Changes

===Virus Structure===

===Virus Structure===

The BVDV genome comprises a single strand of positive sense RNA which is around 12.3 kilobases in length<ref name="three">Donis, R O(1995) '''Molecular biology of bovine viral diarrhea virus and its interactions with the host.''' ''The Veterinary Clinics of North America: Food Animal Practice'' 11(3), 393-424.</ref>. The genome is read in one 3898-codon open reading frame that contains no non-coding sequences. BVDV polyprotein is translated directly from the ORF and is cleaved by viral and cellular proteinases to form mature viral proteins<ref name="three"/><ref name="four">Dubovi, E J (1990) '''Molecular biology of bovine virus diarrhoea virus.''' ''Revue Scientifique et Technique'', 9(1), 105-114.</ref>. At either end of the ORF, 5’ and 3’ untranslated regions exist. These regions are long, allowing them to accomomdate functions conferred in eukaryotic DNA by the 5’ cap and the 3' poly-A tail, such as controlling the initiation of translation, facilitating the entry of replicases, and contributing to RNA stability<ref name="four"/>. BVDV's RNA genome encodes both structural and non-structural proteins. These include Npro, whose protease action generates the N-terminus of the protein C. C is the capsid protein that packages genomic RNA and assists in the formation of the eventual enveloped virion. Erns, E1 and E2 are all glycoproteins, with Erns possessing RNase activity involved in viral replication and pathogenesis<ref name="five">Van Gennip, H G P et al (2005) '''Dimerisation of glycoprotein Erns of classical swine fever virus is not essential for viral replication and infection.''' ''Archives of Virology'', 150(1), 2271-2286.</ref>. E1 is membrane-anchored and initiates the translocation of the antigenic protein E2 to the envelope³. P7 has an uncertain function⁶. NS2-3 is the first non-structural protein to be translated. Sequence similarities are shown by NS2-3 to a region that in other Flaviviridae is split into two distinct polypeptides, NS2 and NS3. In BVDV, NS2 and NS3 can be expressed as separate polypeptides: NS3 is found exclusively in cytopathic isolates from 6 hours post-infection, making it a marker of this biotype³. NS2 is also expressed as a discrete polypeptide in some cytopathic isolates. NS2-3, along with the other non-structural proteins, plays an important role in genome replication. A serine protease domain within NS2-3 functions to release NS4A, NS4B, NS5A and NS5B⁷. NS4A is a cofactor for the serine protease⁷, and NS5B possesses an RNA-dependent RNA polymerase activity⁸. Knowledge of the role of NS4B is limited.

The BVDV genome comprises a single strand of positive sense RNA which is around 12.3 kilobases in length<ref name="three">Donis, R O(1995) '''Molecular biology of bovine viral diarrhea virus and its interactions with the host.''' ''The Veterinary Clinics of North America: Food Animal Practice'' 11(3), 393-424.</ref>. The genome is read in one 3898-codon open reading frame that contains no non-coding sequences. BVDV polyprotein is translated directly from the ORF and is cleaved by viral and cellular proteinases to form mature viral proteins<ref name="three"/><ref name="four">Dubovi, E J (1990) '''Molecular biology of bovine virus diarrhoea virus.''' ''Revue Scientifique et Technique'', 9(1), 105-114.</ref>. At either end of the ORF, 5’ and 3’ untranslated regions exist. These regions are long, allowing them to accomomdate functions conferred in eukaryotic DNA by the 5’ cap and the 3' poly-A tail, such as controlling the initiation of translation, facilitating the entry of replicases, and contributing to RNA stability<ref name="four"/>. BVDV's RNA genome encodes both structural and non-structural proteins. These include Npro, whose protease action generates the N-terminus of the protein C. C is the capsid protein that packages genomic RNA and assists in the formation of the eventual enveloped virion. Erns, E1 and E2 are all glycoproteins, with Erns possessing RNase activity involved in viral replication and pathogenesis<ref name="five">Van Gennip, H G P et al (2005) '''Dimerisation of glycoprotein Erns of classical swine fever virus is not essential for viral replication and infection.''' ''Archives of Virology'', 150(1), 2271-2286.</ref>. E1 is membrane-anchored and initiates the translocation of the antigenic protein E2 to the envelope<ref name="three"/>. P7 has an uncertain function<ref name="six">Tautz, N et al (1999) '''Establishment and Characterization of Cytopathogenic and Noncytopathogenic Pestivirus Replicons.''' ''Journal of Virology'', 73(11), 9422–9432.</ref>. NS2-3 is the first non-structural protein to be translated. Sequence similarities are shown by NS2-3 to a region that in other Flaviviridae is split into two distinct polypeptides, NS2 and NS3. In BVDV, NS2 and NS3 can be expressed as separate polypeptides: NS3 is found exclusively in cytopathic isolates from 6 hours post-infection, making it a marker of this biotype<ref name="three"/>. NS2 is also expressed as a discrete polypeptide in some cytopathic isolates. NS2-3, along with the other non-structural proteins, plays an important role in genome replication. A serine protease domain within NS2-3 functions to release NS4A, NS4B, NS5A and NS5B<ref name="seven">Harada, T et al (2000) '''E2-p7 Region of the Bovine Viral Diarrhea Virus Polyprotein: Processing and Functional Studies.''' ''Journal of Virology'', 74(20), 9498–9506.</ref>. NS4A is a cofactor for the serine protease<ref name="seven"/>, and NS5B possesses an RNA-dependent RNA polymerase activity<ref name="eight">Zhong, W et al (1998) '''Identification and Characterization of an RNA-Dependent RNA Polymerase Activity within the Nonstructural Protein 5B Region of Bovine Viral Diarrhea Virus.''' ''Journal of Virology'', 72(11), 9365–9369.</ref>. Knowledge of the role of NS4B is limited.

