Abstract
The Y155H amino acid substitution in the neuraminidase gene (NA) has previously been associated with highly reduced inhibition by neuraminidase inhibitors in the seasonal H1N1 influenza A virus which circulated in humans before the 2009 pandemic. During the 2012/13 epidemic season in Spain, two A(H1N1) pdm09 viruses bearing the specific Y155H substitution in the NA were detected and isolated from two patients diagnosed with severe respiratory syndrome and pneumonia requiring admission to the intensive care unit. Contrary to what was observed in the seasonal A(H1N1) viruses, neither of the Y155H A(H1N1) pdm09 viruses described here showed a phenotype of reduced inhibition by NAIs as determined by the neuraminidase enzyme inhibition assay (MUNANA). High-throughput sequencing of the NA of both Y155H viruses showed that they were composed to >99% of H155 variants. We believe that this report can contribute to a better understanding of the biological significance of amino acid substitutions in the neuraminidase protein with regard to susceptibility of influenza viruses to neuraminidase inhibitors. This is of critical importance for optimal management of influenza disease patients.
Highlights
Antiviral drugs are essential in the treatment of influenza disease, especially for severe cases, and can play a very important role in the response to the early phases of a pandemic, when a suitable vaccine may not be available and may take several months to develop [1,2,3]
NA gene analysis was performed on 47 A(H1N1)pdm09 viruses, 45 of which did not have any mutations associated with reduced inhibition by neuraminidase inhibitors (NAIs)
Two viruses bearing the Y155H substitution were detected. These two viruses had been isolated from two severely ill hospitalised patients who had been diagnosed with severe respiratory syndrome and pneumonia and required admission to the intensive care unit (ICU) (Figure 1 and Table 1)
Summary
Antiviral drugs are essential in the treatment of influenza disease, especially for severe cases, and can play a very important role in the response to the early phases of a pandemic, when a suitable vaccine may not be available and may take several months to develop [1,2,3]. Due to rapid emergence and spread of strains highly resistant to adamantanes, these first generation antiviral drugs targeting the influenza virus M2 protein, have been replaced by neuraminidase inhibitors (NAIs), oseltamivir and zanamivir [4]. Several reports describe oseltamivir-resistant A(H1N1)pdm viruses bearing the H275Y NA substitution, isolated from patients both treated and untreated with NAIs [11,12,13,14,15,16], as well as sporadic clusters of patients who acquired infection with these resistant viruses by human-to-human transmission [13,17,18,19] These reports raise concerns that the prevalence of viruses exhibiting reduced inhibition by NAIs may increase in the future, and monitoring for the emergence of such viruses is an essential part of national and international surveillance and prevention programmes
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