Amphotericin B Increases Influenza A Virus Infection by Preventing IFITM3-Mediated Restriction

Lin, Tsai-Yu; Chin, Christopher R.; Everitt, Aaron R.; Clare, Simon; Perreira, Jill M.; Savidis, George; Aker, Aaron M.; John, Sinu P.; Sarlah, David; Carreira, Erick M.; Elledge, Stephen J.; Kellam, Paul; Brass, Abraham L.

Several efforts have recently investigated the mechanism of IFITM-mediated restriction. For example, it has been reported that the IFITMs decrease membrane fluidity and block viral-envelope-induced hemifusion, the latter conclusion predicated on the alleviation of an IFITM block to cell-to-cell fusion by oleic acid . Moreover, it has been postulated that the IFITMs inhibit VSV-g-mediated fusion by disrupting normal lipid trafficking, resulting in elevated levels of cholesterol in the late endosomal and lysosomal membranes (Amini-Bavil-Olyaee et al., 2013) . This last observation may arise from a direct interaction between the IM2 domains of IFITM1, IFITM2, and IFITM3 and the endocytic trafficking protein vesicle-associated membrane protein A (VAPA). IFITM binding to VAPA may interfere with the interaction of VAPA with oxysterol binding protein (OSBP), a known regulator of cholesterol trafficking (Wyles et al., 2002) . Therefore, IFITMs are envisioned to compete with OSBP for binding to VAPA, producing elevated levels of cholesterol that block viral fusion.