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.

Influenza epidemics perennially result in significant morbidity and mortality, with immunocompromised populations being at particularly high risk. During IAV infection, the viral hemagglutinin (HA) proteins bind to host cell receptors. Upon endocytosis and endosomal acidification, the HA protein undergoes a conformational change leading to fusion of the viral and host membranes. Viral ribonucleoproteins (vRNPs) then enter the cytosol and translocate to the nucleus to commence replication (Medina and García-Sastre, 2011) . IFITM1, IFITM2, and IFITM3 comprise a family of restriction factors that possess broad antiviral activities (Brass et al., 2009; Jiang et al., 2010; Mudhasani et al., 2013) . IFITM3 is most active against IAV and resides in late endosomes and lysosomes, while IFITM1 is located on the cell surface and blocks hepatitis C virus (HCV) and the filoviruses Ebola and Marburg (Feeley et al., 2011; Huang et al., 2011; Wilkins et al., 2013) . The IFITM proteins are members of the CD225 protein superfamily and contain two intramembrane domains (IM1 and IM2), which traverse through the cytosolic-facing leaflet of the lipid bilayer and are joined by a conserved intracellular loop (Yount et al., 2012) . IFITM3 plays a critical role in vivo because Ifitm3 À/À mice succumb to a normally mild IAV infection (Bailey et al., 2012; Everitt et al., 2012) . Furthermore, individuals with a variant of IFITM3 are more likely to suffer a worse course of influenza (Everitt et al., 2012; Zhang et al., 2013) . IFITM3 accounts for 50% to 80% of the in vitro protective effects of interferon (IFN) against IAV and blocks viral particle fusion subsequent to endocytosis, thereby preventing the cytosolic entry and nuclear translocation of vRNPs (Feeley et al., 2011; Huang et al., 2011; Weidner et al., 2010) . The IFITMs thus represent a restriction factor family of growing translational importance that protects the host at the earliest stages of infection (Diamond and Farzan, 2013; Perreira et al., 2013) .