title: In vitro and in vivo protection against the highly pathogenic H5N1 influenza virus by an antisense phosphorothioate oligonucleotide.
abstract: BACKGROUND
  Current vaccination strategies and antiviral drugs only provide limited protection against influenza virus infection. In this study, we investigated the use of a novel antisense oligonucleotide (named IV-AS), which is specific for the 5'-terminal conserved sequence found in all eight viral RNA segments of influenza A virus.
  
  
  METHODS
  The activity of IV-AS was monitored both in vitro, in Madin-Darby canine kidney (MDCK) cells, and in vivo using a mouse model. IV-AS was given intranasally to H5N1-infected mice once daily for 6 days starting 6 h after infection. A three-base mismatch of IV-AS was used as a control.
  
  
  RESULTS
  IV-AS inhibited influenza virus A induced cytopathic effects in MDCK cells with the 50% effective concentration (EC50) ranging from 2.2 to 4.4 microM. IV-AS was effective against H5N1 virus in preventing death, lessening weight reduction, inhibiting lung consolidation and reducing lung virus titres. Dosages of 40 and 60 mg/kg/day provided 40% and 60% survival rates and prolonged mean survival days in comparison with the infected control group (P<0.05). The lung index in mice treated with IV-AS, at a dose of 20, 40 or 60 mg/kg/day, had been inhibited on day 4 or 6 (P<0.05 or P<0.01); virus titres in lung had declined to 2.42, 1.51 and 1.54 log10 TCID50/g of lung, respectively, whereas the yields in the infected control mice were 6.00 log10 TCID50/g of lung.
  
  
  CONCLUSIONS
  Our results suggest that the 5'-terminal conserved region of influenza A virus RNA segments can be targeted using antisense technology; therefore, IV-AS is a potential drug for prophylaxis and control of influenza virus infections.
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing 100850, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Duan
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ru-Xian
authors.initials: RX
authors.lastname: Lin
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Xian-Zhu
authors.initials: XZ
authors.lastname: Xia
authors.forename: Sheng-Qi
authors.initials: SQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D054735:Phosphorothioate Oligonucleotides / Q000009:adverse effects / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
chemical_list: D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides