Basic Science Paves the Way to Novel Safe and Effective Pestivirus Vaccines

Pestiviruses are among the economically most important pathogens of livestock. Except for culling, vaccination represents the only feasible way to control pestiviruses. Therefore, a considerable number of pestivirus vaccines have been developed and put on the market. However, these vaccines still have disadvantages that should be eliminated in future approaches, some of which are based on recent findings and will be outlined in this chapter. One of the most important features of ruminant pestiviruses is their extraordinary tendency to establish lifelong persistence as the outcome of intrauterine infection. As a result, 1–2% of cattle worldwide are persistently infected with bovine viral diarrhea virus. The constant dissemination of the virus by these animals is central for maintenance of this pathogen in its host population; therefore, future vaccines must address this highly relevant problem. Elucidation of the molecular features of pestiviruses that are required for the establishment and maintenance of persistent infection has made significant progress, and the present knowledge on this topic is summarized in this chapter. These features include a unique strategy to restrict virus genome replication by a limiting host factor and viral virulence factors Npro and Erns interfering with the innate immune response of the host. Accordingly, a framework of viral functions is involved in the establishment and maintenance of persistence. On the basis of this knowledge, specific mutations in the recently identified virulence factors have resulted in the generation of attenuated viruses, building a perfect basis for future vaccine design.

[1]  M. Hulst,et al.  Dimerisation of glycoprotein Erns of classical swine fever virus is not essential for viral replication and infection , 2005, Archives of Virology.

[2]  G. Kochs,et al.  The interferon response circuit: Induction and suppression by pathogenic viruses , 2005, Virology.

[3]  C. Rice,et al.  Efficient Translation Initiation Is Required for Replication of Bovine Viral Diarrhea Virus Subgenomic Replicons , 2001, Journal of Virology.

[4]  J. Tratschin,et al.  Attenuation of classical swine fever virus by deletion of the viral N(pro) gene. , 2004, Vaccine.

[5]  J. Tratschin,et al.  Classical swine fever virus replicon particles lacking the Erns gene: a potential marker vaccine for intradermal application. , 2006, Veterinary research.

[6]  P. Powell,et al.  Loss of Interferon Regulatory Factor 3 in Cells Infected with Classical Swine Fever Virus Involves the N-Terminal Protease, Npro , 2005, Journal of Virology.

[7]  A. Saalmüller,et al.  Comparison of the effects of RNase-negative and wild-type classical swine fever virus on peripheral blood cells of infected pigs. , 2004, The Journal of general virology.

[8]  B. Charleston,et al.  Establishment of persistent infection with non-cytopathic bovine viral diarrhoea virus in cattle is associated with a failure to induce type I interferon. , 2001, The Journal of general virology.

[9]  M. Orlich,et al.  RNA Recombination between Persisting Pestivirus and a Vaccine Strain: Generation of Cytopathogenic Virus and Induction of Lethal Disease , 2001, Journal of Virology.

[10]  C. Rice,et al.  Noncytopathic Sindbis virus RNA vectors for heterologous gene expression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  E. Dubovi,et al.  Rearrangement of viral sequences in cytopathogenic pestiviruses , 1992, Virology.

[12]  E. Peterhans,et al.  The viral RNase E(rns) prevents IFN type-I triggering by pestiviral single- and double-stranded RNAs. , 2009, Virus research.

[13]  P. V. van Rijn,et al.  Infectious RNA transcribed from an engineered full-length cDNA template of the genome of a pestivirus , 1996, Journal of virology.

[14]  V. Moennig,et al.  Reproduction of mucosal disease with cytopathogenic bovine viral diarrhoea virus selected in vitro , 1990, Veterinary Record.

[15]  D. Rock,et al.  The E2 Glycoprotein of Classical Swine Fever Virus Is a Virulence Determinant in Swine , 2005, Journal of Virology.

[16]  B. Kümmerer,et al.  Recovery of cytopathogenic and noncytopathogenic bovine viral diarrhea viruses from cDNA constructs , 1996, Journal of virology.

