title: Alphavirus Restriction by IFITM Proteins.
abstract: Interferon inducible transmembrane proteins (IFITMs) are broad-spectrum antiviral factors. In cell culture the entry of many enveloped viruses, including orthomyxo-, flavi-, and filoviruses, is inhibited by IFITMs, though the mechanism(s) involved remain unclear and may vary between viruses. We demonstrate that Sindbis and Semliki Forest virus (SFV), which both use endocytosis and acid-induced membrane fusion in early endosomes to infect cells, are restricted by the early endosomal IFITM3. The late endosomal IFITM2 is less restrictive and the plasma membrane IFITM1 does not inhibit normal infection by either virus. IFITM3 inhibits release of the SFV capsid into the cytosol, without inhibiting binding, internalization, trafficking to endosomes or low pH-induced conformational changes in the envelope glycoprotein. Infection by SFV fusion at the cell surface was inhibited by IFITM1, but was equally inhibited by IFITM3. Furthermore, an IFITM3 mutant (Y20A) that is localized to the plasma membrane inhibited infection by cell surface fusion more potently than IFITM1. Together, these results indicate that IFITMs, in particular IFITM3, can restrict alphavirus infection by inhibiting viral fusion with cellular membranes. That IFITM3 can restrict SFV infection by fusion at the cell surface equivalently to IFITM1 suggests that IFITM3 has greater antiviral potency against SFV.
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Weston
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Czieso
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: White
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Rachael S
authors.initials: RS
authors.lastname: Wash
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Diaz-Soria
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.|Division of Infection and Immunity, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Marsh
mesh_terms: D000072283:A549 Cells; D018354:Alphavirus Infections / Q000378:metabolism / Q000821:virology; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012672:Semliki forest virus / Q000502:physiology*; D012845:Sindbis Virus / Q000502:physiology*; D053586:Virus Internalization
chemical_list: D000943:Antigens, Differentiation; C080081:IFITM2 protein, human; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C062010:leu-13 antigen
keywords: IFITM; SFV; Semliki Forest virus; alphavirus; interferon inducible transmembrane protein; restriction factor; virus entry; virus-host interaction