title: Identification and characterization of acyclovir-resistant clinical HSV-1 isolates from children.
abstract: BACKGROUND
  The occurrence of herpes simplex virus (HSV) with acyclovir (ACV) resistance is a cause for concern due to the frequent use of ACV for treatment, suppressive therapy, and prophylaxis of HSV infection. Although HSV infection is prevalent among children, very little is known about the drug susceptibility of HSV circulating in this patient population.
  
  
  OBJECTIVE
  To determine the status of ACV resistant HSV-1 among children.
  
  
  METHODS
  A reporter cell-based HSV infection assay (mVILA) was developed to conveniently evaluate the ACV susceptibility of HSV-1 clinical strains and used to analyze 68 HSV-1 primary isolates from oral lesions in children.
  
  
  RESULTS
  Compared with PRA, mVILA is easier to perform. Using mVILA, HSV-1 isolates C106, C153, and C174 were found completely resistant to ACV, with a greater than 100-fold increase in IC50s. Sequence analysis of thymidine kinase (TK) and DNA polymerase (DNA POL) genes identified 11 new mutations. Structural modeling of the TK and DNA POL proteins suggested structural changes that might alter their interactions with ACV and ACV triphosphate, respectively. The insertion of a single G in a seven-guanine homopolymeric repeat sequence generated a truncated TK protein in C106.
  
  
  CONCLUSIONS
  This study provides preliminary data on the ACV susceptibility status of HSV-1 in children. The prevalence rate of ACV-resistant HSV-1 in children was higher than predicted. Moreover, multiple mechanisms leading to the resistance were identified. These results suggest that new anti-herpetics with different working mechanisms should be valuable.
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Qinchang
authors.initials: Q
authors.lastname: Zhu
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
mesh_terms: D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D013937:Thymidine Kinase / Q000737:chemistry / Q000235:genetics; D014709:Vero Cells; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D000212:Acyclovir