The isolation of interferon-inducing mutants of vesicular stomatitis virus with altered viral P function for the inhibition of total protein synthesis

Francoeur, A M; Poliquin, Laurent; Stanners, Clifford P.

doi:10.1016/0042-6822(87)90065-1

Cited by 38 publications

(43 citation statements)

References 25 publications

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“…There are abundant pDCs in the spleen and lymph nodes, which are absent in the resting CNS, and pDCs monitor for pathogen exposure and produce IFN. It is clear that wt VSV blocks IFN synthesis in infected cells via the biological effects of M protein (Ahmed et al, 2003;Ferran and Lucas-Lenard, 1997;Francoeur et al, 1980Francoeur et al, , 1987Petersen et al, 2000;Stojdl et al, 2003). Any VSV-infected neuronal or extraneuronal cell may have IFN gene expression limited by the activity of VSV M protein.…”

Section: Discussionmentioning

confidence: 99%

“…VSV T1026R1 has been reported as an IFN-inducing mutant of VSV due to the M51R mutation in the M protein (Francoeur et al, 1980(Francoeur et al, , 1987. To test the ability of this virus to replicate in neuronal cells, NB41A3 cells were infected with wt VSV or VSV T1026R1 at m.o.i.…”

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

confidence: 99%

“…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. Subsequent studies using the cloned M gene from wild-type (wt) and T1026R1 virus have shown that wt M inhibits transcription of cellular genes including IFN-β, whereas M from T1026R1 does not (Ferran and Lucas-Lenard, 1997).…”

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: Discussionmentioning

confidence: 99%

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

confidence: 99%

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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“…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. 20 Recently, Stojdl et al 21 demonstrated that VSV M mutants with a single amino-acid (M51R) or two amino-acid (V221F and S226R) substitutions are attenuated in mice because of their potent induction of IFN but retain antitumor activity in vitro and in several animal tumor models, even when applied systemically.…”

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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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“…Indeed, revertants may contain mutations that enhance IFN-inducing capacity (Table 4). These IFN-inducing, temperature-stable revertants are similar to T1026R1 (also derived from an IFN-inducing, ts parent, tsT1026) (Stanners et al, 1977), and possibly like more recent isolates (Francoeur et al, 1987). However, the IFN-inducing capacity of these recently isolated revertants was not measured directly; it was inferred from their mode of isolation.…”

Section: Discussionmentioning

confidence: 99%

Interferon Induction by Viruses. XVII. Non-temperature-sensitive Mutations Regulate Interferon Induction by Vesicular Stomatitis Virus

Sekellick

Marcus²

1989

Journal of General Virology

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SUMMARYWild-type (wt) strains of vesicular stomatitis virus (VSV) strain Indiana are poor to non-inducers of interferon (IFN) which express IFN induction-suppressing activity. At non-permissive temperatures, temperature-sensitive (ts) mutants of this virus are either like their wt parents, or they are good to excellent inducers of IFN. IFN inducibility and IFN induction-suppressing activity are mutually exclusive phenotypes in VSV-Indiana. With one exception, all Orsay ts mutants derived by A. Flamand (CNRS, Gif-sur-Yvette, France), representing the five complementation groups, were poor to non-inducers of IFN and were also capable of suppressing IFN induction by other viruses. In contrast, all Glasgow ts mutants derived by C. R. Pringle (University of Warwick, Coventry, U.K.) were excellent inducers of IFN. We demonstrate that this difference in acquisition of IFN inducibility relates primarily to the origin of the mutations; spontaneous for Orsay, and mutagen-derived for Glasgow. Tests with newly generated spontaneous and mutagen-derived mutants, and temperature-stable revertants of IFN-inducing ts mutants indicate that IFN inducibility results from non-ts, multiple mutations rarely acquired spontaneously, but generated frequently upon mutagenesis with 5-fluorouracil. The capacity of VSV-Indiana to induce IFN is considered intrinsic to the virus, but is only manifested when the dominant IFN induction-suppressing phenotype is lost through mutagenesis. Thus, non-ts mutations appear to regulate the expression of the IFN induction-suppressing phenotype, and hence the IFN inducibility of VSV-Indiana.

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The isolation of interferon-inducing mutants of vesicular stomatitis virus with altered viral P function for the inhibition of total protein synthesis

Cited by 38 publications

References 25 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

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

Interferon Induction by Viruses. XVII. Non-temperature-sensitive Mutations Regulate Interferon Induction by Vesicular Stomatitis Virus

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