Enhanced Mammalian Transmissibility of Seasonal Influenza A/H1N1 Viruses Encoding an Oseltamivir-Resistant Neuraminidase

被引:41
作者
Bouvier, Nicole M. [1 ,2 ]
Rahmat, Saad [2 ]
Pica, Natalie [2 ]
机构
[1] Mt Sinai Sch Med, Div Infect Dis, New York, NY USA
[2] Mt Sinai Sch Med, Dept Microbiol, New York, NY USA
关键词
IN-VITRO; A VIRUS; GUINEA-PIG; H1N1; PATHOGENESIS; MODEL; EFFICIENCY; INFECTION; MUTATION; FERRET;
D O I
10.1128/JVI.07242-12
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Between 2007 and 2009, oseltamivir resistance developed among seasonal influenza A/H1N1 (sH1N1) virus isolates at an exponential rate, without a corresponding increase in oseltamivir usage. We hypothesized that the oseltamivir-resistant neuraminidase (NA), in addition to being relatively insusceptible to the antiviral effect of oseltamivir, might confer an additional fitness advantage on these viruses by enhancing their transmission efficiency among humans. Here we demonstrate that an oseltamivir-resistant clinical isolate, an A/Brisbane/59/2007(H1N1)-like virus isolated in New York State in 2008, transmits more efficiently among guinea pigs than does a highly similar, contemporaneous oseltamivir-sensitive isolate. With reverse genetics reassortants and point mutants of the two clinical isolates, we further show that expression of the oseltamivir-resistant NA in the context of viral proteins from the oseltamivir-sensitive virus (a 7:1 reassortant) is sufficient to enhance transmissibility. In the guinea pig model, the NA is the critical determinant of transmission efficiency between oseltamivir-sensitive and -resistant Brisbane/59-like sH1N1 viruses, independent of concurrent drift mutations that occurred in other gene products. Our data suggest that the oseltamivir-resistant NA (specifically, one or both of the companion mutations, H275Y and D354G) may have allowed resistant Brisbane/59-like viruses to outtransmit sensitive isolates. These data provide in vivo evidence of an evolutionary mechanism that would explain the rapidity with which oseltamivir resistance achieved fixation among sH1N1 isolates in the human reservoir.
引用
收藏
页码:7268 / 7279
页数:12
相关论文
共 57 条
[1]  
[Anonymous], 2009, 2008 2009 INFL SEAS
[2]   Characterization of drug-resistant recombinant influenza A/H1N1 viruses selected in vitro with peramivir and zanamivir [J].
Baz, Mariana ;
Abed, Yacine ;
Boivin, Guy .
ANTIVIRAL RESEARCH, 2007, 74 (02) :159-162
[3]   Effect of the Neuraminidase Mutation H274Y Conferring Resistance to Oseltamivir on the Replicative Capacity and Virulence of Old and Recent Human Influenza A(H1N1) Viruses [J].
Baz, Mariana ;
Abed, Yacine ;
Simon, Philippe ;
Hamelin, Marie-Eve ;
Boivin, Guy .
JOURNAL OF INFECTIOUS DISEASES, 2010, 201 (05) :740-745
[4]   Influenza Virus Respiratory Infection and Transmission Following Ocular Inoculation in Ferrets [J].
Belser, Jessica A. ;
Gustin, Kortney M. ;
Maines, Taronna R. ;
Pantin-Jackwood, Mary J. ;
Katz, Jacqueline M. ;
Tumpey, Terrence M. .
PLOS PATHOGENS, 2012, 8 (03) :e1002569
[5]   Influenza A virus transmission: contributing factors and clinical implications [J].
Belser, Jessica A. ;
Maines, Taronna R. ;
Tumpey, Terrence M. ;
Katz, Jacqueline M. .
EXPERT REVIEWS IN MOLECULAR MEDICINE, 2010, 12
[6]   Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance [J].
Bloom, Jesse D. ;
Gong, Lizhi Ian ;
Baltimore, David .
SCIENCE, 2010, 328 (5983) :1272-1275
[7]   Oseltamivir-Resistant Influenza A Viruses Are Transmitted Efficiently among Guinea Pigs by Direct Contact but Not by Aerosol [J].
Bouvier, Nicole M. ;
Lowen, Anice C. ;
Palese, Peter .
JOURNAL OF VIROLOGY, 2008, 82 (20) :10052-10058
[8]   Animal Models for Influenza Virus Pathogenesis and Transmission [J].
Bouvier, Nicole M. ;
Lowen, Anice C. .
VIRUSES-BASEL, 2010, 2 (08) :1530-1563
[9]   Time lines of infection and disease in human influenza: A review of volunteer challenge studies [J].
Carrat, Fabrice ;
Vergu, Elisabeta ;
Ferguson, Neil M. ;
Lemaitre, Magali ;
Cauchemez, Simon ;
Leach, Steve ;
Valleron, Alain-Jacques .
AMERICAN JOURNAL OF EPIDEMIOLOGY, 2008, 167 (07) :775-785
[10]   Oseltamivir-resistant influenza A(H1N1) viruses in south of France, 200712009 [J].
Casalegno, Jean-Sebastien ;
Bouscambert-Duchamp, Maude ;
Caro, Valerie ;
Schuffenecker, Isabelle ;
Sabatier, Murielle ;
Traversier, Aurelien ;
Valette, Martine ;
Lina, Bruno ;
Ferraris, Olivier ;
Escuret, Vanessa .
ANTIVIRAL RESEARCH, 2010, 87 (02) :242-248