Attenuation of classical swine fever virus by deletion of the viral Npro gene

Mayer, Daniel; Hofmann, Martin; Tratschin, Jon Duri

doi:10.1016/j.vaccine.2003.08.006

Cited by 65 publications

(57 citation statements)

References 48 publications

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“…N pro is a cysteine autoprotease that cleaves itself from the core protein (53). It has been shown to be important in virulence and in the inhibition of interferon production (52,107,108). The L protein of FMDV is a cysteine protease responsible for early cleavage of the translation initiation factor eIF4G during FMDV infection, resulting in the rapid inhibition of host cell protein synthesis (109,110).…”

Section: Possible Functional Relationships With Other Viral Proteinsmentioning

confidence: 99%

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

Vassilaki

Mavromara

2009

IUBMB Life

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Hepatitis C virus (HCV) is an enveloped positive‐strand RNA virus of the Flaviviridae family. It has a genome of about 9,600 nucleotides encoding a large polyprotein (about 3,000 amino acids) that is processed by cellular and viral proteases into at least 10 structural and nonstructural viral proteins. A novel HCV protein has also been identified by our laboratory and others. This protein—known as ARFP (alternative reading frame protein), F (for frameshift) or core+1 (to indicate the position) protein ‐ is synthesized by an open reading frame overlapping the core gene at nucleotide +1 (core+1 ORF). However, almost 10 years after its discovery, we still know little of the biological role of the ARFP/F/core+1 protein. Abolishing core+1 protein production has no affect on HCV replication in cell culture or uPA‐SCID mice, suggesting that core+1 protein is probably not important for the HCV reproductive cycle. However, the detection of specific anti‐core+1 antibodies and T‐cell responses in HCV‐infected patients, as reported by many independent laboratories, provides strong evidence that this protein is produced in vivo. Furthermore, analyses of the HCV sequences isolated from patients with hepatocellular carcinoma and in vitro studies have provided strong preliminary evidence to suggest that core+1 protein plays a role in advanced liver disease and liver cancer. The available in vitro data also suggest that certain core function proteins may depend on production of the core+1 protein. We describe here the discovery of the various forms of the core+1 protein and what is currently known about the mechanisms of their production and their biochemical and functional properties. We also provide a detailed summary of the results of patient‐based research. © 2009 IUBMB IUBMB Life, 61(7): 739–752, 2009

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Section: Possible Functional Relationships With Other Viral Proteinsmentioning

confidence: 99%

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

Vassilaki

Mavromara

2009

IUBMB Life

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“…N pro is a cysteine-like autoprotease unique to pestiviruses that is self-cleaved from the polyprotein (4,5). N pro was shown to interfere with poly(I·C)-induced type I interferon (IFN) production (5) and to influence the virulence of CSFV (6). In addition, CSFV N pro is involved in inhibition of type I IFN signaling and has been reported to interact with IFN regulatory factor 3 (IRF3), which induces its proteasomal degradation and results in the loss of IRF3 (7,8).…”

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confidence: 99%

Poly(C)-Binding Protein 1, a Novel N ^pro -Interacting Protein Involved in Classical Swine Fever Virus Growth

Sun

et al. 2013

J Virol

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Npro is a multifunctional autoprotease unique to pestiviruses. The interacting partners of the N pro protein of classical swine fever virus (CSFV), a swine pestivirus, have been insufficiently defined. Using a yeast two-hybrid screen, we identified poly(C)-binding protein 1 (PCBP1) as a novel interacting partner of the CSFV N pro protein and confirmed this by coimmunoprecipitation, glutathione S-transferase (GST) pulldown, and confocal assays. Knockdown of PCBP1 by small interfering RNA suppressed CSFV growth, while overexpression of PCBP1 promoted CSFV growth. Furthermore, we showed that type I interferon was downregulated by PCBP1, as well as N pro . Our results suggest that cellular PCBP1 positively modulates CSFV growth.

