Inhibition of influenza A H3N8 virus infections in mice by morpholino oligomers.
New methods to combat influenza A virus (FLUAV) in humans and animals are needed. The H3N8 subtype virus was the cause of the pandemic of 1890 and has recently undergone cross-species transmission from horses to dogs in the USA. In 2007 H3N8 spread to Australia, a continent previously devoid of equine influenza. Here, we show that antisense-peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), delivered by intranasal administration, are able to inhibit the replication of FLUAV A/Eq/Miami/1/63 (H3N8) in mice by over 95% compared to controls. Monitoring of body weight and immune cell infiltrates in the lungs of noninfected mice indicated that PPMO treatment was not toxic at a concentration shown to be effectively antiviral in vivo. In addition, we detected a naturally occurring mutation within the PPMO target site of a viral gene that may be the cause of resistance to one of the two antisense PPMO sequences tested. These data indicate that PPMOs targeting highly conserved regions of FLUAV are promising novel therapeutic candidates.
Lupfer
Christopher
C
Genetics Program, College of Agricultural Science, Oregon State University, Corvallis, OR 97331, USA.
Stein
David A
DA
Mourich
Dan V
DV
Tepper
Samuel E
SE
Iversen
Patrick L
PL
Pastey
Manoj
M
D000281:Administration, Intranasal; D000818:Animals; D001483:Base Sequence; D005260:Female; D005814:Genes, Viral; D053123:Influenza A Virus, H3N8 Subtype / Q000187:drug effects* / Q000235:genetics*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology*; D009976:Orthomyxoviridae Infections / Q000517:prevention & control* / Q000821:virology; D012367:RNA, Viral / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D014758:Viral Core Proteins / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics
D007252:Influenza Vaccines; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D020319:Oligodeoxyribonucleotides, Antisense; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1