[17]  G. Meyers,et al.  Mutation of Cysteine 171 of Pestivirus Erns RNase Prevents Homodimer Formation and Leads to Attenuation of Classical Swine Fever Virus , 2009, Journal of Virology.

[18]  S. Blome,et al.  Cytopathogenicity of Classical Swine Fever Virus Correlates with Attenuation in the Natural Host , 2008, Journal of Virology.

[19]  Ying-hua Chen,et al.  Marker vaccine strategies and candidate CSFV marker vaccines. , 2007, Vaccine.

[20]  M. Hulst,et al.  Passage of Classical Swine Fever Virus in Cultured Swine Kidney Cells Selects Virus Variants That Bind to Heparan Sulfate due to a Single Amino Acid Change in Envelope Protein Erns , 2000, Journal of Virology.

[21]  M. Beer,et al.  Packaged replicons of bovine viral diarrhea virus are capable of inducing a protective immune response. , 2007, Virology.

[22]  G. Meyers,et al.  The Pestivirus Glycoprotein Erns Is Anchored in Plane in the Membrane via an Amphipathic Helix* , 2007, Journal of Biological Chemistry.

[23]  T. Harada,et al.  Establishment and Characterization of Cytopathogenic and Noncytopathogenic Pestivirus Replicons , 1999, Journal of Virology.

[24]  T. Harada,et al.  E2-p7 Region of the Bovine Viral Diarrhea Virus Polyprotein: Processing and Functional Studies , 2000, Journal of Virology.

[25]  Z. Lu,et al.  Removal of a N-linked glycosylation site of classical swine fever virus strain Brescia Erns glycoprotein affects virulence in swine. , 2008, Virology.

[26]  M. Orlich,et al.  Mutations in the 5′ Nontranslated Region of Bovine Viral Diarrhea Virus Result in Altered Growth Characteristics , 2000, Journal of Virology.

[27]  E. Peterhans,et al.  RNase-dependent inhibition of extracellular, but not intracellular, dsRNA-induced interferon synthesis by Erns of pestiviruses. , 2008, The Journal of general virology.

[28]  D. Rock,et al.  Mutations in the carboxyl terminal region of E2 glycoprotein of classical swine fever virus are responsible for viral attenuation in swine. , 2007, Virology.

[29]  C. Rice,et al.  Infectious Bovine Viral Diarrhea Virus (Strain NADL) RNA from Stable cDNA Clones: a Cellular Insert Determines NS3 Production and Viral Cytopathogenicity , 1998, Journal of Virology.

[30]  E. Peterhans,et al.  Bovine viral diarrhoea virus and bovine herpesvirus-1 prime uninfected macrophages for lipopolysaccharide-triggered apoptosis by interferon-dependent and -independent pathways. , 2000, The Journal of general virology.

[31]  A. C. Vlot,et al.  Determinants of Virulence of Classical Swine Fever Virus Strain Brescia , 2004, Journal of Virology.

[32]  D. Anderson,et al.  Molecular cloning and nucleotide sequence of the pestivirus bovine viral diarrhea virus. , 1988, Virology.

[33]  A. Saalmüller,et al.  Localization of pestiviral envelope proteins E(rns) and E2 at the cell surface and on isolated particles. , 1999, The Journal of general virology.

[34]  J. Sur,et al.  Mutation of E1 glycoprotein of classical swine fever virus affects viral virulence in swine. , 2005, Virology.

[35]  Z. Hong,et al.  The Amino-Terminal Domain of Bovine Viral Diarrhea Virus Npro Protein Is Necessary for Alpha/Beta Interferon Antagonism , 2006, Journal of Virology.

[36]  N. Tautz,et al.  Persistence of Bovine Viral Diarrhea Virus Is Determined by a Cellular Cofactor of a Viral Autoprotease , 2005, Journal of Virology.

[37]  R. Schneider,et al.  Identification of a structural glycoprotein of an RNA virus as a ribonuclease. , 1993, Science.

