The molecular pathogenesis of Semliki Forest virus: a model virus made useful?

Atkins, Gregory J.; Sheahan, B. J.; Liljeström, Peter

doi:10.1099/0022-1317-80-9-2287

Cited by 80 publications

(87 citation statements)

References 92 publications

(133 reference statements)

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“…In SFVinfected cells, the replicase produces double-stranded (ds) RNA when synthesizing the viral mRNA. 39 Also, the SFV replication causes the infected cell to undergo apoptosis. 39 Most likely due to the cellular recognition of dsRNA as a pathogen-associated molecular pattern (PAMP), 40 a potent interferon (IFN) response is activated in SFV-infected cells.…”

Section: Codon Optimization and Rna Amplification For Hcv Ns3/4amentioning

confidence: 99%

“…39 Also, the SFV replication causes the infected cell to undergo apoptosis. 39 Most likely due to the cellular recognition of dsRNA as a pathogen-associated molecular pattern (PAMP), 40 a potent interferon (IFN) response is activated in SFV-infected cells. 41 The activation of the cellular IFN system is intended to inhibit the SFV-mediated protein expression.…”

Section: Codon Optimization and Rna Amplification For Hcv Ns3/4amentioning

confidence: 99%

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Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

et al. 2004

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We have recently shown that the NS3-based genetic immunogens should contain also hepatitis C virus (HCV) nonstructural (NS) 4A to utilize fully the immunogenicity of NS3. The next step was to try to enhance immunogenicity by modifying translation or mRNA synthesis. To enhance translation efficiency, a synthetic NS3/4A-based DNA (coNS3/4A-DNA) vaccine was generated in which the codon usage was optimized (co) for human cells. In a second approach, expression of the wild-type (wt) NS3/4A gene was enhanced by mRNA amplification using the Semliki forest virus (SFV) replicon (wtNS3/4A-SFV). Transient tranfections of human HepG2 cells showed that the coNS3/4A gene gave 11-fold higher levels of NS3 as compared to the wtNS3/4A gene when using the CMV promoter. We have previously shown that the presence of NS4A enhances the expression by SFV. Both codon optimization and mRNA amplification resulted in an improved immunogenicity as evidenced by higher levels of NS3-specific antibodies. This improved immunogenicity also resulted in a more rapid priming of cytotoxic T lymphocytes (CTLs). Since HCV is a noncytolytic virus, the functionality of the primed CTL responses was evaluated by an in vivo challenge with NS3/4A-expressing syngeneic tumor cells. The priming of a tumor protective immunity required an endogenous production of the immunogen and CD8 þ CTLs, but was independent of B and CD4 þ T cells. This model confirmed the more rapid in vivo activation of an NS3/4A-specific tumor-inhibiting immunity by codon optimization and mRNA amplification. Finally, therapeutic vaccination with the coNS3/4A gene using gene gun 6-12 days after injection of tumors significantly reduced the tumor growth in vivo. Codon optimization and mRNA amplification effectively enhances the overall immunogenicity of NS3/4A. Thus, either, or both, of these approaches should be utilized in an NS3/4A-based HCV genetic vaccine.

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Section: Codon Optimization and Rna Amplification For Hcv Ns3/4amentioning

confidence: 99%

Section: Codon Optimization and Rna Amplification For Hcv Ns3/4amentioning

confidence: 99%

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

et al. 2004

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“…Although some members of the alphavirus genus are known to cause human disease, laboratory strains of SFV are considered to be nonpathogenic to humans. 21 Moreover, the recombinant SFV system was derived from an attenuated strain. 21 Alphaviruses are genetically relatively simple with a genome of approximately 10 kb.…”

Section: Discussionmentioning

confidence: 99%

“…21 Moreover, the recombinant SFV system was derived from an attenuated strain. 21 Alphaviruses are genetically relatively simple with a genome of approximately 10 kb. Recombinant RNA consists of four genes together encoding the viral replicase and the transgene.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, alphaviruses, including SFV, have a very broad host cell specificity. 19 Cells infected with either native or replication-defective recombinant alphaviruses die by apoptosis 20,21 ensuring that the foreign genetic material does not persist within the organism. These characteristics make alphavirus-based vectors very promising systems for use in gene therapy approaches where transient gene expression is desirable.…”

Section: Gene Therapymentioning

confidence: 99%

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