IFITM3 inhibits influenza A virus infection by preventing cytosolic entry.

Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Charlestown, Massachusetts, United States of America.
PLoS Pathogens (Impact Factor: 8.06). 10/2011; 7(10):e1002337. DOI: 10.1371/journal.ppat.1002337
Source: PubMed

ABSTRACT To replicate, viruses must gain access to the host cell's resources. Interferon (IFN) regulates the actions of a large complement of interferon effector genes (IEGs) that prevent viral replication. The interferon inducible transmembrane protein family members, IFITM1, 2 and 3, are IEGs required for inhibition of influenza A virus, dengue virus, and West Nile virus replication in vitro. Here we report that IFN prevents emergence of viral genomes from the endosomal pathway, and that IFITM3 is both necessary and sufficient for this function. Notably, viral pseudoparticles were inhibited from transferring their contents into the host cell cytosol by IFN, and IFITM3 was required and sufficient for this action. We further demonstrate that IFN expands Rab7 and LAMP1-containing structures, and that IFITM3 overexpression is sufficient for this phenotype. Moreover, IFITM3 partially resides in late endosomal and lysosomal structures, placing it in the path of invading viruses. Collectively our data are consistent with the prediction that viruses that fuse in the late endosomes or lysosomes are vulnerable to IFITM3's actions, while viruses that enter at the cell surface or in the early endosomes may avoid inhibition. Multiple viruses enter host cells through the late endocytic pathway, and many of these invaders are attenuated by IFN. Therefore these findings are likely to have significance for the intrinsic immune system's neutralization of a diverse array of threats.

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    ABSTRACT: Animal cells use a wide variety of mechanisms to slow or prevent replication of viruses. These mechanisms are usually mediated by antiviral proteins whose expression and activities can be constitutive but are frequently amplified by interferon induction. Among these interferon-stimulated proteins, members of the IFITM (interferon-induced transmembrane) family are unique because they prevent infection before a virus can traverse the lipid bilayer of the cell. At least three human IFITM proteins-IFITM1, IFITM2, and IFITM3-have antiviral activities. These activities limit infection in cultured cells by many viruses, including dengue virus, Ebola virus, influenza A virus, severe acute respiratory syndrome coronavirus, and West Nile virus. Murine Ifitm3 controls influenza A virus infection in vivo, and polymorphisms in human IFITM3 correlate with the severity of both seasonal and highly pathogenic avian influenza virus. Here we review the discovery and characterization of the IFITM proteins, describe the spectrum of their antiviral activities, and discuss potential mechanisms underlying these effects.
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    ABSTRACT: The interferon-induced transmembrane (IFITM) proteins protect cells from diverse virus infections by inhibiting virus-cell fusion. IFITM proteins also inhibit HIV-1 replication through mechanisms only partially understood. We show that when expressed in uninfected lymphocytes, IFITM proteins exert protective effects during cell-free virus infection, but this restriction can be overcome upon HIV-1 cell-to-cell spread. However, when present in virus-producing lymphocytes, IFITM proteins colocalize with viral Env and Gag proteins and incorporate into nascent HIV-1 virions to limit entry into new target cells. IFITM in viral membranes is associated with impaired virion fusion, offering additional and more potent defense against virus spread. Thus, IFITM proteins act additively in both productively infected cells and uninfected target cells to inhibit HIV-1 spread, potentially conferring these proteins with greater breadth and potency against enveloped viruses. Copyright © 2014 Elsevier Inc. All rights reserved.

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