Interferon-induced transmembrane protein 3 blocks fusion of sensitive but not resistant viruses by partitioning into virus-carrying endosomes

Suddala, Krishna C.; Lee, Christine C.; Meraner, Paul; Marin, Mariana; Markosyan, Ruben M.; Desai, Tanay M.; Cohen, Fredric S.; Brass, Abraham L.; Melikyan, Gregory B.

Recent studies have documented the ability of IFITMs to interfere with viral fusion when incorporated into the viral membrane [34, [36] [37] [38] . In fact, IFITMs appear to more potently inhibit HIV-1 infection when incorporated into virions, as compared to their expression in target cells [38] . It is tempting to assume that the same mechanism of the IFITMs' antiviral activity is functional in both cellular and viral membranes, but this notion has not been explicitly tested. The ability of IFITM3 to inhibit IAV fusion irrespective of whether it is expressed in the target or viral membrane (Fig 8B) supports the universal mechanism of IFITM3-mediated restriction that involves altering the properties of lipid membranes, as opposed to interacting with viral or cellular proteins. Our finding that AmphoB rescues the fusion-competence of IAVpp containing IFITM3, similar to its antagonistic effect on the cell-expressed IFITM3 [35] , is also consistent with the common mechanism of virus restriction. Moreover, the static nature of the viral membrane, which is in stark contrast to the highly dynamic cell membranes, supports a direct effect of AmphoB on the viral membrane, perhaps through alterations of membrane fluidity [22, 35] . Thus, virions containing IFITMs in their membranes could provide a tractable model for mechanistic studies of these proteins.