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Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.

Hamelin ME, Baz M, Abed Y, Couture C, Joubert P, Beaulieu E, Bellerose N, Plante M, Mallett C, Schumer G, Kobinger GP, Boivin G - PLoS Pathog. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CHUQ-CHUL Research Center in Infectious Diseases and Laval University, Québec City, Québec, Canada.

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 alpha2,6 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.

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Related in: MedlinePlus

Body temperature of ferrets infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Body temperatures were recorded by implanted thermometers during 14 days post-inoculation in groups of 4–5 ferrets infected with WT (A/Québec/147023/2009) or oseltamivir-resistant H274Y mutant (A/Québec/147365/2009) pH1N1 isolates.
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ppat-1001015-g006: Body temperature of ferrets infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Body temperatures were recorded by implanted thermometers during 14 days post-inoculation in groups of 4–5 ferrets infected with WT (A/Québec/147023/2009) or oseltamivir-resistant H274Y mutant (A/Québec/147365/2009) pH1N1 isolates.

Mentions: Intranasal inoculation of ferrets with the WT and H274Y mutant pH1N1 isolates resulted in a strong anti-A/California/07/2009 serum antibody response on day 14 (hemagglutination inhibition reciprocal geometric mean titers went from <20 to 4208 and from <20 to 3135, respectively). Notably, all ferrets had preexisting HI antibodies against seasonal A/H1N1 (A/Brisbane/59/07) but titers were similar in the two groups of ferrets pre- and post-infection (Table S1). A pyrexic response was seen between days 2 and 8 post-inoculation (Figure 6). Interestingly, temperature curves were biphasic with a major peak on days 2–3 and another lower peak on days 5–6 in both groups of ferrets. The area under the curve (AUC) of temperatures over the course of the 14-day experiment was similar for both groups of ferrets i.e. 233.9±0.5787 for the WT and 233.2±0.8669 for the H274Y mutant (P = 0.5156). Also, the mean percentage of body weight loss over time was not significantly different in animals infected with the WT or the H274Y mutant virus (Figure S4). The maximum weight loss (day 7 and day 3) was 7.54% and 4.15% for the WT and H274Y mutant viruses, respectively (P = 0.0515). By the end of the 14-day observation period, the ferrets had returned to their initial weight with no mortality.


Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.

Hamelin ME, Baz M, Abed Y, Couture C, Joubert P, Beaulieu E, Bellerose N, Plante M, Mallett C, Schumer G, Kobinger GP, Boivin G - PLoS Pathog. (2010)

Body temperature of ferrets infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Body temperatures were recorded by implanted thermometers during 14 days post-inoculation in groups of 4–5 ferrets infected with WT (A/Québec/147023/2009) or oseltamivir-resistant H274Y mutant (A/Québec/147365/2009) pH1N1 isolates.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908621&req=5

ppat-1001015-g006: Body temperature of ferrets infected with wild-type (WT) or H274Y mutant isolates of pH1N1.Body temperatures were recorded by implanted thermometers during 14 days post-inoculation in groups of 4–5 ferrets infected with WT (A/Québec/147023/2009) or oseltamivir-resistant H274Y mutant (A/Québec/147365/2009) pH1N1 isolates.
Mentions: Intranasal inoculation of ferrets with the WT and H274Y mutant pH1N1 isolates resulted in a strong anti-A/California/07/2009 serum antibody response on day 14 (hemagglutination inhibition reciprocal geometric mean titers went from <20 to 4208 and from <20 to 3135, respectively). Notably, all ferrets had preexisting HI antibodies against seasonal A/H1N1 (A/Brisbane/59/07) but titers were similar in the two groups of ferrets pre- and post-infection (Table S1). A pyrexic response was seen between days 2 and 8 post-inoculation (Figure 6). Interestingly, temperature curves were biphasic with a major peak on days 2–3 and another lower peak on days 5–6 in both groups of ferrets. The area under the curve (AUC) of temperatures over the course of the 14-day experiment was similar for both groups of ferrets i.e. 233.9±0.5787 for the WT and 233.2±0.8669 for the H274Y mutant (P = 0.5156). Also, the mean percentage of body weight loss over time was not significantly different in animals infected with the WT or the H274Y mutant virus (Figure S4). The maximum weight loss (day 7 and day 3) was 7.54% and 4.15% for the WT and H274Y mutant viruses, respectively (P = 0.0515). By the end of the 14-day observation period, the ferrets had returned to their initial weight with no mortality.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CHUQ-CHUL Research Center in Infectious Diseases and Laval University, Québec City, Québec, Canada.

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 alpha2,6 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.

Show MeSH
Related in: MedlinePlus