Abstract:
:Neuraminidase (NA) inhibitors (NAIs) are widely used antiviral drugs for the treatment of humans with influenza virus infections. There have been widespread reports of NAI resistance among seasonal A(H1N1) viruses, and most have been identified in oseltamivir-exposed patients or those treated with other NAIs. Thus, monitoring and identifying NA markers conferring resistance to NAIs-particularly newly introduced treatments-are critical to the management of viral infections. Therefore, we screened and identified substitutions conferring resistance to laninamivir by enriching random mutations in the NA gene of the 2009 pandemic influenza [A(H1N1)pdm09] virus followed by deep sequencing of the laninamivir-selected variants. After the generation of single mutants possessing each identified mutation, two A(H1N1)pdm09 recombinants possessing novel NA gene substitutions (i.e., D199E and P458T) were shown to exhibit resistance to more than one NAI. Of note, mutants possessing P458T-which is located outside of the catalytic or framework residue of the NA active site-exhibited highly reduced inhibition by all four approved NAIs. Using MDCK cells, we observed that the in vitro viral replication of the two recombinants was lower than that of the wild type (WT). Additionally, in infected mice, decreased mortality and/or mean lung viral titers were observed in mutants compared with the WT. Reverse mutations to the WT were observed in lung homogenate samples from D199E-infected mice after 3 serial passages. Overall, the novel NA substitutions identified could possibly emerge in influenza A(H1N1)pdm09 viruses during laninamivir therapy and the viruses could have altered NAI susceptibility, but the compromised in vitro/in vivo viral fitness may limit viral spreading.IMPORTANCE With the widespread emergence of NAI-resistant influenza virus strains, continuous monitoring of mutations that confer antiviral resistance is needed. Laninamivir is the most recently approved NAI in several countries; few data exist related to the in vitro selection of viral mutations conferring resistance to laninamivir. Thus, we screened and identified substitutions conferring resistance to laninamivir by random mutagenesis of the NA gene of the 2009 pandemic influenza [A(H1N1)pdm09] virus strain followed by deep sequencing of the laninamivir-selected variants. We found several novel substitutions in NA (D199E and P458T) in an A(H1N1)pdm09 background which conferred resistance to NAIs and which had an impact on viral fitness. Our study highlights the importance of continued surveillance for potential antiviral-resistant variants and the development of alternative therapeutics.
journal_name
J Viroljournal_title
Journal of virologyauthors
Lloren KKS,Kwon JJ,Choi WS,Jeong JH,Ahn SJ,Choi YK,Baek YH,Song MSdoi
10.1128/JVI.01825-18subject
Has Abstractpub_date
2019-03-05 00:00:00issue
6eissn
0022-538Xissn
1098-5514pii
JVI.01825-18journal_volume
93pub_type
杂志文章abstract::African swine fever virus induces in convalescent pigs antibodies that neutralized the virus before and after binding to susceptible cells, inhibiting both virus attachment and internalization. A further analysis of the neutralization mechanisms mediated by the different viral proteins showed that antibodies to protei...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.8.5689-5694.1996
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2007-03-01 00:00:00
abstract:UNLABELLED:The genome of nonsegmented negative-strand RNA viruses is tightly embedded within a nucleocapsid made of a nucleoprotein (N) homopolymer. To ensure processive RNA synthesis, the viral polymerase L in complex with its cofactor phosphoprotein (P) binds the nucleocapsid that constitutes the functional template....
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pub_type: 杂志文章
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更新日期:2014-09-01 00:00:00
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pub_type: 杂志文章
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更新日期:2006-07-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.66.7.4233-4241.1992
更新日期:1992-07-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.6.2798-2812.1989
更新日期:1989-06-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.21.1.105-112.1977
更新日期:1977-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2013-08-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.10.6653-6657.1996
更新日期:1996-10-01 00:00:00
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:1998-11-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.2.1629-1634.1997
更新日期:1997-02-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2003-05-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.18.8234-8242.2000
更新日期:2000-09-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.10.4.795-800.1972
更新日期:1972-10-01 00:00:00
abstract::Noroviruses (NoVs) are a leading cause of gastroenteritis worldwide, yet host factors that restrict NoV replication are not well understood. Here, we use a CRISPR activation genome-wide screening to identify host genes that can inhibit murine norovirus (MNoV) replication in human cells. Our screens identified with hig...
journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2018-12-10 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
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更新日期:2015-04-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.00584-06
更新日期:2007-01-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.70.11.7517-7526.1996
更新日期:1996-11-01 00:00:00
abstract::Pathogens such as HIV-1, with their minimalist genomes, must navigate cellular networks and rely on hijacking and manipulating the host machinery for successful replication. Limited overlap of host factors identified as vital for pathogen replication may be explained by considering that pathogens target, rather than s...
journal_title:Journal of virology
pub_type: 杂志文章,评审
doi:10.1128/JVI.03684-14
更新日期:2015-05-01 00:00:00