title: Subclinical generation of acyclovir-resistant herpes simplex virus with mutation of homopolymeric guanosine strings during acyclovir therapy.
abstract: BACKGROUND
  Suppressive therapy in patients with genital herpes has been used in Japan since 2006. Susceptibility and resistance of herpes simplex virus (HSV)-2 to acyclovir were examined in genital isolates from patients receiving suppressive therapy and compared with those from those naïve to acyclovir and receiving episodic treatment with acyclovir.
  
  
  OBJECTIVE
  The aim of this study was to analyze the effect of acyclovir use on the susceptibility to acyclovir and analysis of the thymidine kinase gene by acyclovir treatment.
  
  
  METHODS
  Genital HSV isolates were obtained from three patients groups. Susceptibility to acyclovir, the frequency of acyclovir-resistant clones and mutations in the thymidine kinase gene of acyclovir-resistant clones were determined.
  
  
  RESULTS
  Susceptibility to ACV was significantly higher in isolates from patients receiving suppressive therapy than those naïve to acyclovir and receiving episodic treatment, but the frequencies of resistant clones were similar among the three groups. Mutation in guanosine homopolymeric strings (G-string mutation) was significantly more frequent in clones during episodic treatment and suppressive therapy than clones from patients naïve to ACV. The frequency of G-string mutation was significantly less frequent in isolates from patients naïve to ACV than those experienced ACV therapy.
  
  
  CONCLUSIONS
  The frequency of acyclovir-resistant mutants was not increased by episodic and suppressive therapy, but exposure to acyclovir significantly generated G-string mutations, possibly induced by acyclovir. Acyclovir therapy had no substantial effects on the susceptibility of HSV-2 or frequency of resistant virus but did generate subclinical G-string mutants in patients' HSV-2.
authors.affiliation: Department of Virology, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Daikoku
authors.affiliation: Department of Virology, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Tannai
authors.affiliation: Department of Dermatology, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Dermatology, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Onoe
authors.affiliation: Department of Dermatology, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
authors.forename: Koma
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Miyamoto Central Clinic, Kawasaki, Kanagawa 210-0004, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Onoye
authors.affiliation: Mizonokuchi Hospital, School of Medicine, Teikyo University, Kanagawa 213-8507, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Mizonokuchi Hospital, School of Medicine, Teikyo University, Kanagawa 213-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawana
authors.affiliation: Department of Virology, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Division of Maternal Nursing, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Virology, University of Toyama, Toyama 930-0194, Japan. Electronic address: kshiraki@med.u-toyama.ac.jp.
authors.forename: Kimiyasu
authors.initials: K
authors.lastname: Shiraki
mesh_terms: D000212:Acyclovir / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D006151:Guanosine; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013937:Thymidine Kinase / Q000235:genetics*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; D006151:Guanosine; D013937:Thymidine Kinase; D000212:Acyclovir
keywords: Acyclovir; G-string mutation; Herpes simplex virus; Suppressive therapy; Susceptibility; Thymidine kinase