[38]  A. Siddiqui,et al.  Pestivirus translation initiation occurs by internal ribosome entry. , 1995, Virology.

[39]  R. Schneider,et al.  RNase of classical swine fever virus: biochemical characterization and inhibition by virus-neutralizing monoclonal antibodies , 1996, Journal of virology.

[40]  N. Tautz,et al.  Dissection of a viral autoprotease elucidates a function of a cellular chaperone in proteolysis , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Coria Mf,et al.  Specific immune tolerance in an apparently healthy bull persistently infected with bovine viral diarrhea virus. , 1978 .

[42]  J. Tratschin,et al.  Npro of classical swine fever virus is an antagonist of double-stranded RNA-mediated apoptosis and IFN-α/β induction , 2005 .

[43]  J. Tratschin,et al.  Classical Swine Fever Virus Interferes with Cellular Antiviral Defense: Evidence for a Novel Function of Npro , 2003, Journal of Virology.

[44]  A. Barrett,et al.  Epitope mapping of the gp53 envelope protein of bovine viral diarrhea virus. , 1992, Virology.

[45]  P. V. van Rijn,et al.  Recombinant classical swine fever (CSF) viruses derived from the Chinese vaccine strain (C-strain) of CSF virus retain their avirulent and immunogenic characteristics. , 2000, Vaccine.

[46]  M. Orlich,et al.  Evidence for the presence of two novel pestivirus species. , 2001, Virology.

[47]  C. Rice,et al.  The NS5A Protein of Bovine Viral Diarrhea Virus Contains an Essential Zinc-Binding Site Similar to That of the Hepatitis C Virus NS5A Protein , 2006, Journal of Virology.

[48]  S. Lemon,et al.  Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. , 2007, Virology.

[49]  K. Wiesmüller,et al.  Identification of T-cell epitopes in the structural and non-structural proteins of classical swine fever virus. , 2002, The Journal of general virology.

[50]  S. Goodbourn,et al.  The NPro Product of Bovine Viral Diarrhea Virus Inhibits DNA Binding by Interferon Regulatory Factor 3 and Targets It for Proteasomal Degradation , 2006, Journal of Virology.

[51]  J. McCauley,et al.  Interactions of bovine viral diarrhoea virus glycoprotein E(rns) with cell surface glycosaminoglycans. , 2000, The Journal of general virology.

[52]  B. Kümmerer,et al.  The genetic basis for cytopathogenicity of pestiviruses. , 2000, Veterinary microbiology.

[53]  G. Meyers,et al.  Recovery of Virulent and RNase-Negative Attenuated Type 2 Bovine Viral Diarrhea Viruses from Infectious cDNA Clones , 2002, Journal of Virology.

[54]  M. Collett,et al.  Pestivirus gene expression: protein p80 of bovine viral diarrhea virus is a proteinase involved in polyprotein processing. , 1991, Virology.

[55]  B. Charleston,et al.  Bovine Viral Diarrhea Virus: Prevention of Persistent Fetal Infection by a Combination of Two Mutations Affecting Erns RNase and Npro Protease , 2007, Journal of Virology.

[56]  S. Goodbourn,et al.  The Npro product of classical swine fever virus and bovine viral diarrhea virus uses a conserved mechanism to target interferon regulatory factor-3. , 2007, The Journal of general virology.

[57]  J. McCauley,et al.  Identification of the glycosaminoglycan-binding site on the glycoprotein E(rns) of bovine viral diarrhoea virus by site-directed mutagenesis. , 2002, The Journal of general virology.

[58]  S. Evans,et al.  The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine , 2003, FEBS letters.

[59]  R. Meloen,et al.  A Structural Model of Pestivirus Erns Based on Disulfide Bond Connectivity and Homology Modeling Reveals an Extremely Rare Vicinal Disulfide , 2002, Journal of Virology.

[60]  M. Clarke,et al.  Experimental production of fatal mucosal disease in cattle , 1984, Veterinary Record.

[61]  R. Donis,et al.  Neutralizing monoclonal antibodies to bovine viral diarrhoea virus bind to the 56K to 58K glycoprotein. , 1988, The Journal of general virology.

