Free energy simulations reveal a double mutant avian H5N1 virus hemagglutinin with altered receptor binding specificity

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.

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The role of receptor binding specificity in interspecies transmission of influenza viruses

Current Opinion in Virology ◽

10.1016/j.coviro.2012.03.003 ◽

2012 ◽

Vol 2 (2) ◽

pp. 160-167 ◽

Cited By ~ 189

Author(s):

Masaki Imai ◽

Yoshihiro Kawaoka

Keyword(s):

Receptor Binding ◽

Binding Specificity ◽

Influenza Viruses ◽

Interspecies Transmission ◽

Receptor Binding Specificity

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Molecular characterization and receptor binding specificity of H9N2 avian influenza viruses based on poultry-related environmental surveillance in China between 2013 and 2016

Virology ◽

10.1016/j.virol.2019.01.002 ◽

2019 ◽

Vol 529 ◽

pp. 135-143 ◽

Cited By ~ 10

Author(s):

Shumei Zou ◽

Ye Zhang ◽

Xiyan Li ◽

Hong Bo ◽

Hejiang Wei ◽

...

Keyword(s):

Avian Influenza ◽

Molecular Characterization ◽

Receptor Binding ◽

Binding Specificity ◽

Influenza Viruses ◽

Environmental Surveillance ◽

Avian Influenza Viruses ◽

Receptor Binding Specificity

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Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity

Nature ◽

10.1038/304076a0 ◽

1983 ◽

Vol 304 (5921) ◽

pp. 76-78 ◽

Cited By ~ 481

Author(s):

G. N. Rogers ◽

J. C. Paulson ◽

R. S. Daniels ◽

J. J. Skehel ◽

I. A. Wilson ◽

...

Keyword(s):

Amino Acid ◽

Receptor Binding ◽

Binding Specificity ◽

Single Amino Acid ◽

Amino Acid Substitutions ◽

Receptor Binding Specificity

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Identification of Molecular Markers Associated with Alteration of Receptor-Binding Specificity in a Novel Genotype of Highly Pathogenic Avian Influenza A(H5N1) Viruses Detected in Cambodia in 2013

Journal of Virology ◽

10.1128/jvi.01887-14 ◽

2014 ◽

Vol 88 (23) ◽

pp. 13897-13909 ◽

Cited By ~ 25

Author(s):

S. Rith ◽

C. T. Davis ◽

V. Duong ◽

B. Sar ◽

S. V. Horm ◽

...

Keyword(s):

Molecular Markers ◽

Avian Influenza ◽

Receptor Binding ◽

Influenza A ◽

Highly Pathogenic Avian Influenza ◽

Binding Specificity ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza ◽

Novel Genotype ◽

Receptor Binding Specificity

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Evidence that the alpha-subunit influences the specificity of receptor binding of the equine gonadotrophins

Journal of Endocrinology ◽

10.1677/joe.0.1550241 ◽

1997 ◽

Vol 155 (2) ◽

pp. 241-245 ◽

Cited By ~ 6

Author(s):

M Chopineau ◽

N Martinat ◽

H Marichatou ◽

C Troispoux ◽

C Auge-Gouillou ◽

...

Keyword(s):

Receptor Binding ◽

Molecular Basis ◽

Binding Specificity ◽

Chorionic Gonadotrophin ◽

Beta Subunit ◽

Alpha Subunit ◽

Beta Hcg ◽

In Vitro Bioassays ◽

Receptor Binding Specificity

Horse LH/chorionic gonadotrophin (eLH/CG) exhibits, in addition to its normal LH activity, a high FSH activity in all other species tested. Donkey LH/CG (dkLH/CG) also exhibits FSH activity in other species, but about ten times less than the horse hormone. In order to understand the molecular basis of these dual gonadotrophic activities of eLH/CG and dkLH/CG better, we expressed, in COS-7 cells, hybrids between horse and donkey subunits, between horse or donkey alpha-subunit and human CG beta (hCG beta), and also between the porcine alpha-subunit and horse or donkey LH/CG beta. The resultant recombinant hybrid hormones were measured using specific FSH and LH in vitro bioassays which give an accurate measure of receptor binding specificity and activation. Results showed that it is the beta-subunit that determines the level of FSH activity, in agreement with the belief that it is the beta-subunit which determines the specificity of action of the gonadotrophins. However, donkey LH/CG beta combined with a porcine alpha-subunit exhibited no FSH activity although it showed full LH activity. Moreover, the hybrid between horse or donkey alpha-subunit and hCG beta also exhibited only LH activity. Thus, the low FSH activity of dkLH/CG requires an equine (donkey or horse) alpha-subunit combined with dkLH/CG beta. These results provide the first evidence that an alpha-subunit can influence the specificity of action of a gonadotrophic hormone.

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