title: Characterization of DNA polymerase-associated acyclovir-resistant herpes simplex virus type 1: mutations, sensitivity to antiviral compounds, neurovirulence, and in-vivo sensitivity to treatment.
abstract: Acyclovir (ACV)-resistant (ACV(r)) mutants were generated from plaque-purified ACV-sensitive herpes simplex virus type 1 (HSV-1) by culturing the virus in Vero cells in the presence of 2-amino-7-(1,3-dihydroxy-2-propoxymethyl) purine (S2242). Three DNA polymerase (DNApol)-associated ACV(r) HSV-1 generated under ACV selection in a previous study (Suzutani, T., Ishioka, K., De Clercq, E., et al., Antimicrob. Agents Chemother., 47, 1707-1713, 2003) were also included. The sensitivity of the mutants to other antivirals and their neurovirulence were determined. The treatment efficacy of ACV and ganciclovir (GCV) against ACV(r) HSV-1 infections was evaluated in mice. Amino acid substitutions were demonstrated in conserved regions II and III in DNApol in 5 of the 6 mutants, while the other substitution was located in non-conserved regions. DNApol-associated ACV(r) clones showed cross-resistance to foscarnet, penciclovir, and vidarabine but were sensitive or hypersensitive to GCV, brivudin, sorivudine, and spongothymidine. The ACV(r) clone with an N815S mutation in DNApol showed similar neurovirulence to that of the parent virus; however, those with other mutations showed attenuation. GCV was effective in the treatment of the ACV(r) clone with similar virulence to that of parent HSV-1, while ACV was less effective in mice. These results indicate the importance of the characterization of HSV-1 isolates for the proper treatment of HSV-1 infections exhibiting ACV-resistance.
authors.affiliation: Department of Virology 1, National Institute of Infectious Diseases.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Wang
authors.forename: Mutsuyo
authors.initials: M
authors.lastname: Takayama-Ito
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kinoshita-Yamaguchi
authors.forename: Satsuki
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suzutani
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamichi
authors.forename: Chang-Kweng
authors.initials: CK
authors.lastname: Lim
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kurane
authors.forename: Masayuki
authors.initials: M
authors.lastname: Saijo
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D020803:Encephalitis, Herpes Simplex / Q000188:drug therapy / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D012641:Selection, Genetic; D012692:Serial Passage; D016896:Treatment Outcome; D014709:Vero Cells; D010948:Viral Plaque Assay; D014774:Virulence
chemical_list: D000998:Antiviral Agents; D004259:DNA-Directed DNA Polymerase; D000212:Acyclovir