Characterization of DNA Polymerase-Associated Acyclovir-Resistant Herpes Simplex Virus Type 1: Mutations, Sensitivity to Antiviral Compounds, Neurovirulence, and In-Vivo Sensitivity to Treatment

[摘要] References(51)Cited-By(2)Acyclovir (ACV)-resistant (ACVr) 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 ACVr 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 ACVr 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 ACVr clones showed cross-resistance to foscarnet, penciclovir, and vidarabine but were sensitive or hypersensitive to GCV, brivudin, sorivudine, and spongothymidine. The ACVr 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 ACVr 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.

[学科分类] 传染病学

[关键词] HSV-1;DNA polymerase;mutation;antiviral compounds;resistance;neurovirulence;in vivo drug treatment