mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3

• DOI: 10.1073/pnas.1811892115
• Publication Date: 2018-10-09T15:50:07Z
• Authors: Guoli Shi; Stosh Ozog; Bruce E. Torbett; Alex A. Compton
• Keywords: Sirolimus; 0301 basic medicine; 0303 health sciences; Multidisciplinary; TOR Serine-Threonine Kinases; Membrane Proteins; RNA-Binding Proteins; Endosomes; Virus Internalization; Antiviral Agents; 7. Clean energy; Cell Line; 3. Good health; Protein Transport; 03 medical and health sciences; HEK293 Cells; PNAS Plus; Virus Diseases; Cell Line, Tumor; Host-Pathogen Interactions; Humans; HeLa Cells

SignificanceGene delivery by virus-like particles holds enormous therapeutic potential to correct inherited genetic disorders and to prevent infectious disease. However, cells express antiviral factors that prevent virus infection and, consequently, limit the success of gene therapy. Here, we reveal the mechanism by which the drug rapamycin improves lentivirus-mediated gene delivery. Rapamycin treatment led to degradation of IFITM3, a broad and potent antiviral protein which inhibits virus entry into cells. IFITM3 is selectively cleared from endosomes, the sites where viral and cellular membranes fuse, and is sorted for disposal in lysosomes. While revealing an immunosuppressive function with clinical benefits, we caution that rapamycin use in humans may facilitate infection by pathogenic viruses like Influenza A virus.