Newly formed genomic material is packaged by structural proteins to create the BVDV virion which is 40-60nm in diameter. The capsid is surrounded by a membranous envelope, in which the glycoproteins ''E1'' and ''E2'' are anchored. Naked BVDV RNA is infectious^{3, 4}, and so it can be deduced that the virions do not contain enzymes necessary for RNA replication: these are provided by the host cell.

Newly formed genomic material is packaged by structural proteins to create the BVDV virion which is 40-60nm in diameter. The capsid is surrounded by a membranous envelope, in which the glycoproteins ''E1'' and ''E2'' are anchored. Naked BVDV RNA is infectious<ref name="three"/><ref name="four"/>, and so it can be deduced that the virions do not contain enzymes necessary for RNA replication: these are provided by the host cell.

===Virus Genotypes===

===Virus Genotypes===

There are two antigenically distinct⁹ genotypes of BVDV, type 1 and type 2, which are most accurately characterised based on sequence variation.  BVDV-1 and BVDV-2 contain 11 and 3 subtypes respectively, which have been demonstrated by analysis of the 5’UTR¹⁰. Despite the large antigenic differences between the genotypes, some cross-protection against type 2 viruses is afforded by type 1 vaccines^{11, 12, 13}.

There are two antigenically distinct<ref name="nine">Paton, D J et al (1995) '''A proposed division of the pestivirus genus using monoclonal antibodies, supported by cross-neutralisation assays and genetic sequencing.''' ''Veterinary Research'', 26, 82-109.</ref> genotypes of BVDV, type 1 and type 2, which are most accurately characterised based on sequence variation.  BVDV-1 and BVDV-2 contain 11 and 3 subtypes respectively, which have been demonstrated by analysis of the 5’UTR<ref name="ten">Vilcek, S et al (2001) '''Bovine viral diarrhoea virus genotype 1 can be separated into at least eleven groups.''' ''Archives of Virology'', 146, 99-115. </ref>. Despite the large antigenic differences between the genotypes, some cross-protection against type 2 viruses is afforded by type 1 vaccines<ref name="eleven">Carman, S et al (1998) '''Severe acute bovine viral diarrhea in Ontario, 1993-1995.''' ''Journal of Veterinary Diagnostic Investigation'', 10, 27-35. </ref><ref name="twelve">Cortese, V S et al (1998) '''Clinical and immunologic responses of vaccinated and unvaccinated calves to infection with a virulent type-II isolate of bovine viral diarrhea virus.''' ''Journal of the American Veterinary Medical Association'', 213, 1312-1319. </ref><ref name="thirteen">Van Oirschot, J T et al (1999) '''Vaccination of cattle against bovine viral diarrhoea.''' ''Veterinary Microbiology'', 64, 169-183.</ref>.

In general, the genotypes do not differ in virulence. It was, at one time, considered that BVDV-1 species which are found worldwide caused milder disease ¹⁴, whereas BVDV-2 isolates typically caused more severe disease which is often haemorrhagic and was associated with a high mortality rate^{11, 15}. This is no longer the case. The relationship between genotype and virulence is, however, not fixed: some type 2 strains cause mild or subclinical disease¹⁶, and the spectrum disease caused by type 1 viruses is broad. Type 2 viruses were first reported in Canada and the USA and have a more limited distribution than type 1 isolates.  

In general, the genotypes do not differ in virulence. It was, at one time, considered that BVDV-1 species which are found worldwide caused milder disease ¹⁴, whereas BVDV-2 isolates typically caused more severe disease which is often haemorrhagic and was associated with a high mortality rate^{11, 15}. This is no longer the case. The relationship between genotype and virulence is, however, not fixed: some type 2 strains cause mild or subclinical disease¹⁶, and the spectrum disease caused by type 1 viruses is broad. Type 2 viruses were first reported in Canada and the USA and have a more limited distribution than type 1 isolates.