Single H5N1 influenza A neuraminidase mutation develops resistance to oseltamivir due to distorted conformational and drug binding landscape: multiple molecular dynamics analyses

RSC Advances ◽  
2015 ◽  
Vol 5 (14) ◽  
pp. 10849-10861 ◽  
Author(s):  
Ndumiso N. Mhlongo ◽  
Mahmoud E. S. Soliman
Keyword(s):  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Drug Binding ◽  
Single Mutation ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Dynamics Analyses ◽  
Orally Active ◽  
Pathogenic H5n1

Clinical studies showed that a single mutation, I117V, develops severe resistance to oseltamivir, the first orally active influenza A neuraminidase inhibitor, in highly pathogenic H5N1 influenza A viruses.

scholarly journals Neuraminidase Inhibitor Sensitivity and Receptor-Binding Specificity of Cambodian Clade 1 Highly Pathogenic H5N1 Influenza Virus

2011 ◽  
Vol 55 (5) ◽  
pp. 2004-2010 ◽  
Author(s):  
M. Naughtin ◽  
J. C. Dyason ◽  
S. Mardy ◽  
S. Sorn ◽  
M. von Itzstein ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Receptor Binding ◽  
Reverse Genetics ◽  
Binding Specificity ◽  
Neuraminidase Inhibitor ◽  
H5n1 Influenza Virus ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Receptor Binding Specificity ◽  
Pathogenic H5n1

ABSTRACTThe evolution of the highly pathogenic H5N1 influenza virus produces genetic variations that can lead to changes in antiviral susceptibility and in receptor-binding specificity. In countries where the highly pathogenic H5N1 virus is endemic or causes regular epidemics, the surveillance of these changes is important for assessing the pandemic risk. In Cambodia between 2004 and 2010, there have been 26 outbreaks of highly pathogenic H5N1 influenza virus in poultry and 10 reported human cases, 8 of which were fatal. We have observed naturally occurring mutations in hemagglutinin (HA) and neuraminidase (NA) of Cambodian H5N1 viruses that were predicted to alter sensitivity to neuraminidase inhibitors (NAIs) and/or receptor-binding specificity. We tested H5N1 viruses isolated from poultry and humans between 2004 and 2010 for sensitivity to the NAIs oseltamivir (Tamiflu) and zanamivir (Relenza). All viruses were sensitive to both inhibitors; however, we identified a virus with a mildly decreased sensitivity to zanamivir and have predicted that a V149A mutation is responsible. We also identified a virus with a hemagglutinin A134V mutation, present in a subpopulation amplified directly from a human sample. Using reverse genetics, we verified that this mutation is adaptative for human α2,6-linked sialidase receptors. The importance of an ongoing surveillance of H5N1 antigenic variance and genetic drift that may alter receptor binding and sensitivities of H5N1 viruses to NAIs cannot be underestimated while avian influenza remains a pandemic threat.

Characterization of pseudoparticles paired with hemagglutinin and neuraminidase from highly pathogenic H5N1 influenza and avian influenza A (H7N9) viruses

2018 ◽  
Vol 253 ◽  
pp. 20-27 ◽  
Author(s):  
Fengwei Zhang ◽  
Shanshan Wang ◽  
Yanan Wang ◽  
Xuechai Shang ◽  
Hongjuan Zhou ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Influenza A ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Pathogenic H5n1

scholarly journals Are Ducks Contributing to the Endemicity of Highly Pathogenic H5N1 Influenza Virus in Asia?

2005 ◽  
Vol 79 (17) ◽  
pp. 11269-11279 ◽  
Author(s):  
K. M. Sturm-Ramirez ◽  
D. J. Hulse-Post ◽  
E. A. Govorkova ◽  
J. Humberd ◽  
P. Seiler ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Virus Disease ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
Highly Pathogenic ◽  
Main Site ◽  
H5n1 Influenza ◽  
Pathogenic H5n1 ◽  
Virus Isolates