[62]  N. Tautz,et al.  Processing of poly-ubiquitin in the polyprotein of an RNA virus. , 1993, Virology.

[63]  J. Tratschin,et al.  Nonstructural proteins NS2-3 and NS4A of classical swine fever virus: essential features for infectious particle formation. , 2007, Virology.

[64]  C. Peters,et al.  Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) , 2004, Virology.

[65]  P. V. van Rijn,et al.  Epitope mapping of envelope glycoprotein E1 of hog cholera virus strain Brescia. , 1993, The Journal of general virology.

[66]  G. Meyers,et al.  The Carboxy-Terminal Sequence of the Pestivirus Glycoprotein Erns Represents an Unusual Type of Membrane Anchor , 2005, Journal of Virology.

[67]  A. Gorbalenya,et al.  Temporal Modulation of an Autoprotease Is Crucial for Replication and Pathogenicity of an RNA Virus , 2004, Journal of Virology.

[68]  J. Gillespie,et al.  A cytopathogenic strain of virus diarrhea virus. , 1960, The Cornell veterinarian.

[69]  J. Tratschin,et al.  Classical Swine Fever Virus Can Remain Virulent after Specific Elimination of the Interferon Regulatory Factor 3-Degrading Function of Npro , 2008, Journal of Virology.

[70]  H. Thiel,et al.  Hog cholera virus: molecular composition of virions from a pestivirus , 1991 .

[71]  E. Peterhans,et al.  Noncytopathic Bovine Viral Diarrhea Virus Inhibits Double-Stranded RNA-Induced Apoptosis and Interferon Synthesis , 2001, Journal of Virology.

[72]  H. Thiel,et al.  N-Terminal Protease of Pestiviruses: Identification of Putative Catalytic Residues by Site-Directed Mutagenesis , 1998, Journal of Virology.

[73]  P. V. van Rijn,et al.  Chimeric classical swine fever viruses containing envelope protein E(RNS) or E2 of bovine viral diarrhoea virus protect pigs against challenge with CSFV and induce a distinguishable antibody response. , 2000, Vaccine.

[74]  M. Clarke,et al.  Variation in the intracellular polypeptide profiles from different isolates of bovine virus diarrhoea virus , 2005, Archives of Virology.

[75]  A. Kaiser,et al.  NS3 serine protease of bovine viral diarrhea virus: characterization of active site residues, NS4A cofactor domain, and protease-cofactor interactions. , 2000, Virology.

[76]  H. Thiel,et al.  Pestivirus glycoprotein which induces neutralizing antibodies forms part of a disulfide-linked heterodimer , 1990, Journal of virology.

[77]  M. Murcko,et al.  Bovine viral diarrhea virus NS3 serine proteinase: polyprotein cleavage sites, cofactor requirements, and molecular model of an enzyme essential for pestivirus replication , 1997, Journal of virology.

[78]  J. Tratschin,et al.  Classical Swine Fever Virus Npro Interacts with Interferon Regulatory Factor 3 and Induces Its Proteasomal Degradation , 2007, Journal of Virology.

[79]  J. Tratschin,et al.  Analysis of classical swine fever virus replication kinetics allows differentiation of highly virulent from avirulent strains. , 2000, Veterinary microbiology.

[80]  A. Saalmüller,et al.  Mutations Abrogating the RNase Activity in Glycoprotein Erns of the Pestivirus Classical Swine Fever Virus Lead to Virus Attenuation , 1999, Journal of Virology.

[81]  W. Zhong,et al.  Identification and Characterization of an RNA-Dependent RNA Polymerase Activity within the Nonstructural Protein 5B Region of Bovine Viral Diarrhea Virus , 1998, Journal of Virology.

[82]  S. Lemon,et al.  The influence of downstream protein-coding sequence on internal ribosome entry on hepatitis C virus and other flavivirus RNAs. , 2001, RNA.

