Involvement of cardiovirus leader in hostcell-restricted virus expression.

Kong, Wing-Pui; Ghadge, Ghanashyam D.

doi:10.1073/pnas.91.5.1796

Cited by 62 publications

(65 citation statements)

References 12 publications

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“…The KJ6 derivative with the L cys mutation was called TM659 (Table 1). In agreement with previous data (14), both the L cys and L ⌬7-67 mutant viruses formed plaques on BHK-21 cells comparable in size to plaques formed by the parental viruses. On L929 cells, however, the mutants formed only minute to undetectable plaques while parental viruses formed mediumsized plaques.…”

Section: Construction Of L Mutant Virusessupporting

confidence: 92%

“…The leader (L) protein of TMEV is a 76-amino-acid-long acidic protein corresponding to the N terminus of the viral polyprotein. L contains a zincbinding C-H-C-C motif critical for its function in vitro (3,14). In vivo, the L protein was demonstrated to be essential for neurovirulence of the GDVII strain (1).…”

mentioning

confidence: 99%

“…In vitro, L is required for viral propagation in L929 cells but not in BHK-21 cells. Since the latter cells are reportedly non-IFN responsive, Kong et al (14) postulated that the L protein could antagonize the cell interferon response.…”

mentioning

confidence: 99%

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The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

Pesch

Eyll

Michiels

2001

J Virol

115

145

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Theiler's virus is a picornavirus responsible for a persistent infection of the central nervous system of the mouse, leading to a chronic demyelinating disease considered to be a model for multiple sclerosis. The leader (L) protein encoded by Theiler's virus is a 76-amino-acid-long peptide containing a zinc-binding motif. This motif is conserved in the L proteins of all cardioviruses, including encephalomyocarditis virus. The L protein of Theiler's virus was suggested to interfere with the alpha/beta interferon (IFN-␣/␤) response (W.-P. Kong, G. D. Ghadge, and R. P. Roos, Proc. Natl. Acad. Sci. USA 91:1796-1800, 1994). We show that expression of the L protein indeed inhibits the production of alpha/beta interferon by infected L929 cells. The L protein specifically inhibits the transcription of the IFN-␣4 and IFN-␤ genes, which are known to be activated early in response to viral infection. Mutation of the zinc finger was sufficient to block the anti-interferon activity, outlining the importance of this motif in the L protein function. In agreement with the anti-interferon role of the L protein, a virus bearing a mutation in the zinc-binding motif was dramatically impaired in its ability to persist in the central nervous system of SJL/J mice.Theiler's murine encephalomyelitis virus (TMEV) (or Theiler's virus), a member of the Picornavirus family, is a naturally occurring enteric pathogen of the mouse, responsible for central nervous system (CNS) infections (32). The neurovirulent strains (GD7 and FA) cause an acute lethal encephalomyelitis. The persistent strains (DA and BeAn) induce a biphasic disease after intracerebral inoculation of susceptible mice (18). After a mild encephalomyelitis lasting about 2 weeks, mice develop a chronic demyelinating disease, which serves as an experimental model of multiple sclerosis (for review, see references 8 and 25).TMEV can be recovered from the spinal cord white matter virtually lifelong, indicating that active viral replication occurs during persistence despite the host immune response. Viral persistence appears to be required to induce the chronic demyelinating disease, but the exact mechanisms involved in persistence are still poorly understood. Among the viral determinants of persistence identified, the capsid plays a crucial role, probably affecting the tropism of the virus in the CNS (2, 11, 22). However, viral factors allowing the virus to escape the host immune response could also play a pivotal role in establishing persistence.Antagonism of the innate immune response mediated by alpha/beta interferons (IFNs-␣/␤) is a common determinant of virulence (33). Indeed, IFNs-␣/␤ are cytokines produced by most cell types in response to viral infection. The antiviral action of IFNs is mediated by the activation of proteins, such as protein kinase R (PKR), the 2Ј-5Ј-oligodenylate synthetase, or the Mx proteins, known to interfere with the viral cycle (29).The genome of picornaviruses is translated as a long precursor polyprotein that undergoes autoproteolytic cleavage to yiel...

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Section: Construction Of L Mutant Virusessupporting

confidence: 92%

mentioning

confidence: 99%

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The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

Pesch

Eyll

Michiels

2001

J Virol

115

145

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“…In addition, lack of p220 inactivation by HAV and thus failure of host cell shut-off (De Chastonay & Siegl, 1987) suggest that 2A of HAV has features distinct from that of poliovirus 2A Macadam et al, 1994). This is consistent with the idea that the diverse functions of a related gene product encoded by different picornaviruses may result from the varied requirements of the virus for growth in different host cells (Kong et al, 1994). Hence, it is unlikely that 2A of HAV functions in the same manner as the 2A proteins of other picornaviruses, and its function remains unknown.…”

Section: Discussionsupporting

confidence: 73%

Identification of hepatitis A virus non-structural protein 2B and its release by the major virus protease 3C

Gosert

Cassinotti

Siegl

et al. 1996

Journal of General Virology

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The RNA genome of hepatitis A virus (HAV) encodes a giant polyprotein that is putatively cleaved proteolytically into four structural and seven non-structural proteins. So far, most of the proposed non-structural proteins and their respective cleavage sites have not been identified. A vaccinia virus recombinant (vRGORF) containing the complete HAV ORF under the control of the bacteriophage T7 promoter was used to express HAY in recombinant animal cells (BT7-H) that constitutively expressed T7 DNA-dependent RNA polymerase. A HAV-specific 27.5 kDa expression product was identified as peptide 2B. The 27.5 kDa 2B antigen was also found in HAV-infected MRC-5 cells. The N-terminal amino acid residues of the new peptide 2B are Ala-Lys-Ile-Ser-Leu-Phe and polyprotein cleavage between 2A and 2B occurred at amino acids 836-837 (Gln-Ala). Furthermore, heterologous expression in the same system of regions P1-P2 and of the protease 3C (3C pr°) gene, showed that P1-P2 polyprotein is not cleaved autocatalytically but by 3C p'°. Hence, 3C vr° is effective in cleaving the polyprotein 2A-2B junction.

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“…The L protein of these viruses does not have any known proteinase activity, but this protein has been reported to be an essential factor in virus replication in IFN-␣/␤-competent cells (25,55) and is required for neurovirulence of the GDVII strain of Theiler's virus (5). More recently, cardiovirus L protein has been associated with the inhibition of IFN-␣/␤ production (11,50,55,56).…”

mentioning

confidence: 99%

The Leader Proteinase of Foot-and-Mouth Disease Virus Inhibits the Induction of Beta Interferon mRNA and Blocks the Host Innate Immune Response

Santos

Botton

Weiblen

et al. 2006

J Virol

172

146

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Involvement of cardiovirus leader in hostcell-restricted virus expression.

Cited by 62 publications

References 12 publications

The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

Identification of hepatitis A virus non-structural protein 2B and its release by the major virus protease 3C

The Leader Proteinase of Foot-and-Mouth Disease Virus Inhibits the Induction of Beta Interferon mRNA and Blocks the Host Innate Immune Response

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