ABSTRACT Wild waterfowl are the natural reservoir of all influenza A viruses, and these viruses are usually nonpathogenic in these birds. However, since late 2002, H5N1 outbreaks in Asia have resulted in mortality among waterfowl in recreational parks, domestic flocks, and wild migratory birds. The evolutionary stasis between influenza virus and its natural host may have been disrupted, prompting us to ask whether waterfowl are resistant to H5N1 influenza virus disease and whether they can still act as a reservoir for these viruses. To better understand the biology of H5N1 viruses in ducks and attempt to answer this question, we inoculated juvenile mallards with 23 different H5N1 influenza viruses isolated in Asia between 2003 and 2004. All virus isolates replicated efficiently in inoculated ducks, and 22 were transmitted to susceptible contacts. Viruses replicated to higher levels in the trachea than in the cloaca of both inoculated and contact birds, suggesting that the digestive tract is not the main site of H5N1 influenza virus replication in ducks and that the fecal-oral route may no longer be the main transmission path. The virus isolates' pathogenicities varied from completely nonpathogenic to highly lethal and were positively correlated with tracheal virus titers. Nevertheless, the eight virus isolates that were nonpathogenic in ducks replicated and transmitted efficiently to naïve contacts, suggesting that highly pathogenic H5N1 viruses causing minimal signs of disease in ducks can propagate silently and efficiently among domestic and wild ducks in Asia and that they represent a serious threat to human and veterinary public health.

H5N1 influenza A viruses from 2002 are highly pathogenic in waterfowl

2004 ◽  
Vol 1263 ◽  
pp. 200-204 ◽  
Author(s):  
Katharine M Sturm-Ramirez ◽  
Trevor Ellis ◽  
Barry Bousfield ◽  
Yi Guan ◽  
Malik Peiris ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
H5n1 Influenza

scholarly journals Differential Contribution of PB1-F2 to the Virulence of Highly Pathogenic H5N1 Influenza A Virus in Mammalian and Avian Species

2011 ◽  
Vol 7 (8) ◽  
pp. e1002186 ◽  
Author(s):  
Mirco Schmolke ◽  
Balaji Manicassamy ◽  
Lindomar Pena ◽  
Troy Sutton ◽  
Rong Hai ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Avian Species ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Pathogenic H5n1 ◽  
Differential Contribution

scholarly journals Genetic versus antigenic differences among highly pathogenic H5N1 avian influenza A viruses: Consequences for vaccine strain selection

Virology ◽  
2017 ◽  
Vol 503 ◽  
pp. 83-93 ◽  
Author(s):  
Ben Peeters ◽  
Sylvia Reemers ◽  
Jos Dortmans ◽  
Erik de Vries ◽  
Mart de Jong ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Vaccine Strain ◽  
Influenza A ◽  
Strain Selection ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
H5n1 Avian Influenza ◽  
Pathogenic H5n1

scholarly journals Apoptotic and Early Innate Immune Responses to PB1-F2 Protein of Influenza A Viruses Belonging to Different Subtypes in Human Lung Epithelial A549 Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Gunisha Pasricha ◽  
Sanjay Mukherjee ◽  
Alok K. Chakrabarti
Keyword(s):  
Inflammatory Response ◽  
Influenza A ◽  
H5n1 Virus ◽  
A549 Cells ◽  
Terminal Region ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
Lung Epithelial ◽  
Pathogenic H5n1

PB1-F2 is a multifunctional protein and contributes to the pathogenicity of influenza A viruses. PB1-F2 is known to have strain and cell specific functions. In this study we have investigated the apoptotic and inflammatory responses of PB1-F2 protein from influenza viruses of diverse pathogenicities in A549 lung epithelial cells. Overexpression of PB1-F2 resulted in apoptosis and heightened inflammatory response in A549 cells. Comparison revealed that the response varied with each subtype. PB1-F2 protein from highly pathogenic H5N1 virus induced least apoptosis but maximum inflammatory response. Results indicated that apoptosis was mediated through death receptor ligands TNFα and TRAIL via Caspase 8 activation. Significant induction of cytokines/chemokines CXCL10, CCL5, CCL2, IFNα, and IL-6 was noted in A549 cells transfected with PB1-F2 gene construct of 2008 West Bengal H5N1 virus (H5N1-WB). On the contrary, PB1-F2 construct from 2007 highly pathogenic H5N1 isolate (H5N1-M) with truncated N-terminal region did not evoke as exuberant inflammatory response as the other H5N1-WB with full length PB1-F2, signifying the importance of N-terminal region of PB1-F2. Sequence analysis revealed that PB1-F2 proteins derived from different influenza viruses varied at multiple amino acid positions. The secondary structure prediction showed each of the PB1-F2 proteins had distinct helix-loop-helix structure. Thus, our data substantiate the notion that the contribution of PB1-F2 to influenza pathogenicity is greatly strain specific and involves multiple host factors. This data demonstrates that PB1-F2 protein of influenza A virus, when expressed independently is minimally apoptotic and strongly influences the early host response in A549 cells.

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