Drug Discovery Opinion

Viruses are economical with their own genetic information, relying on requisition of host cellular proteins to complete their lifecycle. In a study to identify cellular proteins required by the H1N1 influenza virus, collaborators from Howard Hughes Medical Institute, Harvard Medical School, Massachusetts General Hospital, Yale Medical School, and the Wellcome Trust Sanger Institute have now made an unexpected discovery.

The research team set up large arrays of cultured human cells and used siRNA molecules to block expression of individual genes. They then examined the effect of the knockdowns on H1N1 activity by measuring changes in the presence of viral protein on the surface on infected cells. The work identified more than 120 genes which were required to be expressed for H1N1 infectivity but, surprisingly, also identified a class of genes that permitted greater influenza replication when they were blocked.

The proteins encoded by these genes were members of the interferon-inducible transmembrane (IFITM) family, IFITM-1, IFITM-2 and IFITM-3. These IFITMs were known to be produced at low levels in most cells, and at higher levels in cells exposed to immune-stimulating interferon, but their functions were poorly understood. Knockdown of IFITM-3, in particular, increased replication of H1N1 by 5 to 10-fold. Conversely, by over-expressing IFITM-3 the team were able to completely inhibit H1N1 replication.

To the researchers’ surprise, increased expression of IFITMs also blocked the replication of completely different viruses, including strains of West Nile and Dengue viruses. Although the proteins are not effective against all viruses, the discovery could lead to new antiviral therapeutics. Further work is required to elucidate the precise mechanisms by which the IFITMs exert their effects.

The study is published in the early online edition of the journal Cell.

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