Abstract
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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Lindenbach BD, Thiel HJ, Rice CM (2007) Flaviviridae: the viruses and their replication. In: Knipe DM, Howley PM (eds) Fields virology, vol 1, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1101–1152
Avalos-Ramirez R, Orlich M, Thiel H-J, Becher P (2001) Evidence for the presence of two novel pestivirus species. Virology 286:456–465
Gillespie JH, Baker JA, McEntee K (1960) A cytopathogenic strain of virus diarrhea virus. Cornell Vet 50:73–79
Baker JC (1987) Bovine viral diarrhea virus: a review. J Am Vet Med Assoc 190:1449–1458
Risatti GR et al (2005) The E2 glycoprotein of classical swine fever virus is a virulence determinant in swine. J Virol 79:3787–3796
Risatti GR et al (2007) Mutations in the carboxyl terminal region of E2 glycoprotein of classical swine fever virus are responsible for viral attenuation in swine. Virology 364:371–382
Van Gennip HG, Vlot AC, Hulst MM, De Smit AJ, Moormann RJ (2004) Determinants of virulence of classical swine fever virus strain Brescia. J Virol 78:8812–8823
Becher P, Orlich M, Thiel H-J (2001) RNA recombination between persisting pestivirus and a vaccine strain: generation of cytopathogenic virus and induction of lethal disease. J Virol 75:6256–6264
Collett MS et al (1988) Molecular cloning and nucleotide sequence of the pestivirus bovine viral diarrhea virus. Virology 165:191–199
Renard A, Dino D, Martial J (1987) Vaccines and diagnostics derived from bovine diarrhea virus. European Patent application number 86870095.6:publication number 02.08672
Poole TL et al (1995) Pestivirus translation occurs by internal ribosome entry. Virology 206:750–754
Thiel H-J, Stark R, Weiland E, Rümenapf T, Meyers G (1991) Hog cholera virus: molecular composition of virions from a pestivirus. J Virol 65:4705–4712
Paton DJ, Lowings JP, Barrett AD (1992) Epitope mapping of the gp53 envelope protein of bovine viral diarrhea virus. Virology 190:763–772
Weiland S, Ahl R, Stark R, Weiland F, Thiel H-J (1992) A second envelope glycoprotein mediates neutralization of a pestivirus, hog cholera virus. J Virol 66:3677–3682
Weiland S et al (1990) Pestivirus glycoprotein which induces neutralizing antibodies forms part of a disulfide linked heterodimer. J Virol 64:3563–3569
van Rijn PA, van Gennip HG, de Meijer EJ, Moormann RJ (1993) Epitope mapping of envelope glycoprotein E1 of hog cholera virus strain Brescia. J Gen Virol 74(10):2053–2060
Donis RO, Corapi W, Dubovi EJ (1988) Neutralizing monoclonal antibodies to bovine viral diarrhoea virus bind to the 56K to 58K glycoprotein. J Gen Virol 69(1):77–86
Maurer K, Krey T, Moennig V, Thiel HJ, Rumenapf T (2004) CD46 is a cellular receptor for bovine viral diarrhea virus. J Virol 78:1792–1799
Krey T et al (2006) Function of bovine CD46 as a cellular receptor for bovine viral diarrhea virus is determined by complement control protein 1. J Virol 80:3912–3922
Hulst MM, van Gennip HG, Moormann RJ (2000) 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 E(rns). J Virol 74:9553–9561
Iqbal M, Flick-Smith H, McCauley JW (2000) Interactions of bovine viral diarrhoea virus glycoprotein E(rns) with cell surface glycosaminoglycans. J Gen Virol 81:451–459
Iqbal M, McCauley JW (2002) Identification of the glycosaminoglycan-binding site on the glycoprotein E(rns) of bovine viral diarrhoea virus by site-directed mutagenesis. J Gen Virol 83:2153–2159
Rumenapf T, Unger G, Strauss JH, Thiel HJ (1993) Processing of the envelope glycoproteins of pestiviruses. J Virol 67:3288–3294
Fetzer C, Tews BA, Meyers G (2005) The carboxy-terminal sequence of the pestivirus glycoprotein E(rns) represents an unusual type of membrane anchor. J Virol 79:11901–11913
Tews BA, Meyers G (2007) The pestivirus glycoprotein Erns is anchored in plane in the membrane via an amphipathic helix. J Biol Chem 282:32730–32741
