title: In vitro anti-influenza A activity of interferon (IFN)-λ1 combined with IFN-β or oseltamivir carboxylate.
abstract: Influenza viruses, which can cross species barriers and adapt to new hosts, pose a constant potential threat to human health. The influenza pandemic of 2009 highlighted the rapidity with which an influenza virus can spread worldwide. Currently available antivirals have a number of limitations against influenza, and novel antiviral strategies, including novel drugs and drug combinations, are urgently needed. Here, we evaluated the in vitro effects of interferon (IFN)-β, IFN-λ1, oseltamivir carboxylate (a neuraminidase (NA) inhibitor), and combinations of these agents against two seasonal (i.e., H1N1 and H3N2) influenza A viruses. We observed that A/California/04/09 (H1N1) and A/Panama/2007/99 (H3N2) isolates were equally sensitive to the antiviral activity of IFN-β and oseltamivir carboxylate in A549 and Calu-3 cells. In contrast, IFN-λ1 exhibited substantially lower protective potential against the H1N1 strain (64-1030-fold ↓, P<0.05), and was ineffective against H3N2 virus in both cell lines. Three dimensional analysis of drug-drug interactions revealed that IFN-λ1 interacted with IFN-β and oseltamivir carboxylate in an additive or synergistic manner, respectively, to inhibit influenza A virus replication in human airway epithelial cells. Overall, the present study demonstrated that anti-influenza agents with different mechanisms of action (e.g., a NA inhibitor combined with IFN-λ1) exerted a significantly greater (P<0.05) synergistic effect compared to co-treatment with drugs that target the same signaling pathway (i.e., IFN-β plus IFN-λ1) in vitro. Our findings provide support for the combined use of interferon plus oseltamivir as a potential means for treating influenza infections.
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: Natalia.Ilyushina@fda.hhs.gov.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Ilyushina
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D016899:Interferon-beta / Q000494:pharmacology*; D007372:Interferons; D007378:Interleukins / Q000008:administration & dosage*; D053139:Oseltamivir / Q000031:analogs & derivatives* / Q000494:pharmacology; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016899:Interferon-beta; D007372:Interferons; D007378:Interleukins; D053139:Oseltamivir; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C535162:oseltamivir carboxylate
keywords: Combination therapy; IFN-β; IFN-λ; Influenza A virus; Oseltamivir carboxylate