Abstract
Influenza viruses are a leading cause of morbidity and mortality worldwide. These air-borne pathogens are able to cross the species barrier, leading to regular seasonal epidemics and sporadic pandemics. Influenza viruses also possess a high genetic variability, which allows for the acquisition of resistance mutations to antivirals. Combination therapies with two or more drugs targeting different mechanisms of viral replication have been considered an advantageous option to not only enhance the effectiveness of the individual treatments, but also reduce the likelihood of resistance emergence. Using an in vitro infection model, we assessed the barrier to viral resistance of a combination therapy with the neuraminidase inhibitor oseltamivir and human interferon lambda against the pandemic H1N1 A/Netherlands/602/2009 (H1N1pdm09) virus. We serially passaged the virus in a cell line derived from human bronchial epithelial cells in the presence or absence of increasing concentrations of oseltamivir alone or oseltamivir plus interferon lambda. While the treatment with oseltamivir alone quickly induced the emergence of antiviral resistance through a single mutation in the neuraminidase gene, the co-administration of interferon lambda delayed the emergence of drug-resistant influenza virus variants. Our results suggest a possible clinical application of interferon lambda in combination with oseltamivir to treat influenza.
Highlights
Influenza is an infectious respiratory disease caused in humans by influenza A (IAV)and influenza B (IBV) viruses
neuraminidase inhibitors (NAIs) provide the front line of defense against IV infection and the response to the influenza pandemic will probably rely on the extensive use of this class of antivirals, combined with other transmission control measures [62]
Since resistant variants can arise either naturally or as a result of drug administration, it is very likely that the use of NAIs on the scale anticipated for the control of pandemic influenza will create a unique selective pressure for the emergence and spread of resistant strains [63]
Summary
Influenza is an infectious respiratory disease caused in humans by influenza A (IAV)and influenza B (IBV) viruses. In the past hundred years, four influenza pandemics occurred, all associated with higher mortality rates than seasonal epidemics [3]. In this time frame, globalization has driven social and economic changes that have enhanced the threat of disease emergence and accelerated the spread of novel strains. Globalization has driven social and economic changes that have enhanced the threat of disease emergence and accelerated the spread of novel strains Due to their error-prone polymerase, IVs rapidly acquire genetic variability that inevitably culminates in the emergence of resistance to antivirals. Even changes in a very small number of amino acid residues in the targeted viral protein can be sufficient to reduce or completely block the efficacy of a drug [4]
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