Hulst MM, Himes G, Newbigin E, Moormann RJM (1994) Glycoprotein E2 of classical swine fever virus: expression in insect cells and identification as a ribonuclease. Virology 200:558–565
Schneider R, Unger G, Stark R, Schneider-Scherzer E, Thiel H-J (1993) Identification of a structural glycoprotein of an RNA virus as a ribonuclease. Science 261:1169–1171
Windisch JM et al (1996) RNase of classical swine fever virus: biochemical characterization and inhibition by virus-neutralizing monoclonal antibodies. J Virol 70:352–358
Harada T, Tautz N, Thiel H-J (2000) E2-p7 region of the bovine viral diarrhea virus polyprotein: processing and functional studies. J Virol 74:9498–9506
Luik P et al (2009) The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy. Proc Natl Acad Sci U S A 106:12712–12716
Steinmann E et al (2007) Hepatitis C virus p7 protein is crucial for assembly and release of infectious virions. PLoS Pathog 3:e103
Griffin SD et al (2003) The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine. FEBS Lett 535:34–38
Lackner T et al (2004) Temporal modulation of an autoprotease is crucial for replication and pathogenicity of an RNA virus. J Virol 78:10765–10775
Agapov EV et al (1998) Noncytopathic sindbis virus RNA vectors for heterologous gene expression. Proc Natl Acad Sci U S A 95:12989–12994
Moulin HR et al (2007) Nonstructural proteins NS2-3 and NS4A of classical swine fever virus: essential features for infectious particle formation. Virology 365:376–389
Tautz N, Kaiser A, Thiel H-J (2000) NS3 serine protease of bovine viral diarrhea virus: characterization of active site residues, NS4A cofactor domain, and protease-cofactor interactions. Virology 273:351–363
Wiskerchen M, Collett MS (1991) Pestivirus gene expression: protein p80 of bovine viral diarrhea virus is a proteinase involved in polyprotein processing. Virology 184:341–350
Xu J et al (1997) Bovine viral diarrhea virus NS3 serine proteinase: polyprotein cleavage sites, cofactor requirements, and molecular model of an enzyme essential for pestivirus replication. J Virol 71:5312–5322
Tellinghuisen TL, Paulson MS, Rice CM (2006) The NS5A protein of bovine viral diarrhea virus contains an essential zinc-binding site similar to that of the hepatitis C virus NS5A protein. J Virol 80:7450–7458
Zhong W, Gutshall LL, Del Vecchio AM (1998) Identification and characterization of an RNA-dependent RNA polymerase activity within the nonstructural protein 5B region of bovine viral diarrhea virus. J Virol 72:9365–9369
Meyers G, Tautz N, Becher P, Thiel H-J, Kümmerer B (1996) Recovery of cytopathogenic and noncytopathogenic bovine viral diarrhea viruses from cDNA constructs. J Virol 70:8606–8613
Moormann RJM, van Gennip HGP, Miedema GKW, Hulst MM, van Rijn PA (1996) Infectious RNA transcribed from an engineered full-length cDNA template of the genome of a pestivirus. J Virol 70:763–770
Brownlie J, Clarke MC, Howard CJ (1984) Experimental production of fatal mucosal disease in cattle. Vet Rec 114:535–536
Moennig V, Frey H-R, Liebler E, Polenz P, Liess B (1990) Reproduction of mucosal disease with cytopathogenic bovine viral diarrhoea virus selected in vitro. Vet Rec 127:200–203
Brackenbury LS, Carr BV, Charleston B (2003) Aspects of the innate and adaptive immune responses to acute infections with BVDV. Vet Microbiol 96:337–344
Haller O, Kochs G, Weber F (2006) The interferon response circuit: induction and suppression by pathogenic viruses. Virology 344:119–130
Coria MF, McClurkin AW (1978) Specific immunotolerance in an apparently healthy bull persistently infected with BVD virus. J Am Vet Med Assoc 172:449–451
Thiel H-J, Plagemann PGW, Moennig V (1996) Pestiviruses. In: Fields BN, Knipe DM, Howley PM (eds) Fields virology, vol 1, 3rd edn. Lippincott Raven, Philadelphia, pp 1059–1073
Meyers G, Tautz N, Dubovi EJ, Thiel H-J (1996) Origin and diversity of cytopathogenic pestiviruses. International symposium of bovine viral diarrhea virus – a 50 year review.
