Changes in H5N1 influenza virus hemagglutinin receptor binding domain affect systemic spread

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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Computational Prediction of the Epitopes of HA1 Protein of Influenza Viruses to its Neutralizing Antibodies

Antibodies ◽

10.3390/antib8010002 ◽

2018 ◽

Vol 8 (1) ◽

pp. 2

Author(s):

Xiaoyan Zeng ◽

Fiona Legge ◽

Chao Huang ◽

Xiao Zhang ◽

Yongjun Jiao ◽

...

Keyword(s):

Influenza Virus ◽

Crystal Structures ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Computational Prediction ◽

Binding Domain ◽

Influenza Viruses ◽

New Method ◽

Receptor Binding Domain ◽

Antibody Recognition

In this work, we have used a new method to predict the epitopes of HA1 protein of influenza virus to several antibodies HC19, CR9114, BH151 and 4F5. While our results reproduced the binding epitopes of H3N2 or H5N1 for the neutralizing antibodies HC19, CR9114, and BH151 as revealed from the available crystal structures, additional epitopes for these antibodies were also suggested. Moreover, the predicted epitopes of H5N1 HA1 for the newly developed antibody 4F5 are located at the receptor binding domain, while previous study identified a region 76-WLLGNP-81 as the epitope. The possibility of antibody recognition of influenza virus via different mechanism by binding to different epitopes of an antigen is also discussed.

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Expression of H5N1 influenza virus hemagglutinin protein fused with protein transduction domain in an alphavirus replicon system

Journal of Virological Methods ◽

10.1016/j.jviromet.2009.07.012 ◽

2010 ◽

Vol 163 (1) ◽

pp. 31-39 ◽

Cited By ~ 1

Author(s):

Shi-gui Yang ◽

Jian-er Wo ◽

Min-wei Li ◽

Fen-fang Mi ◽

Cheng-bo Yu ◽

...

Keyword(s):

Influenza Virus ◽

Protein Transduction ◽

Protein Transduction Domain ◽

H5n1 Influenza Virus ◽

H5n1 Influenza ◽

Influenza Virus Hemagglutinin ◽

Hemagglutinin Protein

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Monoclonal Antibody Responses after Recombinant Hemagglutinin Vaccine versus Subunit Inactivated Influenza Virus Vaccine: a Comparative Study

Journal of Virology ◽

10.1128/jvi.01150-19 ◽

2019 ◽

Vol 93 (21) ◽

Cited By ~ 3

Author(s):

Carole Henry ◽

Anna-Karin E. Palm ◽

Henry A. Utset ◽

Min Huang ◽

Irvin Y. Ho ◽

...

Keyword(s):

Influenza Virus ◽

Receptor Binding ◽

Mammalian Cells ◽

Influenza Virus Infection ◽

Binding Domain ◽

Antibody Responses ◽

Surface Glycoprotein ◽

Immune Memory ◽

Receptor Binding Domain ◽

Production Strategies

ABSTRACT Vaccination is the best measure of protection against influenza virus infection. Vaccine-induced antibody responses target mainly the hemagglutinin (HA) surface glycoprotein, composed of the head and the stalk domains. Recently two novel vaccine platforms have been developed for seasonal influenza vaccination: a recombinant HA vaccine produced in insect cells (Flublok) and Flucelvax, prepared from virions produced in mammalian cells. In order to compare the fine specificity of the antibodies induced by these two novel vaccine platforms, we characterized 42 Flublok-induced monoclonal antibodies (MAbs) and 38 Flucelvax-induced MAbs for avidity, cross-reactivity, and any selectivity toward the head versus the stalk domain. These studies revealed that Flublok induced a greater proportion of MAbs targeting epitopes near the receptor-binding domain on HA head (hemagglutinin inhibition-positive MAbs) than Flucelvax, while the two vaccines induced similar low frequencies of stalk-reactive MAbs. Finally, mice immunized with Flublok and Flucelvax also induced similar frequencies of stalk-reactive antibody-secreting cells, showing that HA head immunodominance is independent of immune memory bias. Collectively, our results suggest that these vaccine formulations are similarly immunogenic but differ in the preferences of the elicited antibodies toward the receptor-binding domain on the HA head. IMPORTANCE There are ongoing efforts to increase the efficacy of influenza vaccines and to promote production strategies that can rapidly respond to newly emerging viruses. It is important to understand if current alternative seasonal vaccines, such as Flublok and Flucelvax, that use alternate production strategies can induce protective influenza-specific antibodies and to evaluate what type of epitopes are targeted by distinct vaccine formulations.

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