tetano
Editor, Senior Moderator
J Virol. 2015 Jun 17. pii: JVI.00583-15. [Epub ahead of print]
[h=1]Targeting importin-α7 as a therapeutic approach against pandemic influenza viruses.[/h] Resa-Infante P[SUP]1[/SUP], Paterson D[SUP]2[/SUP], Bonet J[SUP]3[/SUP], Otte A[SUP]1[/SUP], Oliva B[SUP]3[/SUP], Fodor E[SUP]2[/SUP], Gabriel G[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Viral drug resistance is believed to occur less likely 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 potential cellular drug target to combat pandemic influenza. Surprisingly, only five viral lung-to-lung passages were required to achieve 100% lethality in importin-α7[SUP]-/-[/SUP] mice that are otherwise 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[SUP]-/-[/SUP] mouse-adapted strain became even more virulent for wild-type mice compared to 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 multi-target approach to reduce viral drug resistance.
[h=4]IMPORTANCE:[/h] Here, we investigated the longstanding hypothesis based on in vitro studies that viral drug resistance occurs 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 - that 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 multi-target approach using compounds against viral as well as cellular factors to reduce the risk of viral drug resistance and potentially increased virulence.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26085167 [PubMed - as supplied by publisher]
[h=1]Targeting importin-α7 as a therapeutic approach against pandemic influenza viruses.[/h] Resa-Infante P[SUP]1[/SUP], Paterson D[SUP]2[/SUP], Bonet J[SUP]3[/SUP], Otte A[SUP]1[/SUP], Oliva B[SUP]3[/SUP], Fodor E[SUP]2[/SUP], Gabriel G[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Viral drug resistance is believed to occur less likely 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 potential cellular drug target to combat pandemic influenza. Surprisingly, only five viral lung-to-lung passages were required to achieve 100% lethality in importin-α7[SUP]-/-[/SUP] mice that are otherwise 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[SUP]-/-[/SUP] mouse-adapted strain became even more virulent for wild-type mice compared to 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 multi-target approach to reduce viral drug resistance.
[h=4]IMPORTANCE:[/h] Here, we investigated the longstanding hypothesis based on in vitro studies that viral drug resistance occurs 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 - that 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 multi-target approach using compounds against viral as well as cellular factors to reduce the risk of viral drug resistance and potentially increased virulence.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26085167 [PubMed - as supplied by publisher]