Meyers G, Thiel H-J (1996) Molecular characterization of pestiviruses. Adv Virus Res 47:53–117
Kümmerer BM, Tautz N, Becher P, Thiel H-J, Meyers G (2000) The genetic basis for cytopathogenicity of pestiviruses. Vet Microbiol 77:117–128
Tautz N, Meyers G, Thiel H-J (1993) Processing of poly-ubiquitin in the polyprotein of an RNA virus. Virology 197:74–85
Meyers G et al (1992) Rearrangement of viral sequences in cytopathogenic pestiviruses. Virology 191:368–386
Pocock DH, Howard CJ, Clarke MC, Brownlie J (1987) Variation in the intracellular polypeptide profiles from different isolates of bovine viral diarrhea virus. Arch Virol 94:43–53
Mendez E, Ruggli N, Collett MS, Rice CM (1998) Infectious bovine viral diarrhea virus (strain NADL) RNA from stable cDNA clones: a cellular insert determines NS3 production and viral cytopathogenicity. J Virol 72:4737–4745
Schweizer M, Peterhans E (2001) Noncytopathic bovine viral diarrhea virus inhibits double-stranded RNA-induced apoptosis and interferon synthesis. J Virol 75:4692–4698
Lackner T, Muller A, Konig M, Thiel HJ, Tautz N (2005) Persistence of bovine viral diarrhea virus is determined by a cellular cofactor of a viral autoprotease. J Virol 79:9746–9755
Lackner T, Thiel HJ, Tautz N (2006) Dissection of a viral autoprotease elucidates a function of a cellular chaperone in proteolysis. Proc Natl Acad Sci U S A 103:1510–1515
Gallei A et al (2008) Cytopathogenicity of classical swine fever virus correlates with attenuation in the natural host. J Virol 82:9717–9729
Müller A, Rinck G, Thiel H-J, Tautz N (2003) Cell-derived sequences located in the structural genes of a cytopathogenic pestivirus. J Virol 77:10663–10669
Rinck G et al (2001) A cellular J-domain protein modulates polyprotein processing and cytopathogenicity of a pestivirus. J Virol 75:9470–9482
Perler L, Schweizer M, Jungi TW, Peterhans E (2000) Bovine viral diarrhoea virus and bovine herpesvirus-1 prime uninfected macrophages for lipopolysaccharide-triggered apoptosis by interferon-dependent and -independent pathways. J Gen Virol 81:881–887
Rümenapf T, Stark R, Heimann M, Thiel H-J (1998) N-terminal protease of pestiviruses: identification of putative catalytic residues by site-directed mutagenesis. J Virol 72:2544–2547
Tratschin JD, Moser C, Ruggli N, Hofmann MA (1998) Classical swine fever virus leader proteinase Npro is not required for viral replication in cell culture. J Virol 72:7681–7684
Mittelholzer C, Moser C, Tratschin JD, Hofmann MA (2000) Analysis of classical swine fever virus replication kinetics allows differentiation of highly virulent from avirulent strains. Vet Microbiol 74:293–308
Mayer D, Hofmann MA, Tratschin JD (2004) Attenuation of classical swine fever virus by deletion of the viral N(pro) gene. Vaccine 22:317–328
Ruggli N et al (2005) N(pro) of classical swine fever virus is an antagonist of double-stranded RNA-mediated apoptosis and IFN-alpha/beta induction. Virology 340:265–276
Ruggli N et al (2003) Classical swine fever virus interferes with cellular antiviral defense: evidence for a novel function of N(pro). J Virol 77:7645–7654
La Rocca SA et al (2005) Loss of interferon regulatory factor 3 in cells infected with classical swine fever virus involves the N-terminal protease, Npro. J Virol 79:7239–7247
Gil LHVG et al (2006) The amino-terminal domain of bovine viral diarrhea virus Npro protein is necessary for alpha/beta interferon antagonism. J Virol 80:900–911
Hilton L et al (2006) The NPro product of bovine viral diarrhea virus inhibits DNA binding by interferon regulatory factor 3 and targets it for proteasomal degradation. J Virol 80:11723–11732
Baigent SJ et al (2002) Inhibition of beta interferon transcription by noncytopathogenic bovine viral diarrhea virus is through an interferon regulatory factor 3-dependent mechanism. J Virol 76:8979–8988
