Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt

Abstract

In December 2006, three human specimens were received that were suspected positive for influenza A(H5N1). The specimens were tested using real time PCR. And the presence of A(H5N1) virus was confirmed in 2 patients (16F and 26M), The NA sequence from A(H5N1) positive specimens collected before and after antiviral therapy revealed a mutation (N294S) (N295S according to N1 numbering), previously associated with resistance to oseltamivir. When tested with NA inhibition assays, the two N294S viruses from Egypt exhibited from 57 to 138-fold reduction in susceptibility to oseltamivir, depending on the assay. To our knowledge, this is the first time oseltamivir resistance has been detected in A(H5N1) infecting a human prior to treatment.

A screening assay for neuraminidase inhibitors using neuraminidases N1 and N3 from a baculovirus expression system

“…Blocking neuraminidase action by specific inhibitors prevents the release of newly formed viral particles thus blocking virus spreading to neighbouring cells. The confirmed occurrence of oseltamivir resistant avian influenza virus [5][6][7] …”

Epidemiology, ecology and gene pool of influenza A virus in Egypt: Will Egypt be the epicentre of the next influenza pandemic?

“…61,164,165 The infection is concentrated mainly in the Nile Delta, the influenza epicentre in Egypt. 15,155,166 Fortunately, the vast majority of the Egyptian strains are sensitive to the NA inhibitor oseltamivir 55,61,166,167 which may also explain the lower case-fatality rate of H5N1 in human in Egypt. Nevertheless, the continuous evolution of H5N1 in Egypt makes it a potential candidate for being a possible pandemic virus.…”

Effect of an Asparagine-to-Serine Mutation at Position 294 in Neuraminidase on the Pathogenicity of Highly Pathogenic H5N1 Influenza A Virus

“…Although amino acid substitutions at position 116, 117, 119, 248, or 252 in NA are also thought to reduce the oseltamivir sensitivity of H5N1 viruses (17,18,24), the contribution of these substitutions to the clinical manifestations of H5N1 virus infection remains unknown. In contrast, the NA H274Y and N294S substitutions were detected in fatal cases, even though drug treatment was initiated early (i.e., within 48 h of onset of symptoms) (9), suggesting the potential virulence of H5N1 virus variants with these NA mutations for oseltamivir resistance. In fact, A/Vietnam/1203/04 (H5N1)-based recombinant viruses possessing either the NA H274Y or N294S substitution exhibited lethality similar to that of the wild-type virus in a mouse model (19,22,32).…”