Abstract
BackgroundAmong Influenza neuraminidase inhibitors (NAIs), oseltamivir corresponds to the most widely used agent to treat influenza disease. However since 2001, several cases of resistance to NAIs have been reported for circulating seasonal A(H1N1) Influenza viruses. A direct resistance mechanism may be invoked, involving critical mutations in the viral NA gene that prevent the drug binding to its target. Same phenomenon is reported for adamantanes drugs and mutations in the M2 channel protein gene of Influenza viruses.MethodsReverse-Transcription/Restriction Fragment Length Polymorphism (RT-PCR/RFLP) method, phenotypic testing for oseltamivir resistance, and sequencing of NA, HA and M2 genes were used in this study. Phylogenetic analyses were performed using BioEdit and Mega 5 softwares for alignment of sequences and phylogenetic trees building respectively.ResultsUsing a simple RT-PCR/RFLP method, we found that the 86 seasonal A(H1N1) isolates from 2008 bear the oseltamivir resistance-associated mutation (H274Y) in the NA gene. In contrast all isolates isolated in Senegal in 2007 were sensitive to oseltamivir. These results were first confirmed by finding high IC50 values using a phenotypic testing for oseltamivir resistance, and secondly by sequencing the whole NA gene. Regarding M2 gene, no mutation associated to adamantanes resistance was characterized of the isolates.ConclusionsThe present work provides evidence of circulation of drug-resistant seasonal A(H1N1) viruses during the 2008 influenza season (July to September) in Senegal. The results are in favor of multiple introductions of oseltamivir resistant viruses (ORV) A(H1N1) in Senegal.Phylogenetic analyses of isolates with complete sequences of N1 and HA1 genes showed that they belong to clade 2B and suggest sequential introductions in Africa.
Highlights
Among Influenza neuraminidase inhibitors (NAIs), oseltamivir corresponds to the most widely used agent to treat influenza disease
This suggests a high frequency of the H274Y mutation in the N1 gene and a potential resistance to oseltamivir of the studied viruses
Even if some studies supported that oseltamivir resistance is low in patients treated with oseltamivir [23], two previous studies in Japan revealed that oseltamivir resistance emerged in 18% and 16% of treated Japanese children with influenza virus A(H3N2) and A(H1N1) infection respectively [24,25]
Summary
Among Influenza neuraminidase inhibitors (NAIs), oseltamivir corresponds to the most widely used agent to treat influenza disease. An important progress in the treatment of influenza during the past decade has been the development of potent, selective inhibitors of the viral neuraminidase (NA) enzyme. This was especially achieved through the structure-based design of carboxylic sialic acid analogues interacting with the NA active site, a highly conserved site in both influenza A and B viruses [1,2]. The major event of the 2007-2008 influenza season in Europe was the emergence of oseltamivir-resistant seasonal A(H1N1) viruses. The overall frequency of oseltamivir resistance in A(H1N1) viruses from Europe was 25%, with variation between countries; Norway detecting the highest proportion (67%), and others have detected proportions as low as 2%, e.g in Spain [9]. Given that the predominant subtype of influenza virus circulating in Senegal during the 2008 season (from July to October) was seasonal A (H1N1), we used these isolates to test whether the spread of oseltamivir-resistant variants may have reached countries in the inter-tropical areas of Africa
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