title: A single-nucleotide polymorphism in a herpesvirus DNA polymerase is sufficient to cause lethal neurological disease.
abstract: Epidemiological studies have shown that a single-nucleotide polymorphism in the equid herpesvirus type 1 DNA polymerase gene is associated with outbreaks of highly lethal neurological disease in horses. Reverse genetics experiments further demonstrated that a G(2254) A(2254) nucleotide mutation introduced in neurovirulent strain Ab4, which resulted in an asparagine for aspartic acid substitution (D(752) N(752)), rendered the virus nonneurovirulent in the equine. Here, we report that the nonneurovirulent strain equid herpesvirus type 1 strain NY03 caused lethal neurological disease in horses after mutation of A(2254) G(2254) (N(752) D(752)), thereby providing final proof that the D(752) allele in the viral DNA polymerase is necessary and sufficient for expression of the lethal neurovirulent phenotype in the natural host. Although virus shedding was comparable between the N(752) and D(752) variants, infection with the latter was accompanied by efficient establishment of prolonged cell-associated viremia in peripheral blood mononuclear cells and neurological disease in 2 of 6 animals.
authors.affiliation: Department of Microbiology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA
authors.forename: Gerlinde R
authors.initials: GR
authors.lastname: Van de Walle
authors.forename: Ryan
authors.initials: R
authors.lastname: Goupil
authors.forename: Cassandra
authors.initials: C
authors.lastname: Wishon
authors.forename: Armando
authors.initials: A
authors.lastname: Damiani
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Osterrieder
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D016590:Aphidicolin / Q000627:therapeutic use; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D014644:Genetic Variation; D006566:Herpesviridae Infections / Q000188:drug therapy / Q000401:mortality; D004861:Herpesvirus 1, Equid / Q000235:genetics* / Q000472:pathogenicity; D006734:Horse Diseases / Q000401:mortality* / Q000821:virology*; D006736:Horses; D008826:Microbial Sensitivity Tests; D020641:Polymorphism, Single Nucleotide; D017201:Virus Shedding
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D016590:Aphidicolin; D004259:DNA-Directed DNA Polymerase