

Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice

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