title: Neurovirulence and latency of drug-resistant clinical herpes simplex viruses in animal models.
abstract: Herpes simplex virus (HSV) resistance to acyclovir or foscarnet results from mutations in viral thymidine kinase (TK) and/or DNA polymerase (pol) genes. Replication kinetics and virulence of TK and/or DNA pol clinical mutants were assessed using models of mouse encephalitis and cotton rat genital infection. Replication capacities in Vero cells of a DNA pol altered strain (L850I) and a TK/DNA pol mutant (C467deletion/A912V) were significantly lower than those of unrelated wild-type (WT) strains, while a double DNA pol mutant (S724N/P920S) demonstrated replication kinetics similar to the WT. The replication of a TK-deficient mutant (G439.5addition) was impaired (low m.o.i.) or unaltered (high m.o.i.) compared to that of a WT virus depending on the viral inoculum. Compared to a survival rate of 6% for mice infected intranasally with WT HSV-1 or -2 viruses, G439.5add, C467deletion/A912V and L850I strains were associated with survival rates of 100% (P < 0.05) whereas mice infected with the S724N/P920S mutant had a survival rate of 33% (P = 0.08). Brain viral titers were higher in mice infected with WT HSV-1 or -2 strains and the double DNA pol mutant. All strains except the DNA pol mutant L850I were able to establish latency in the dorsal root ganglia of cotton rats. A good correlation was generally found between replication kinetics of DNA pol mutants and their neurovirulence potential in mice whereas such correlation was not straightforward for TK mutants.
authors.affiliation: Research Center in Infectious Diseases, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Université Laval, Quebec, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dambrosi
authors.forename: Mélanie
authors.initials: M
authors.lastname: Martin
authors.forename: Kevin
authors.initials: K
authors.lastname: Yim
authors.forename: Brian
authors.initials: B
authors.lastname: Miles
authors.forename: Julio
authors.initials: J
authors.lastname: Canas
authors.forename: Yan
authors.initials: Y
authors.lastname: Sergerie
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D024882:Drug Resistance, Viral; D020803:Encephalitis, Herpes Simplex / Q000473:pathology / Q000821:virology*; D005090:Exodeoxyribonucleases / Q000235:genetics; D005260:Female; D005727:Ganglia, Spinal / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D020125:Mutation, Missense; D017384:Sequence Deletion; D016205:Sigmodontinae; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D016019:Survival Analysis; D013937:Thymidine Kinase / Q000235:genetics; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D014774:Virulence; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus