title: Suppression of generation and replication of acyclovir-resistant herpes simplex virus by a sensitive virus.
abstract: The role of acyclovir-sensitive herpes simplex virus (HSV) was analyzed in the process of its replacement by a resistant virus in vitro and in vivo in the aspect of acyclovir therapy. The mode of replacement of acyclovir-sensitive HSV with acyclovir-resistant HSV was examined by the passages of acyclovir-sensitive wild type HSV in Vero cells under acyclovir-treatment. The development of resistance was monitored more adequately by counting the number of acyclovir-resistant viruses in 10,000 plaque forming units than by the conventional susceptibility assay. The resistance increased with the proportion of thymidine kinase-deficient (TK(-)) viruses, when the susceptibilities of acyclovir-treated HSV population to 5'-iodo-2'deoxyuridine and phosphonoacetic acid were examined. The increased resistance was due to the increased proportion of acyclovir-resistant virus but not intermediately resistant virus. Infection with mixtures of TK(-) and acyclovir-sensitive strains rendered TK(-) sensitive to acyclovir, and virus yields were reduced to the levels of acyclovir-sensitive virus in Vero cells. Their yield reduction depended on the proportion of acyclovir-sensitive viruses and induction of TK activity. This reduction in virus yields of the mixture of TK(-) and acyclovir-sensitive strains was confirmed by acyclovir treatment in the skin of mice with cutaneous infection. Acyclovir treatment combined with superinfection of acyclovir-sensitive virus delayed the development of herpetic skin lesions due to acyclovir-resistant virus and reduced virus yields in the infected skin. Acyclovir-sensitive virus plays an important role in suppressing the generation and replication of acyclovir-resistant virus during acyclovir therapy.
authors.affiliation: Department of Virology, Toyama Medical and Pharmaceutical University, Sugitani, Toyama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Okuda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Koma
authors.initials: K
authors.lastname: Matsuo
authors.forename: Mariko
authors.initials: M
authors.lastname: Honda
authors.forename: Michihito
authors.initials: M
authors.lastname: Niimura
authors.forename: Kimiyasu
authors.initials: K
authors.lastname: Shiraki
mesh_terms: D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D005260:Female; D006561:Herpes Simplex / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007065:Idoxuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010746:Phosphonoacetic Acid / Q000494:pharmacology; D012692:Serial Passage; D013937:Thymidine Kinase / Q000172:deficiency / Q000378:metabolism; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C029954:5'-deoxy-5'-iodouridine; D013937:Thymidine Kinase; D007065:Idoxuridine; D010746:Phosphonoacetic Acid; D000212:Acyclovir