Bauhofer O et al (2007) Classical swine fever virus Npro interacts with interferon regulatory factor 3 and induces its proteasomal degradation. J Virol 81:3087–3096
Seago J et al (2007) The Npro product of classical swine fever virus and bovine viral diarrhea virus uses a conserved mechanism to target interferon regulatory factor-3. J Gen Virol 88:3002–3006
Chen Z et al (2007) Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. Virology 366:277–292
Szymanski MR et al (2009) Zinc binding in pestivirus N(pro) is required for interferon regulatory factor 3 interaction and degradation. J Mol Biol 391:438–449
Ruggli N et al (2009) Classical swine fever virus can remain virulent after specific elimination of the interferon regulatory factor 3-degrading function of Npro. J Virol 83:817–829
Widjojoatmodjo MN, van Gennip HG, Bouma A, van Rijn PA, Moormann RJ (2000) Classical swine fever virus E(rns) deletion mutants: trans-complementation and potential use as nontransmissible, modified, live-attenuated marker vaccines. J Virol 74:2973–2980
Hulst MM, Moormann RJ (2001) Erns protein of pestiviruses. Methods Enzymol 342:431–440
Hausmann Y, Roman-Sosa G, Thiel HJ, Rumenapf T (2004) Classical swine fever virus glycoprotein E rns is an endoribonuclease with an unusual base specificity. J Virol 78:5507–5512
Iqbal M, Poole E, Goodbourn S, McCauley JW (2004) Role for bovine viral diarrhea virus Erns glycoprotein in the control of activation of beta interferon by double-stranded RNA. J Virol 78:136–145
Magkouras I, Matzener P, Rumenapf T, Peterhans E, Schweizer M (2008) RNase-dependent inhibition of extracellular, but not intracellular, dsRNA-induced interferon synthesis by Erns of pestiviruses. J Gen Virol 89:2501–2506
Hulst MM, Panoto FE, Hoekman A, van Gennip HG, Moormann RJ (1998) Inactivation of the RNase activity of glycoprotein Erns of classical swine fever virus results in a cytopathogenic virus. J Virol 72:151–157
Meyer C, Von Freyburg M, Elbers K, Meyers G (2002) Recovery of virulent and RNase-negative attenuated type 2 bovine viral diarrhea viruses from infectious cDNA clones. J Virol 76:8494–8503
Meyers G, Saalmüller A, Büttner M (1999) Mutations abrogating the RNase activity in glycoprotein e(rns) of the pestivirus classical swine fever virus lead to virus attenuation. J Virol 73:10224–10235
von Freyburg M, Ege A, Saalmuller A, Meyers G (2004) Comparison of the effects of RNase-negative and wild-type classical swine fever virus on peripheral blood cells of infected pigs. J Gen Virol 85:1899–1908
Matzener P, Magkouras I, Rumenapf T, Peterhans E, Schweizer M (2009) The viral RNase E(rns) prevents IFN type-I triggering by pestiviral single- and double-stranded RNAs. Virus Res 140:15–23
Weiland F, Weiland E, Unger G, Saalmuller A, Thiel HJ (1999) Localization of pestiviral envelope proteins E(rns) and E2 at the cell surface and on isolated particles. J Gen Virol 80(Pt 5):1157–1165
Langedijk JP et al (2002) A structural model of pestivirus E(rns) based on disulfide bond connectivity and homology modeling reveals an extremely rare vicinal disulfide. J Virol 76:10383–10392
van Gennip HG, Hesselink AT, Moormann RJ, Hulst MM (2005) Dimerization of glycoprotein E(rns) of classical swine fever virus is not essential for viral replication and infection. Arch Virol 150:2271–2286
Tews BA, Schurmann EM, Meyers G (2009) Mutation of cysteine 171 of pestivirus E rns RNase prevents homodimer formation and leads to attenuation of classical swine fever virus. J Virol 83:4823–4834
Charleston B, Fray MD, Baigent S, Carr BV, Morrison WI (2001) Establishment of persistent infection with non-cytopathic bovine viral diarrhoea virus in cattle is associated with a failure to induce type I interferon. J Gen Virol 82:1893–1897
