Abstract
The neuraminidase inhibitor oseltamivir is currently used for treatment of patients infected with the pandemic A/H1N1 (pH1N1) influenza virus, although drug-resistant mutants can emerge rapidly and possibly be transmitted. We describe the characteristics of a pair of oseltamivir-resistant and oseltamivir-susceptible pH1N1 clinical isolates that differed by a single change (H274Y) in the neuraminidase protein. Viral fitness of pH1N1 isolates was assessed in vitro by determining replication kinetics in MDCK α2,6 cells and in vivo by performing experimental infections of BALB/c mice and ferrets. Despite slightly reduced propagation of the mutant isolate in vitro during the first 24 h, the wild-type (WT) and mutant resistant viruses induced similar maximum weight loss in mice and ferrets with an identical pyrexic response in ferrets (AUC of 233.9 and 233.2, P = 0.5156). Similarly, comparable titers were obtained for the WT and the mutant strains on days 1, 3, 6 and 9 post-infection in mouse lungs and on days 1–7 in ferret nasal washes. A more important perivascular (day 6) and pleural (days 6 and 12) inflammation was noted in the lungs of mice infected with the H274Y mutant, which correlated with increased pulmonary levels of IL-6 and KC. Such increased levels of IL-6 were also observed in lymph nodes of ferrets infected with the mutant strain. Furthermore, the H274Y mutant strain was transmitted to ferrets. In conclusion, viral fitness of the H274Y pH1N1 isolate is not substantially altered and has the potential to induce severe disease and to disseminate.
Highlights
The novel influenza A (H1N1) virus was initially detected in Mexico and California in April 2009 and officially became the first pandemic influenza virus of the 21st century on June 11, 2009 [1,2]
During the 2009 pandemic of the novel A/H1N1 virus, the World Health Organization recommended oseltamivir as first-line agent for treatment of patients with severe infections leading to hospitalization and for those with underlying diseases predisposing to pulmonary complications
We characterized the fitness of a pair of oseltamivirsusceptible and oseltamivir-resistant strains emerging from the same familial cluster and that differed by only a single change (H274Y) in the neuraminidase protein
Summary
The novel influenza A (H1N1) virus was initially detected in Mexico and California in April 2009 and officially became the first pandemic influenza virus of the 21st century on June 11, 2009 [1,2]. During the 2008–09 influenza season, almost all characterized influenza A/ Brisbane/59/2007-like (H1N1) strains from North America and Europe were resistant to oseltamivir due to a H274Y (N2 numbering) mutation in the neuraminidase (NA) gene [12,13,14]. The sudden and large dissemination of this mutant A/H1N1 virus occurred in the apparent absence of antiviral pressure suggesting that it had no impairment in viral fitness. This drug resistance mutation has been reported in some A/H5N1 viruses [15,16] and, more recently, in several pH1N1 strains recovered from both immunocompromised and immunocompetent subject [17,18,19,20]. We describe the in vitro and in vivo replicative characteristics of the drug-resistant and wild-type (WT) viruses isolated from this outbreak
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