Oseltamivir-Resistant Pandemic A/H1N1 Virus Is as Virulent as Its Wild-Type Counterpart in Mice and Ferrets

PLoS Pathogens

Marie-Ève Hamelin¹  Yacine Abed¹  Guy Boivin¹  Mariana Baz¹  Corey Mallett²  Nathalie Bellerose²  Martin Plante²  Édith Beaulieu²  Philippe Joubert³  Christian Couture³  Gregg Schumer⁴  Gary P. Kobinger⁴ 

[1] CHUQ-CHUL Research Center in Infectious Diseases and Laval University, Québec City, Québec, Canada;GlaxoSmithKline Biologicals, Laval, Québec, Canada;Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada;National Microbiology Laboratory, Winnipeg, Manitoba, Canada

关键词: Ferrets;    Viral replication;    Inflammation;    Influenza viruses;    Microbial mutation;    Mouse models;    Respiratory infections;    Influenza;   

DOI  :  10.1371/journal.ppat.1001015

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY