Inhibition of Beta Interferon Transcription by Noncytopathogenic Bovine Viral Diarrhea Virus Is through an Interferon Regulatory Factor 3-Dependent Mechanism

Baigent, Susan J.; Zhang, Gang; Fray, Martin; Flick-Smith, Helen C.; Goodbourn, Stephen; McCauley, John W.

doi:10.1128/jvi.76.18.8979-8988.2002

Cited by 128 publications

(105 citation statements)

References 49 publications

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“…Therefore, many, if not most, of the viruses have developed a wide variety of mechanisms aimed at downregulating different components of the cell reaction, first of all the IFN-␣/␤ response, and at increasing viremia to a level sufficient for virus transmission to susceptible organisms or arthropod vectors (2,4,21,28,32,37,43,52). Alternatively, interference with cell reactions opens an opportunity for persistent infection (1,20,33). Intimate interactions between replicating viruses and a developing antiviral response represent a critical factor in viral pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Transcription and Translation in Sindbis Virus-Infected Cells

Gorchakov

Frolova

Frolov

2005

J Virol

127

211

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Section: Discussionmentioning

confidence: 99%

Inhibition of Transcription and Translation in Sindbis Virus-Infected Cells

Gorchakov

Frolova

Frolov

2005

J Virol

127

211

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“…Transcription factors involved in activation of IFN-␤ gene transcription may be induced by viruses through a number of different pathways, with the interferon regulatory factor 3 (IRF-3) pathway being the most prominent (11,15,22,43). Members of the family Flaviviridae, HCV and bovine viral diarrhea virus, have been shown to block the IRF-3 pathway by either preventing IRF-3 phosphorylation (HCV) (11) or directly preventing transcriptional activity of phosphorylated IRF-3 (bovine viral diarrhea virus) (3). Most recent studies with the more closely related flavivirus WNV (New York 2000 strain) showed direct involvement of the IRF-3 pathway in controlling cell-to-cell spread of the virus (12).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Adaptive Mutations in Kunjin Virus Replicon RNA Reveals a Novel Role for the Flavivirus Nonstructural Protein NS2A in Inhibition of Beta Interferon Promoter-Driven Transcription

Liu

Chen

Wang

et al. 2004

J Virol

148

126

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The establishment of persistent noncytopathic replication by replicon RNAs of a number of positive-strand RNA viruses usually leads to generation of adaptive mutations in nonstructural genes. Some of these adaptive mutations (e.g., in hepatitis C virus) increase the ability of RNA replication to resist the antiviral action of alpha/beta interferon (IFN-␣/␤); others (e.g., in Sindbis virus) may also lead to more efficient IFN production. Using puromycin-selectable Kunjin virus (KUN) replicon RNA, we identified two adaptive mutations in the NS2A gene (producing Ala30-to-Pro and Asn101-to-Asp mutations in the gene product; for simplicity, these will be referred to hereafter as Ala30-to-Pro and Asn101-to-Asp mutations) that, when introduced individually or together into the original wild-type (wt) replicon RNA, resulted in ϳ15-to 50-fold more efficient establishment of persistent replication in hamster ( (29), with one long open reading frame coding for 3,433 amino acids in three structural proteins (C, prM, and E) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (7). The gene order of KUN genome RNA is 5Ј-C-(pr)M-E-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-3Ј. We previously constructed the first flavivirus replicons based on KUN cDNA by deleting the majority of the genomic region including structural genes (30) and used them extensively for the development of a gene expression system (2,19,28,30,44,45). KUN replicons were also used extensively in RNA replication and complementation studies (23)(24)(25)(26)(27)32) that contributed substantially to generating a comprehensive model for the formation and operation of the flavivirus RNA replication complex (47,48).The establishment of persistent noncytopathic replication by replicon RNAs of a number of positive-strand RNA viruses was shown to lead to the generation of adaptive mutations in nonstructural genes that either decreased (alphavirus replicons) or enhanced (hepatitis C replicons) RNA replication efficiency (1,4,13,14,34,39,41,50). Some of these adaptive mutations (e.g., in the NS5A protein of the hepatitis C replicon) were shown to increase the ability of RNA replication to resist the antiviral action of alpha/beta interferon (IFN-␣/␤) (41), while others (e.g., in the nsP2 protein of Sindbis virus) were shown to lead to more efficient IFN production (14). IFN response is the first line of cell defense against viral infections, and a majority of viruses have developed various strategies to overcome it, by either inhibiting IFN production or blocking IFN signaling (15,22,35,43). Recent studies of dengue virus have indicated that flaviviruses may interfere with early steps of IFN signaling and have implied roles for the small nonstructural proteins NS2A, NS4A, and NS4B in this process (37).In this study, we describe the identification of adaptive mutations in KUN replicon RNA that confirm an advantage in establishing persistent replication in a number of different cell lines. We also demonstrate that induction of IFN-␤ promoter-* Correspondi...

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“…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. However, if the NS3/4A complex is present, it is possible that the interferon signaling pathways activated by the presence of dsRNA are inhibited.…”

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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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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Inhibition of Beta Interferon Transcription by Noncytopathogenic Bovine Viral Diarrhea Virus Is through an Interferon Regulatory Factor 3-Dependent Mechanism

Cited by 128 publications

References 49 publications

Inhibition of Transcription and Translation in Sindbis Virus-Infected Cells

Inhibition of Transcription and Translation in Sindbis Virus-Infected Cells

Analysis of Adaptive Mutations in Kunjin Virus Replicon RNA Reveals a Novel Role for the Flavivirus Nonstructural Protein NS2A in Inhibition of Beta Interferon Promoter-Driven Transcription

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

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