Meyers G et al (2007) Bovine viral diarrhea virus: prevention of persistent fetal infection by a combination of two mutations affecting Erns RNase and Npro protease. J Virol 81:3327–3338
Tautz N et al (1999) Establishment and characterization of cytopathogenic and noncytopathogenic pestivirus replicons. J Virol 73:9422–9432
Chon SK, Perez DR, Donis RO (1998) Genetic analysis of the internal ribosome entry segment of bovine viral diarrhea virus. Virology 251:370–382
Myers TM et al (2001) Efficient translation initiation is required for replication of bovine viral diarrhea virus subgenomic replicons. J Virol 75:4226–4238
Rijnbrand R et al (2001) The influence of downstream protein-coding sequence on internal ribosome entry on hepatitis C virus and other flavivirus RNAs. RNA 7:585–597
Becher P, Orlich M, Thiel H-J (2000) Mutations in the 5′ nontranslated region of bovine viral diarrhea virus result in altered growth characteristics. J Virol 74:7884–7894
Makoschey B et al (2004) Bovine viral diarrhea virus with deletions in the 5′-nontranslated region: reduction of replication in calves and induction of protective immunity. Vaccine 22:3285–3294
Wang Y et al (2008) 12-nt insertion in 3′ untranslated region leads to attenuation of classic swine fever virus and protects host against lethal challenge. Virology 374:390–398
Risatti GR et al (2005) Mutation of E1 glycoprotein of classical swine fever virus affects viral virulence in swine. Virology 343:116–127
Sainz B Jr, Mossel EC, Peters CJ, Garry RF (2004) Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Virology 329:11–17
Sainz IF, Holinka LG, Lu Z, Risatti GR, Borca MV (2008) Removal of a N-linked glycosylation site of classical swine fever virus strain Brescia Erns glycoprotein affects virulence in swine. Virology 370:122–129
de Smit AJ et al (2000) Recombinant classical swine fever (CSF) viruses derived from the Chinese vaccine strain (C-strain) of CSF virus retain their avirulent and immunogenic characteristics. Vaccine 18:2351–2358
van Gennip HG, van Rijn PA, Widjojoatmodjo MN, de Smit AJ, Moormann RJ (2000) 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. Vaccine 19:447–459
Armengol E et al (2002) Identification of T-cell epitopes in the structural and non-structural proteins of classical swine fever virus. J Gen Virol 83:551–560
Maurer R, Stettler P, Ruggli N, Hofmann MA, Tratschin JD (2005) 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. Vaccine 23:3318–3328
Frey CF et al (2006) Classical swine fever virus replicon particles lacking the Erns gene: a potential marker vaccine for intradermal application. Vet Res 37:655–670
Reimann I, Semmler I, Beer M (2007) Packaged replicons of bovine viral diarrhea virus are capable of inducing a protective immune response. Virology 366:377–386
van Gennip HG, Bouma A, van Rijn PA, Widjojoatmodjo MN, Moormann RJ (2002) Experimental non-transmissible marker vaccines for classical swine fever (CSF) by trans-complementation of E(rns) or E2 of CSFV. Vaccine 20:1544–1556
Dong XN, Chen YH (2007) Marker vaccine strategies and candidate CSFV marker vaccines. Vaccine 25:205–230
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Basel
About this chapter
Cite this chapter
Tautz, N., Meyers, G. (2011). Basic Science Paves the Way to Novel Safe and Effective Pestivirus Vaccines. In: Dormitzer, P., Mandl, C., Rappuoli, R. (eds) Replicating Vaccines. Birkhäuser Advances in Infectious Diseases. Springer, Basel. https://doi.org/10.1007/978-3-0346-0277-8_7
Download citation
DOI: https://doi.org/10.1007/978-3-0346-0277-8_7
Published:
Publisher Name: Springer, Basel
Print ISBN: 978-3-0346-0276-1
Online ISBN: 978-3-0346-0277-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)