title: Targeting Importin-α7 as a Therapeutic Approach against Pandemic Influenza Viruses.
abstract: Viral drug resistance is believed to be less likely to occur if compounds are directed against cellular rather than viral proteins. In this study, we analyzed the feasibility of a crucial viral replication factor, namely, importin-α7, as a cellular drug target to combat pandemic influenza viruses. Surprisingly, only five viral lung-to-lung passages were required to achieve 100% lethality in importin-α7⁻/⁻ mice that otherwise are resistant. Viral escape from importin-α7 requirement was mediated by five mutations in the viral ribonucleoprotein complex and the surface glycoproteins. Moreover, the importin-α7⁻/⁻ mouse-adapted strain became even more virulent for wild-type mice than the parental strain. These studies show that targeting host proteins may still result in viral escape by alternative pathways, eventually giving rise to even more virulent virus strains. Thus, therapeutic intervention strategies should consider a multitarget approach to reduce viral drug resistance. IMPORTANCE Here, we investigated the long-standing hypothesis based on in vitro studies that viral drug resistance occurrence is less likely if compounds are directed against cellular rather than viral proteins. Here, we challenged this hypothesis by analyzing, in an in vivo animal model, the feasibility of targeting the cellular factor importin-α7, which is crucial for human influenza virus replication and pathogenesis, as an efficient antiviral strategy against pandemic influenza viruses. In summary, our studies suggest that resistance against cellular factors is possible in vivo, and the emergence of even more virulent viral escape variants calls for particular caution. Thus, therapeutic intervention strategies should consider a multitarget approach using compounds against viral as well as cellular factors to reduce the risk of viral drug resistance and potentially increased virulence.
authors.forename: Patricia
authors.initials: P
authors.lastname: Resa-Infante
authors.forename: Duncan
authors.initials: D
authors.lastname: Paterson
authors.forename: Jaume
authors.initials: J
authors.lastname: Bonet
authors.forename: Anna
authors.initials: A
authors.lastname: Otte
authors.forename: Baldo
authors.initials: B
authors.lastname: Oliva
authors.forename: Ervin
authors.initials: E
authors.lastname: Fodor
authors.forename: Gülsah
authors.initials: G
authors.lastname: Gabriel
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering; D037521:Virulence Factors / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics; D028901:alpha Karyopherins / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; C558725:KPNA6 protein, mouse; D034741:RNA, Small Interfering; D037521:Virulence Factors; D028901:alpha Karyopherins