title: Cationic amphiphilic drugs enhance entry of lentiviral particles pseudotyped with rabies virus glycoprotein into non-neuronal cells.
abstract: Amiodarone and other cationic amphiphilic drugs (CADs) inhibit cell entry by diverse human pathogenic viruses including Filoviruses, Dengue virus and Japanese encephalitis virus. They are thus considered potential broad spectrum antiviral agents. Here we report the unexpected finding that amiodarone and other CADs markedly enhance rabies virus (RABV) glycoprotein- (GP-) mediated cell entry of pseudotyped lentiviruses into non-neuronal cells but not in neuronal cells. Increased cell entry can also be elicited when CADs are added several hours after pseudoviral attachment. Perturbing endosomal processing with phosphoinosite-3-kinase inhibitors wortmannin and LY294002 mimics the effects of CADs on RABV GP-mediated cell entry. Thus, CADs may enhance RABV GP-mediated cell entry of pseudotyped lentiviruses by promoting a late step of the pseudoviral cell entry process, possibly release from an endosomal compartment into the cytosol. In contrast to the pseudotyped lentiviruses, infection by fully infectious RABV was not enhanced by CADs, indicating, that the observed stimulation of RABV GP mediated lentivirus entry also depended on the used lentivirus vector backbone. In conclusion, we show that while CADs inhibit cell entry of diverse viruses they can also have a paradoxical enhancing effect on the ability of a viral glycoprotein to mediate cell entry depending on the cellular and viral context. Although, we show CAD-mediated enhancement of entry only for pseudoviruses, but not fully infectious RABV, the potential to unexpectedly enhance viral entry should be taken into account when considering use of CADs as antiviral agents.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Institute for Molecular Biology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: A.Klintworth@gmx.de.
authors.forename: Anneke
authors.initials: A
authors.lastname: Klintworth
authors.affiliation: German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald, Insel Riems, Germany. Electronic address: Tobias.Nolden@fli.bund.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Nolden
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Institute for Molecular Biology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: Westhaus.Sandra@mh-hannover.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Westhaus
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Institute for Molecular Biology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: Rohrmann.Katrin@mh-hannover.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rohrmann
authors.affiliation: Department of Nephrology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: David.Sascha@mh-hannover.de.
authors.forename: Sascha
authors.initials: S
authors.lastname: David
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: Manns.Michael@mh-hannover.de.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Institute for Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald, Insel Riems, Germany. Electronic address: Stefan.Finke@fli.bund.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Finke
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: Ciesek.Sandra@mh-hannover.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ciesek
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Institute for Molecular Biology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Center for Infection Research (DZIF), Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: vonhahn.thomas@mh-hannover.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002460:Cell Line; D011992:Endosomes / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016086:Lentivirus / Q000187:drug effects*; D011818:Rabies / Q000188:drug therapy / Q000821:virology; D011820:Rabies virus / Q000187:drug effects / Q000502:physiology*; D011941:Receptors, Adrenergic / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*; D014785:Vision, Ocular
chemical_list: D000998:Antiviral Agents; D006023:Glycoproteins; D011941:Receptors, Adrenergic; D014759:Viral Envelope Proteins
keywords: Amiodarone; Endosome; Receptor