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Cell Rep. 2013 Nov 27;5(4):895-908. doi: 10.1016/j.celrep.2013.10.033. Epub 2013 Nov 21.

Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction.

Author information

1
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
2
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA; Ragon Institute of Massachusetts General Hospital, M.I.T. and Harvard University, Charlestown, MA 02129, USA.
3
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
4
Ragon Institute of Massachusetts General Hospital, M.I.T. and Harvard University, Charlestown, MA 02129, USA.
5
Eidgenössische Technische Hochschule, Deutsch English Department of Chemistry and Applied Biosciences, 8093 Zurich, Switzerland.
6
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA.
7
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; MRC/UCL Centre for Medical Molecular Virology, Division of Infection & Immunity, University College London, Gower Street, London W1CE 6BT, UK.
8
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA; Ragon Institute of Massachusetts General Hospital, M.I.T. and Harvard University, Charlestown, MA 02129, USA. Electronic address: abraham.brass@umassmed.edu.

Abstract

The IFITMs inhibit influenza A virus (IAV) replication in vitro and in vivo. Here, we establish that the antimycotic heptaen, amphotericin B (AmphoB), prevents IFITM3-mediated restriction of IAV, thereby increasing viral replication. Consistent with its neutralization of IFITM3, a clinical preparation of AmphoB, AmBisome, reduces the majority of interferon's protective effect against IAV in vitro. Mechanistic studies reveal that IFITM1 decreases host-membrane fluidity, suggesting both a possible mechanism for IFITM-mediated restriction and its negation by AmphoB. Notably, we reveal that mice treated with AmBisome succumbed to a normally mild IAV infection, similar to animals deficient in Ifitm3. Therefore, patients receiving antifungal therapy with clinical preparations of AmphoB may be functionally immunocompromised and thus more vulnerable to influenza, as well as other IFITM3-restricted viral infections.

PMID:
24268777
PMCID:
PMC3898084
DOI:
10.1016/j.celrep.2013.10.033
[Indexed for MEDLINE]
Free PMC Article

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