[83]  J. H. Strauss,et al.  Processing of the envelope glycoproteins of pestiviruses , 1993, Journal of virology.

[84]  F. Penin,et al.  Hepatitis C Virus p7 Protein Is Crucial for Assembly and Release of Infectious Virions , 2007, PLoS pathogens.

[85]  P. V. van Rijn,et al.  Experimental non-transmissible marker vaccines for classical swine fever (CSF) by trans-complementation of E(rns) or E2 of CSFV. , 2002, Vaccine.

[86]  Charles M. Rice,et al.  Flaviviridae :T he Viruses and Their Replication , 2007 .

[87]  D. Pérez,et al.  Genetic analysis of the internal ribosome entry segment of bovine viral diarrhea virus. , 1998, Virology.

[88]  P. V. van Rijn,et al.  Classical Swine Fever Virus ErnsDeletion Mutants: trans-Complementation and Potential Use as Nontransmissible, Modified, Live-Attenuated Marker Vaccines , 2000, Journal of Virology.

[89]  T. Harada,et al.  A Cellular J-Domain Protein Modulates Polyprotein Processing and Cytopathogenicity of a Pestivirus , 2001, Journal of Virology.

[90]  J. Tratschin,et al.  Zinc binding in pestivirus N(pro) is required for interferon regulatory factor 3 interaction and degradation. , 2009, Journal of molecular biology.

[91]  T. Krey,et al.  Function of Bovine CD46 as a Cellular Receptor for Bovine Viral Diarrhea Virus Is Determined by Complement Control Protein 1 , 2006, Journal of Virology.

[92]  M. Hulst,et al.  Erns protein of pestiviruses. , 2001, Methods in enzymology.

[93]  J. Tratschin,et al.  Oronasal vaccination with classical swine fever virus (CSFV) replicon particles with either partial or complete deletion of the E2 gene induces partial protection against lethal challenge with highly virulent CSFV. , 2005, Vaccine.

[94]  S. Goodbourn,et al.  Inhibition of Beta Interferon Transcription by Noncytopathogenic Bovine Viral Diarrhea Virus Is through an Interferon Regulatory Factor 3-Dependent Mechanism , 2002, Journal of Virology.

[95]  H. Thiel,et al.  Classical Swine Fever Virus Glycoprotein Erns Is an Endoribonuclease with an Unusual Base Specificity , 2004, Journal of Virology.

[96]  Bovine viral diarrhea virus with deletions in the 5'-nontranslated region: reduction of replication in calves and induction of protective immunity. , 2004, Vaccine.

[97]  Baker Jc Bovine viral diarrhea virus: a review. , 1987 .

[98]  H. Thiel,et al.  Molecular characterization of pestiviruses. , 1996, Advances in virus research.

[99]  F. Weiland,et al.  A second envelope glycoprotein mediates neutralization of a pestivirus, hog cholera virus , 1992, Journal of virology.

[100]  R. Dwek,et al.  The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy , 2009, Proceedings of the National Academy of Sciences.

[101]  J. Tratschin,et al.  Classical Swine Fever Virus Leader Proteinase Npro Is Not Required for Viral Replication in Cell Culture , 1998, Journal of Virology.

[102]  B. Charleston,et al.  Aspects of the innate and adaptive immune responses to acute infections with BVDV. , 2003, Veterinary microbiology.

[103]  N. Tautz,et al.  Cell-Derived Sequences in the N-Terminal Region of the Polyprotein of a Cytopathogenic Pestivirus , 2003, Journal of Virology.

[104]  S. Goodbourn,et al.  Role for Bovine Viral Diarrhea Virus Erns Glycoprotein in the Control of Activation of Beta Interferon by Double-Stranded RNA , 2004, Journal of Virology.

[105]  Z. Pan,et al.  12-nt insertion in 3' untranslated region leads to attenuation of classic swine fever virus and protects host against lethal challenge. , 2008, Virology.

[106]  E. Newbigin,et al.  Glycoprotein E2 of classical swine fever virus: expression in insect cells and identification as a ribonuclease. , 1994, Virology.