Abstract
Classical antiviral therapies target viral proteins and are consequently subject to resistance. To counteract this limitation, alternative strategies have been developed that target cellular factors. We hypothesized that such an approach could also be useful to identify broad-spectrum antivirals. The influenza A virus was used as a model for its viral diversity and because of the need to develop therapies against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection by different influenza A virus subtypes which would allow the identification of potential antiviral drugs with a broad anti-influenza spectrum of activity. We analyzed the cellular gene expression response to infection with five different human and avian influenza A virus strains and identified 300 genes as differentially expressed between infected and non-infected samples. The most 20 dysregulated genes were used to screen the connectivity map, a database of drug-associated gene expression profiles. Candidate antivirals were then identified by their inverse correlation to the query signature. We hypothesized that such molecules would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified and their effects were tested in vitro on five influenza A strains. Six of the molecules inhibited influenza viral growth. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five out of the eight identified molecules, demonstrating that this strategy could contribute to identifying new broad anti-influenza agents acting on cellular gene expression. The identified infection signature genes, the expression of which are modified upon infection, could encode cellular proteins involved in the viral life cycle. This is the first study showing that gene expression-based screening can be used to identify antivirals. Such an approach could accelerate drug discovery and be extended to other pathogens.
Highlights
Antiviral drug development is currently based on two approaches: i) the conventional approach of inhibiting the activity of a viral enzyme which often leads to the emergence of drug resistant viruses due to viral genomic variability and ii) the more recent approach of targeting cellular factors that are required for viral replication
The virally induced gene-expression signature Influenza infection induces various intracellular signaling cascades and important downstream gene expression host-cell modifications [46]. Despite their host-range restriction that may reflect the better adaptation to host factors [47], all influenza A viruses can infect the same cells in vitro, prompting us to assume that they may hijack common cellular proteins for their own replication
This is the first study to compare the cellular gene expression modifications induced by five different influenza A virus subtypes
Summary
Antiviral drug development is currently based on two approaches: i) the conventional approach of inhibiting the activity of a viral enzyme which often leads to the emergence of drug resistant viruses due to viral genomic variability and ii) the more recent approach of targeting cellular factors that are required for viral replication. The major recognized advantage of targeting a host factor is to limit the development of resistance as the virus cannot replace a missing cellular protein [1]. Such an approach has been used in antiretroviral therapy with the development of a CCR5 antagonist showing promise as an antiHIV drug [2]. The effective in vitro and in vivo inhibition of two different cellular pathways without inducing resistance has been reported, and both are currently undergoing preclinical trials (recently reviewed in [4])
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