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“…Additionally, attempts to mutate and inactivate E rns in the attenuated C-strain resulted in a virus atypically cytopathic for cell cultures (10, 39). Thus, CSFV IC hold great promise for identifying viral proteins or protein domains functioning in viral virulence and host range and for rationally engineering marker live attenuated CSF vaccines (17,19,21,30,31).Here we have used chimeras of the highly pathogenic Brescia strain and the attenuated vaccine strain CS to identify genetic determinants of CSFV virulence and host range. Results demonstrate that the CSFV E2 glycoprotein is a major determinant of virulence in swine.…”

mentioning

confidence: 99%

The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine

Risatti

Borca

Kutish

et al. 2005

J Virol

133

108

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To identify genetic determinants of classical swine fever virus (CSFV) virulence and host range, chimeras of the highly pathogenic Brescia strain and the attenuated vaccine strain CS were constructed and evaluated for viral virulence in swine. Upon initial screening, only chimeras 138.8v and 337.14v, the only chimeras containing the E2 glycoprotein of CS, were attenuated in swine despite exhibiting unaltered growth characteristics in primary porcine macrophage cell cultures. Additional viral chimeras were constructed to confirm the role of E2 in virulence. Chimeric virus 319.1v, which contained only the CS E2 glycoprotein in the Brescia background, was markedly attenuated in pigs, exhibiting significantly decreased virus replication in tonsils, a transient viremia, limited generalization of infection, and decreased virus shedding. Chimeras encoding all Brescia structural proteins in a CS genetic background remained attenuated, indicating that additional mutations outside the structural region are important for CS vaccine virus attenuation. These results demonstrate that CS E2 alone is sufficient for attenuating Brescia, indicating a significant role for the CSFV E2 glycoprotein in swine virulence.Classical swine fever (CSF) is a highly contagious and often fatal hemorrhagic disease of swine and is caused by Classical swine fever virus (CSFV), a member of the genus Pestivirus of the family Flaviviridae (5). Intermittent CSF outbreaks in Europe and other parts of the world result in significant economic losses. While infection with highly virulent CSFV strains can cause acute CSF characterized by high morbidity and mortality, isolates of moderate to low virulence induce a prolonged, chronic disease (35).CSFV is a small enveloped virus with a single-stranded, 12.5-kb RNA genome of positive polarity. The CSFV genome contains a single open reading frame encoding an approximately 4,000-amino-acid polyprotein which through cellular and viral protease-mediated co-and posttranslational processing gives rise to the following 11 to 12 final cleavage products: NH 2 -Npro-C-E rns -E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH (23). Protein C and the glycoproteins E rns , E1, and E2 represent structural components of the virion (28). E1 and E2 are anchored to the envelope by their carboxy termini, with E rns loosely associated with the envelope. E rns and E2 are present as homodimers linked by disulfide bridges on the surfaces of CSFV virions, whereas E2 is also found dimerized with E1 (28, 37, 38). The genetic basis of CSFV virulence and host range remains poorly understood (35).Development of infectious CSFV cDNA clones has enabled genetic approaches for defining mechanisms of viral replication and pathogenesis. Infectious clones (IC) of the attenuated CSFV C-strain and the pathogenic Alfort/Tübingen and Eystrup strains have been constructed, enabling identification of E rns and N pro as virulence factors in swine and of the role of different E rns mutations in virus attenuation (17, 19). Additionally, attempts to mutate and in...

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Attenuation of classical swine fever virus by deletion of the viral Npro gene

Cited by 65 publications

References 48 publications

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

Poly(C)-Binding Protein 1, a Novel N ^pro -Interacting Protein Involved in Classical Swine Fever Virus Growth

The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine

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Attenuation of classical swine fever virus by deletion of the viral Npro gene

Cited by 65 publications

References 48 publications

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

The HCV ARFP/F/core+1 protein: Production and functional analysis of an unconventional viral product

Poly(C)-Binding Protein 1, a Novel N pro -Interacting Protein Involved in Classical Swine Fever Virus Growth

The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine

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Poly(C)-Binding Protein 1, a Novel N ^pro -Interacting Protein Involved in Classical Swine Fever Virus Growth